38 results on '"Duhyeong Hwang"'
Search Results
2. Author Correction: scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy
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Jennifer Karin Ocasio, Benjamin Babcock, Daniel Malawsky, Seth J. Weir, Lipin Loo, Jeremy M. Simon, Mark J. Zylka, Duhyeong Hwang, Taylor Dismuke, Marina Sokolsky, Elias P. Rosen, Rajeev Vibhakar, Jiao Zhang, Olivier Saulnier, Maria Vladoiu, Ibrahim El-Hamamy, Lincoln D. Stein, Michael D. Taylor, Kyle S. Smith, Paul A. Northcott, Alejandro Colaneri, Kirk Wilhelmsen, and Timothy R. Gershon
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Science - Published
- 2022
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3. Preparation of an Orthotopic, Syngeneic Model of Lung Adenocarcinoma and the Testing of the Antitumor Efficacy of Poly(2-oxazoline) Formulation of Chemo-and Immunotherapeutic Agents
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Natasha Vinod, Duhyeong Hwang, Salma Azam, Amanda Van Swearingen, Elizabeth Wayne, Sloane Fussell, Marina Sokolsky-Papkov, Chad Pecot, and Alexander Kabanov
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Biology (General) ,QH301-705.5 - Abstract
Tumor xenograft models developed by transplanting human tissues or cells into immune-deficient mice are widely used to study human cancer response to drug candidates. However, immune-deficient mice are unfit for investigating the effect of immunotherapeutic agents on the host immune response to cancer (Morgan, 2012). Here, we describe the preparation of an orthotopic, syngeneic model of lung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), to study the antitumor effect of chemo and immunotherapeutic agents in an immune-competent animal. The tumor model is developed by implanting 344SQ LUAD cells derived from the metastases of KrasG12D; p53R172HΔG genetically engineered mouse model into the left lung of a syngeneic host (Sv/129). The 344SQ LUAD model offers several advantages over other models: 1) The immune-competent host allows for the assessment of the biologic effects of immune-modulating agents; 2) The pathophysiological features of the human disease are preserved due to the orthotopic approach; 3) Predisposition of the tumor to metastasize facilitates the study of therapeutic effects on primary tumor as well as the metastases (Chen et al., 2014). Furthermore, we also describe a treatment strategy based on Poly(2-oxazoline) micelles that has been shown to be effective in this difficult-to-treat tumor model (Vinod et al., 2020b).
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- 2021
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4. Preparation and Characterization of Poly(2-oxazoline) Micelles for the Solubilization and Delivery of Water Insoluble Drugs
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Natasha Vinod, Duhyeong Hwang, Salma Azam, Amanda Van Swearingen, Elizabeth Wayne, Sloane Fussell, Marina Sokolsky-Papkov, Chad Pecot, and Alexander Kabanov
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Biology (General) ,QH301-705.5 - Abstract
Many new drug development candidates are highly lipophilic compounds with low water solubility. This constitutes a formidable challenge for the use of such compounds for cancer therapy, where high doses and intravenous injections are needed (Di et al., 2012). Here, we present a poly(2-oxazoline) polymer (POx)-based nanoformulation strategy to solubilize and deliver hydrophobic drugs. POx micelles are prepared by a simple thin-film hydration method. In this method, the drug and polymer are dissolved in a common solvent and allowed to mix, following which the solvent is evaporated using mild heating conditions to form a thin film. The micelles form spontaneously upon hydration with saline. POx nanoformulation of hydrophobic drugs is unique in that it has a high drug loading capacity, which is superior to micelles of conventional surfactants. Moreover, multiple active pharmaceutical ingredients (APIs) can be included within the same POx micelle, thereby enabling the codelivery of binary as well as ternary drug combinations (Han et al., 2012; He et al., 2016).
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- 2021
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5. Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells
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Eiji Kobayashi, Duhyeong Hwang, Anjali Bheda-Malge, Christopher B. Whitehurst, Alexander V. Kabanov, Satoru Kondo, Mitsuharu Aga, Tomokazu Yoshizaki, Joseph S. Pagano, Marina Sokolsky, and Julia Shakelford
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de-ubiquitination ,markers of invasion and metastasis ,poly (2-oxazoline) micelle ,nanoformulation ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Normally ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in the central nervous and reproductive systems of adults, but its de novo expression has been detected in many human cancers. There is a growing body of evidence that UCH-L1 de-ubiquitinating (DUB) activity plays a major pro-metastatic role in certain carcinomas. Here we tested anti-metastatic effects of the small-molecule inhibitor of UCH-L1 DUB activity, LDN-57444, in cell lines from advanced oral squamous cell carcinoma (OSCC) as well as invasive nasopharyngeal (NP) cell lines expressing the major pro-metastatic gene product of Epstein−Barr virus (EBV) tumor virus, LMP1. To overcome the limited aqueous solubility of LDN-57444 we developed a nanoparticle formulation of LDN-57444 by incorporation of the compound in polyoxazoline micellear nanoparticles (LDN-POx). LDN-POx nanoparticles were equal in effects as the native compound in vitro. Our results demonstrate that inhibition of UCH-L1 DUB activity with LDN or LDN-POx inhibits secretion of exosomes and reduces levels of the pro-metastatic factor in exosomal fractions. Both forms of UCH-L1 DUB inhibitor suppress motility of metastatic squamous carcinoma cells as well as nasopharyngeal cells expressing EBV pro-metastatic Latent membrane protein 1 (LMP1) in physiological assays. Moreover, treatment with LDN and LDN-POx resulted in reduced levels of pro-metastatic markers, a decrease of carcinoma cell adhesion, as well as inhibition of extra-cellular vesicle (ECV)-mediated transfer of viral invasive factor LMP1. We suggest that soluble inhibitors of UCH-L1 such as LDN-POx offer potential forms of treatment for invasive carcinomas including EBV-positive malignancies.
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- 2019
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6. Genetically modified macrophages accomplish targeted gene delivery to the inflamed brain in transgenic Parkin Q311X(A) mice: importance of administration routes
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Haney, Matthew J., Zhao, Yuling, Fay, James, Duhyeong, Hwang, Wang, Mengzhe, Wang, Hui, Li, Zibo, Lee, Yueh Z., Karuppan, Mohan K., El-Hage, Nazira, Kabanov, Alexander V., and Batrakova, Elena V.
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- 2020
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7. Poly(2-oxazoline)-based polyplexes as a PEG-free plasmid DNA delivery platform
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Dina N. Yamaleyeva, Naoki Makita, Duhyeong Hwang, Matthew J. Haney, Rainer Jordan, and Alexander V. Kabanov
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The present study expands the versatility of cationic poly(2-oxazoline) (POx) copolymers as a PEG-free platform for gene delivery to immune cells, such as monocytes and macrophages. Several block copolymers are developed by varying non-ionic hydrophilic blocks (poly(2-methyl-2-oxazoline) (pMeOx) or poly(2-ethyl-2-oxazoline) (pEtOx), cationic blocks, and an optional hydrophobic block (poly(2-isopropyl-2-oxazoline) (iPrOx). The cationic blocks are produced by side chain modification of 2-methoxy-carboxyethyl-2-oxazoline (MestOx) block precursor with diethylenetriamine (DET) or tris(2-aminoethyl)amine (TREN). For the attachment of a targeting ligand, mannose, we employed azide-alkyne cycloaddition click chemistry methods. Of the two cationic side chains, polyplexes made with DET-containing copolymers transfect macrophages significantly better than those made with TREN-based copolymer. Likewise, non-targeted pEtOx-based diblock copolymer is more active in cell transfection than pMeOx-based copolymer. The triblock copolymer with hydrophobic block iPrOx performs poorly compared to the diblock copolymer which lacks this additional block. Surprisingly, attachment of a mannose ligand to either of these copolymers is inhibitory for transfection. Despite similarities in size and design, mannosylated polyplexes result in lower cell internalization compared to non-mannosylated polyplexes. Thus, PEG-free, non-targeted DET- and pEtOx-based diblock copolymer outperforms other studied structures in the transfection of macrophages and displays transfection levels comparable to GeneJuice, a commercial non-lipid transfection reagent.
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- 2022
8. High-Dose Paclitaxel and its Combination with CSF1R Inhibitor in Polymeric Micelles for Chemoimmunotherapy of Triple Negative Breast Cancer
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Chaemin Lim, Duhyeong Hwang, Mostafa Yazdimamaghani, Hannah Marie Atkins, Hyesun Hyun, Yuseon Shin, Jacob D. Ramsey, Charles M. Perou, Marina Sokolsky-Papkov, and Alexander V. Kabanov
- Abstract
The presence of immunosuppressive immune cells in cancer is a significant barrier to the generation of therapeutic immune responses. Similarly, in vivo triple-negative breast cancer (TNBC) models often contain prevalent tumor-associated macrophages in the tumor microenvironment (TME), resulting in breast cancer initiation, invasion, and metastasis by generating immunosuppressive environment. Here, we test systemic chemoimmunotherapy using small-molecule agents, paclitaxel (PTX), and colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX3397, to enhance the adaptive T cell immunity against TNBCs in immunocompetent mouse TNBC models. PTX and PLX3397 are very poorly soluble in water and shown poor therapeutic outcomes in TNBC animal models in conventional formulation. To address the challenge for the delivery of insoluble drugs to TNBC, we use high-capacity poly(2-oxazoline) (POx)-based polymeric micelles to greatly improve the solubility and widen the therapeutic index of such drugs. The results demonstrate that high-dose PTX in POx, even as a single agent, exerts strong effects on TME and induces the long-term immune memory. In addition, we demonstrate that the PTX and PLX3397 combination provides consistent therapeutic improvement across several TNBC models, resulting from the repolarization of the immunosuppressive TME and enhanced T cell immune response that suppress both the primary tumor growth and metastasis. Overall, the work emphasizes the benefit of drug reformulation and outlines potential translational path for both PTX and PTX with PLX3397 combination therapy using POx polymeric micelles for the treatment of TNBC.
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- 2022
9. Abstract 1810: Enhanced anti-breast tumor cancer activity using nano-formulated TLR 7/8 agonist and PI3K inhibitor
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Mostafa Yazdimamaghani, Oleg Kolupaev, Chaemin Lim, Duhyeong Hwang, Alexander Kabanov, and Jonathan Serody
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Cancer Research ,Oncology - Abstract
Triple-negative breast cancer (TNBC) is characterized by high cell proliferation, abundant heterogeneity, frequent incidence of lung and brain metastases, repeated disease recurrence, and the worst prognosis among all breast cancer subtypes. Extensive evidence from translational studies indicates immunosuppressive cell infiltration into the tumor microenvironment (TME) promotes tumor immune escape and inhibits the efficient antitumor immune response. Previously, we have shown that a large proportion of tumor-infiltrating lymphocytes in claudin-low subtype of TNBC are CD4+FoxP3+ Tregs. Infiltration of Treg in TME is associated with suppressing effector T cell responses, accelerated tumor growth, and poor clinical outcomes. Herein, to convert immunosuppressive TME of TNBC to immune-inflamed immunophenotype we used polymeric micelles nanoparticles for co-delivering immunomodulatory small molecule drugs. We used a novel Full Spectral Flow Cytometry approach for immunophenotyping tumors. We identified significant infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs) in the orthotopic T11 TNBC tumor. The small molecule resiquimod, an imidazoquinoline Toll-like receptor (TLR) 7/8 agonist, and idelalisib, an inhibitor of phosphatidylinositol 3-kinase (PI3K) p110δ were incorporated in poly(2-oxazoline) block copolymer polymeric micelle NPs. Drug exposure to tumor cells was increased by the small-size nanoparticles associated with the preferential accumulation of NPs in tumors. The resiquimod and idelalisib were used to differentiate MDSC and selectively decrease the number and function of Tregs in TME, respectively. Following targeted radiation therapy in combination with iv administration of nanoformulation to animals bearing orthotopic T11 TNBC tumors, we observed significant suppression of tumor growth and enhanced overall survival compared to targeted radiotherapy alone. Radiation therapy in combination with both nanoformulated resiquimod and idelalisib induced optimal tumor control, increasing median survival with over 50% complete response rate, while all mice in the nanoformulation groups or radiation alone group succumbed to tumor growth. Enhanced adaptive T cell immunity against TNBCs and effective therapeutic improvement in immunocompetent mice following radiotherapy were only observed with simultaneous depletion of Tregs and MDSC. These data suggest radiotherapy in combination with nanoparticle co-delivery of immunomodulators inhibiting MDSCs and Treg, has promising potential for future clinical trials and translation for the treatment of TNBC patients. Citation Format: Mostafa Yazdimamaghani, Oleg Kolupaev, Chaemin Lim, Duhyeong Hwang, Alexander Kabanov, Jonathan Serody. Enhanced anti-breast tumor cancer activity using nano-formulated TLR 7/8 agonist and PI3K inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1810.
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- 2023
10. Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval
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Duhyeong Hwang, Jacob D. Ramsey, and Alexander V. Kabanov
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Drug ,Polymers ,Drug Compounding ,media_common.quotation_subject ,Pharmaceutical Science ,Nanotechnology ,macromolecular substances ,02 engineering and technology ,Micelle ,Article ,03 medical and health sciences ,Drug Delivery Systems ,Animals ,Humans ,Drug Interactions ,Micelles ,030304 developmental biology ,media_common ,Active ingredient ,0303 health sciences ,Polymeric micelles ,Chemistry ,technology, industry, and agriculture ,021001 nanoscience & nanotechnology ,Small molecule ,Pharmaceutical Preparations ,Solubility ,Solubilization ,Drug delivery ,Nanoparticles ,Nanomedicine ,0210 nano-technology - Abstract
Over the last three decades, polymeric micelles have emerged as a highly promising drug delivery platform for therapeutic compounds. Particularly, poorly soluble small molecules with high potency and significant toxicity were encapsulated in polymeric micelles. Polymeric micelles have shown improved pharmacokinetic profiles in preclinical animal models and enhanced efficacy with a superior safety profile for therapeutic drugs. Several polymeric micelle formulations have reached the clinical stage and are either in clinical trials or are approved for human use. This furthers interest in this field and underscores the need for additional learning of how to best design and apply these micellar carriers to improve the clinical outcomes of many drugs. In this review, we provide detailed information on polymeric micelles for the solubilization of poorly soluble small molecules in topics such as the design of block copolymers, experimental and theoretical analysis of drug encapsulation in polymeric micelles, pharmacokinetics of drugs in polymeric micelles, regulatory approval pathways of nanomedicines, and current outcomes from micelle formulations in clinical trials. We aim to describe the latest information on advanced analytical approaches for elucidating molecular interactions within the core of polymeric micelles for effective solubilization as well as for analyzing nanomedicine’s pharmacokinetic profiles. Taking into account the considerations described within, academic and industrial researchers can continue to elucidate novel interactions in polymeric micelles and capitalize on their potential as drug delivery vehicles to help improve therapeutic outcomes in systemic delivery.
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- 2020
11. scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy
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Michael D. Taylor, Marina Sokolsky, Daniel S Malawsky, Benjamin Babcock, Duhyeong Hwang, Elias P. Rosen, Jiao Zhang, Jeremy M. Simon, Lipin Loo, Ibrahim El-Hamamy, Jennifer Ocasio, Kyle S. Smith, Rajeev Vibhakar, Mark J. Zylka, Maria C. Vladoiu, Timothy R. Gershon, Olivier Saulnier, Seth J. Weir, Taylor Dismuke, Kirk C. Wilhelmsen, Alejandro Colaneri, Paul A. Northcott, and Lincoln Stein
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0301 basic medicine ,Male ,Cancer therapy ,Pyridines ,medicine.medical_treatment ,General Physics and Astronomy ,Stem cell marker ,Targeted therapy ,Mice ,0302 clinical medicine ,Single-cell analysis ,Cerebellum ,Cancer genomics ,Anilides ,Molecular Targeted Therapy ,RNA-Seq ,Sonic hedgehog ,lcsh:Science ,education.field_of_study ,Multidisciplinary ,Smoothened Receptor ,3. Good health ,030220 oncology & carcinogenesis ,Gain of Function Mutation ,Neoplastic Stem Cells ,Female ,Stem cell ,Single-Cell Analysis ,medicine.drug ,Signal Transduction ,Science ,Population ,Vismodegib ,Mice, Transgenic ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,medicine ,Animals ,Humans ,Hedgehog Proteins ,education ,Cerebellar Neoplasms ,Cell Proliferation ,MyoD Protein ,Medulloblastoma ,General Chemistry ,medicine.disease ,CNS cancer ,030104 developmental biology ,Drug Resistance, Neoplasm ,biology.protein ,Cancer research ,Transcription Factor HES-1 ,lcsh:Q - Abstract
Targeting oncogenic pathways holds promise for brain tumor treatment, but inhibition of Sonic Hedgehog (SHH) signaling has failed in SHH-driven medulloblastoma. Cellular diversity within tumors and reduced lineage commitment can undermine targeted therapy by increasing the probability of treatment-resistant populations. Using single-cell RNA-seq and lineage tracing, we analyzed cellular diversity in medulloblastomas in transgenic, medulloblastoma-prone mice, and responses to the SHH-pathway inhibitor vismodegib. In untreated tumors, we find expected stromal cells and tumor-derived cells showing either a spectrum of neural progenitor-differentiation states or glial and stem cell markers. Vismodegib reduces the proliferative population and increases differentiation. However, specific cell types in vismodegib-treated tumors remain proliferative, showing either persistent SHH-pathway activation or stem cell characteristics. Our data show that even in tumors with a single pathway-activating mutation, diverse mechanisms drive tumor growth. This diversity confers early resistance to targeted inhibitor therapy, demonstrating the need to target multiple pathways simultaneously., Although the hedgehog (HH) pathway is known to be deregulated in medulloblastoma, inhibitors of the pathway have shown disappointing clinical benefit. Using single-cell sequencing in a mouse model of the disease, the authors show that the response to the HH pathway inhibitor vismodegib is cell-type specific.
- Published
- 2019
12. TMIC-79. MYELOID-DIRECTED TREATMENT USING THE TLR7/8 AGONIST RESIQUIMOD IMPROVES THE SURVIVAL OF MICE WITH MEDULLOBLASTOMA AND ENHANCES EFFICACY OF RADIOTHERAPY
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Coral del Mar Alicea Pauneto, Duhyeong Hwang, Christopher Park, Marina Sokolsky, and Timothy Gershon
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
We show the therapeutic potential of myeloid-directed immunomodulatory treatment for medulloblastoma. Patients with medulloblastoma, the most common malignant pediatric brain tumor, need new treatments, as standard therapy produces disabling neurotoxicities and fails 20% of patients. About 30% of medulloblastomas show hyperactivation of the SHH (Sonic Hedgehog) signaling pathway, and these tumors have large myeloid populations in the tumor microenvironment (TME). We analyzed whether activating toll-like receptors on these myeloid cells would slow tumor growth. Our prior single-cell RNA sequencing studies in both patient samples and mouse models showed that 10% of the cells in SHH medulloblastoma are myeloid cells and that these cells uniquely express TLR7 and TLR8. We treated mice genetically engineered to develop SHH medulloblastomas with the TLR7/8 agonist resiquimod, administered systemically either as free drug or in polyoxazoline nanoparticles (POx-resiquimod), and compared POx-resiquimod+radiotherapy to radiotherapy alone. We found that POx-resiquimod extended the survival time of mice with medulloblastoma, while free drug failed to show benefit. PK studies showed that POx-resiquimod increased tumor drug exposure, consistent with increased efficacy. Mechanistically, POx-resiquimod increases tumor myeloid populations and decreased the fraction of myeloid cells that expressed IGF1. POx-resiquimod plus radiation therapy, moreover, was superior to either POx-resiquimod alone, or radiotherapy alone. Together our data show that the TLR7/8 agonist resiquimod, delivered in nanoparticle formulation, produces a significant anti-tumor effect in SHH medulloblastoma, and increased the efficacy of radiotherapy. As radiotherapy is the mainstay of current medulloblastoma treatment, we propose that TLR7/8-agonist therapy such as resiquimod may be added to current regimens to reduce the radiation dose needed for efficacy, and to increase the fraction of successfully treated patients.
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- 2022
13. Bioequivalence Assessment of High-Capacity Polymeric Micelle Nanoformulation of Paclitaxel and Abraxane® in Rodent and Non-Human Primate Models Using a Stable Isotope Tracer Assay
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Stephan T. Stern, Stephanie A. Montgomery, Chaemin Lim, Hong Yuan, Duhyeong Hwang, Jonathan E. Frank, Jacob D. Ramsey, Marina Sokolsky-Papkov, Kelsie S. Snapp, Natasha Vinod, Sarah L. Skoczen, Alexander V. Kabanov, Zibo Li, and Mengzhe Wang
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Drug ,chemistry.chemical_compound ,Pharmacokinetics ,Paclitaxel ,Chemistry ,In vivo ,Pharmacodynamics ,media_common.quotation_subject ,Nanomedicine ,Pharmacology ,Nanocarriers ,Bioequivalence ,media_common - Abstract
The in vivo fate of nanoformulated drugs is governed by the physicochemical properties of the drug and the functionality of nanocarriers. Nanoformulations such as polymeric micelles, which physically encapsulate poorly soluble drugs, release their payload into the bloodstream during systemic circulation. This results in three distinct fractions of the drug-nanomedicine: encapsulated, protein-bound, and free drug. Having a thorough understanding of the pharmacokinetic (PK) profiles of each fraction is essential to elucidate mechanisms of nanomedicine-driven changes in drug exposure and PK/PD relationships pharmacodynamic activity. Here, we present a comprehensive preclinical assessment of the poly(2-oxazoline)-based polymeric micelle of paclitaxel (PTX) (POXOL hl-PM), including bioequivalence comparison to the clinically approved paclitaxel nanomedicine, Abraxane®. Physicochemical characterization and toxicity analysis of POXOL hl-PM was conducted using standardized protocols by the Nanotechnology Characterization Laboratory (NCL). The bioequivalence of POXOL hl-PM to Abraxane® was evaluated in rats and rhesus macaques using the NCL’s established stable isotope tracer ultrafiltration assay (SITUA) to delineate the plasma PK of each PTX fraction. The SITUA study revealed that POXOL hl-PM and Abraxane® had comparable PK profiles not only for total PTX but also for the distinct drug fractions, suggesting bioequivalence in given animal models. The comprehensive preclinical evaluation of POXOL hl-PM in this study showcases a series of widely-applicable standardized studies by NCL for assessing nanoformulations prior to clinical investigation.GRAPHICAL ABSTRACT
- Published
- 2021
14. Drug-dependent morphological transitions in spherical and worm-like polymeric micelles define stability and pharmacological performance of micellar drugs
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Duhyeong Hwang, Marina Sokolsky-Papkov, Alexander V. Kabanov, Jacob D. Ramsey, Chaemin Lim, Joshua D. Strauss, Susana C. M. Teixeira, and Chi-Duen Poon
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Drug ,Drug dependent ,Polymeric micelles ,Chemistry ,media_common.quotation_subject ,Biophysics ,Nanomedicine ,Micelle ,Tumor tissue ,media_common - Abstract
Significant advances in physicochemical properties of polymeric micelles enable optimization of therapeutic drug efficacy, supporting nanomedicine manufacturing and clinical translation. Yet, the effect of micelle morphology on pharmacological efficacy has not been adequately addressed. We addressed this gap by assessing pharmacological efficacy of polymeric micelles with spherical and worm-like morphologies. We observed that poly(2-oxazoline)-based polymeric micelles can be elongated over time from a spherical structure to worm-like structure, with elongation influenced by several conditions, including the amount and type of drug loaded into the micelles. We further evaluated the role of different morphologies of olaparib micelles on pharmacological performance against a triple-negative breast cancer tumor (TNBC) model. Spherical micelles accumulated rapidly in the tumor tissue while retaining large amounts of drug; worm-like micelles accumulated more slowly and only upon releasing significant amounts of drug. These findings suggest that the dynamic character of the drug–micelle structure and the micelle morphology play a critical role in pharmacological performance, and that spherical micelles are better suited for systemic delivery of anticancer drugs to tumors when drugs are loosely associated with the polymeric micelles.
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- 2021
15. Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib
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Virginia Godfrey, Alexander V. Kabanov, Marina Sokolsky-Papkov, Timothy R. Gershon, Daniel S Malawsky, Duhyeong Hwang, Chaemin Lim, Taylor Dismuke, and Jacob D. Ramsey
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Medulloblastoma ,business.industry ,Brain tumor ,Vismodegib ,mTORC1 ,Palbociclib ,medicine.disease ,Gemcitabine ,medicine ,Cancer research ,business ,Sapanisertib ,Etoposide ,medicine.drug - Abstract
CDK4/6 inhibitors hold promise for brain tumor treatment, but efficacy has been limited by recurrence in both preclinical models and clinical trials. To address recurrence, we tested a nanoparticle formulation of the CDK4/6 inhibitor palbociclib (POx-palbo) in mice genetically-engineered to develop SHH-driven medulloblastoma. We then analyzed medulloblastomas in mice receiving palbociclib treatment, and compared the efficacy of combining palbociclib with specific inhibitors suggested by our analysis. POx-Palbo showed reduced toxicity compared to conventional palbociclib, was tolerable in parenteral administration, improved CNS pharmacokinetics, and extended survival of mice with medulloblastoma. Recurrence, however, remained problematic as fractions of tumor cells proliferated during therapy. ScRNA-seq identified a gene expression pattern unique to proliferating medulloblastoma cells in POx-Palbo-treated mice, marked by up-regulation of the glutamate transporterSlc1a2and down-regulation of diverse ribosomal genes. Reduced mTORC1 signaling, suggested by ribosomal suppression in POx-Palbo-treated tumors was confirmed by decreased 4EBP1 phosphorylation (p4EBP1). Further reducing mTORC1 activity by combining POx-Palbo with the mTORC1 inhibitor sapanisertib produced mutually enhancing effects, with increased suppression of both pRB and p4EBP1, and prolonged mouse survival compared to either agent alone. In contrast, targeting cell cycle progression by combining POx-Palbo with the SHH-pathway inhibitor vismodegib, or with the replication-targeting agents gemcitabine or etoposide, failed to enhance efficacy. Our data show the potential of nanoparticle formulation and scRNA-seq analysis of resistance to improve brain tumor treatment, and identify POx-palbo plus sapanisertib as effective combinatorial therapy for SHH medulloblastoma. This combination may be appropriate for testing in patients with recurrence, who need new options.
- Published
- 2021
16. MEDB-56. POx NPs mediated delivery of (TLR7/8) agonist resiquimod improves treatment outcomes in SHH medulloblastoma by targeting tumor associated macrophages
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Duhyeong Hwang, Coral del Mar Alicea, Chaemin Lim, Christopher Park, Timothy Gershon, and Marina Sokolsky-Papkov
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
Cancer immunotherapy, the utilization of the patients’ own immune system to treat cancer, has emerged as a powerful new strategy in cancer treatment. Recent clinical data has demonstrated immunotherapy to be effective in a wide range of cancers, including lung, bladder, renal cell, colorectal, gastro-esophageal, and head and neck cancers5-11. However, clinical reports of immune-based treatments for medulloblastomas are scarce and preliminary. Therefore, there is a need in developing strategies to improve medulloblastoma immunotherapy. Our recent studies have confirmed that SHH medulloblastomas are enriched in Tumor Associated Macrophages (TAMs) and unlike other tumors, TAMs are associated with positive outcomes and play a positive role by impairing tumor growth. Overall, analysis of TME in medulloblastomas reveals TAMs as a potential therapeutic target. Resiquimod is a synthetic small molecule agonist of Toll-like receptors 7 and 8 (TLR7/8) that modulates innate immune cells. We have loaded resiquimod into ultra-high-capacity polyoxazoline (POx) block copolymers forming small, homogeneous nanoparticles (POx-resiquimod). Our recent study shows that loading into POx nanoparticles improves drug delivery to tumors and treatment with 3 injections of POx-res as the single-agent treatment results in a profound anti-tumor effect G-Smo mice while treatment with free drug shows no therapeutic benefit. Our data also shows that that the tumors of G-Smo mice are enriched with the mixed populations of anti-inflammatory and pro-inflammatory macrophages and the treatment with POx-resiquimod have enhanced infiltration of macrophages into the tumors, enhanced the repolarization of macrophages to M1 subtype and decreased tumor cells viability. These studies show for the first time that targeting the medulloblastoma TME with POx-resiquimod can produce a significant anti-tumor effect. Furthermore, combination of POx-resiquimod with radiation resulted in long term survivals, showing potential therapeutic combination. The expression of TLR7/8 on TAMs in patient-derived medulloblastoma samples suggests that resiquimod may produce similar anti-medulloblastoma effects in humans.
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- 2022
17. Nanoformulated Remdesivir with Extremely Low Content of Poly(2‐oxazoline)‐Based Stabilizer for Aerosol Treatment of COVID‐19
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Jacob D. Ramsey, Ian E. Stewart, Emily A. Madden, Chaemin Lim, Duhyeong Hwang, Mark T. Heise, Anthony J. Hickey, and Alexander V. Kabanov
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Alanine ,Polymers and Plastics ,SARS-CoV-2 ,Respiratory Aerosols and Droplets ,Bioengineering ,Antiviral Agents ,Adenosine Monophosphate ,COVID-19 Drug Treatment ,Excipients ,Biomaterials ,Materials Chemistry ,Humans ,RNA, Viral ,Oxazoles ,Biotechnology - Abstract
The rise of the novel virus SARS-CoV2 which causes the disease known as COVID-19 has led to a global pandemic claiming millions of lives. With no clinically approved treatment for COVID-19, physicians initially struggled to treat the disease, and a need remains for improved antiviral therapies in this area. It is conceived early in the pandemic that an inhalable formulation of the drug remdesivir which directly targets the virus at the site of infection could improve therapeutic outcomes in COVID-19. A set of requirements are developed that would be conducive to rapid drug approval: 1) try to use GRAS reagents 2) minimize excipient concentration and 3) achieve a working concentration of 5 mg/mL remdesivir to obtain a deliverable dose which is 5-10% of the IV dose. In this work, it is discovered that Poly(2-oxazoline) block copolymers can stabilize drug nanocrystal suspensions and provide suitable formulation characteristics for aerosol delivery while maintaining antiviral efficacy. The authors believe POx block copolymers can be used as a semi-ubiquitous stabilizer for the rapid development of nanocrystal formulations for new and existing diseases.
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- 2022
18. Preparation and Characterization of Poly(2-oxazoline) Micelles for the Solubilization and Delivery of Water Insoluble Drugs
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Alexander V. Kabanov, Salma H. Azam, Amanda E.D. Van Swearingen, Elizabeth Wayne, Natasha Vinod, Chad V. Pecot, Marina Sokolsky-Papkov, Sloane Christian Fussell, and Duhyeong Hwang
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chemistry.chemical_classification ,Active ingredient ,Drug ,Aqueous solution ,Strategy and Management ,Mechanical Engineering ,media_common.quotation_subject ,Metals and Alloys ,Polymer ,Oxazoline ,Combinatorial chemistry ,Micelle ,Industrial and Manufacturing Engineering ,Solvent ,chemistry.chemical_compound ,Drug development ,chemistry ,Methods Article ,media_common - Abstract
Many new drug development candidates are highly lipophilic compounds with low water solubility. This constitutes a formidable challenge for the use of such compounds for cancer therapy, where high doses and intravenous injections are needed ( Di et al., 2012 ). Here, we present a poly(2-oxazoline) polymer (POx)-based nanoformulation strategy to solubilize and deliver hydrophobic drugs. POx micelles are prepared by a simple thin-film hydration method. In this method, the drug and polymer are dissolved in a common solvent and allowed to mix, following which the solvent is evaporated using mild heating conditions to form a thin film. The micelles form spontaneously upon hydration with saline. POx nanoformulation of hydrophobic drugs is unique in that it has a high drug loading capacity, which is superior to micelles of conventional surfactants. Moreover, multiple active pharmaceutical ingredients (APIs) can be included within the same POx micelle, thereby enabling the codelivery of binary as well as ternary drug combinations ( Han et al., 2012 ; He et al., 2016 ).
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- 2021
19. Preparation of an Orthotopic, Syngeneic Model of Lung Adenocarcinoma and the Testing of the Antitumor Efficacy of Poly(2-oxazoline) Formulation of Chemo-and Immunotherapeutic Agents
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Chad V. Pecot, Duhyeong Hwang, Elizabeth Wayne, Alexander V. Kabanov, Natasha Vinod, Amanda E.D. Van Swearingen, Salma H. Azam, Marina Sokolsky-Papkov, and Sloane Christian Fussell
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Drug ,Lung ,business.industry ,Strategy and Management ,Mechanical Engineering ,media_common.quotation_subject ,Therapeutic effect ,Metals and Alloys ,Cancer ,medicine.disease ,Primary tumor ,Industrial and Manufacturing Engineering ,Immune system ,medicine.anatomical_structure ,Genetically Engineered Mouse ,Methods Article ,medicine ,Cancer research ,Adenocarcinoma ,business ,media_common - Abstract
Tumor xenograft models developed by transplanting human tissues or cells into immune-deficient mice are widely used to study human cancer response to drug candidates. However, immune-deficient mice are unfit for investigating the effect of immunotherapeutic agents on the host immune response to cancer (Morgan, 2012). Here, we describe the preparation of an orthotopic, syngeneic model of lung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), to study the antitumor effect of chemo and immunotherapeutic agents in an immune-competent animal. The tumor model is developed by implanting 344SQ LUAD cells derived from the metastases of Kras(G12D); p53(R172HΔG )genetically engineered mouse model into the left lung of a syngeneic host (Sv/129). The 344SQ LUAD model offers several advantages over other models: 1) The immune-competent host allows for the assessment of the biologic effects of immune-modulating agents; 2) The pathophysiological features of the human disease are preserved due to the orthotopic approach; 3) Predisposition of the tumor to metastasize facilitates the study of therapeutic effects on primary tumor as well as the metastases ( Chen et al., 2014 ). Furthermore, we also describe a treatment strategy based on Poly(2-oxazoline) micelles that has been shown to be effective in this difficult-to-treat tumor model ( Vinod et al., 2020b ).
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- 2021
20. IMMU-05. IMMUNOTHERAPY WITH RESIQUIMOD REPOLARIZES TUMOR-ASSOCIATED MYELOID CELLS AND IMPROVES EVENT-FREE SURVIVAL IN A TRANSGENIC MOUSE MODEL OF SONIC-HEDGEHOG (SHH) MEDULLOBLASTOMA
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Taylor Dismuke, Andrew M. Donson, Morrent Thang, Marina Sokolsky, Christopher Park, Timothy R. Gershon, Rajeev Vibhakar, Duhyeong Hwang, and Chaemin Lim
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Genetically modified mouse ,Medulloblastoma ,Cancer Research ,Toll-like receptor ,biology ,business.industry ,medicine.medical_treatment ,Immunotherapy ,medicine.disease ,chemistry.chemical_compound ,Oncology ,chemistry ,Tumor progression ,medicine ,Adjuvant therapy ,biology.protein ,Cancer research ,Neurology (clinical) ,Sonic hedgehog ,Resiquimod ,business - Abstract
Resiquimod is a synthetic small molecule agonist of Toll-like receptors 7 and 8 (TLR-7/8) that modulates innate immune cells. We found TLR-7/8 are expressed in medulloblastoma exclusively by tumor-associated myeloid cells (TAMs). We tested whether systemically administered resiquimod modulated TAMs in a genetic Sonic hedgehog (SHH) medulloblastoma model, and whether this modulation would be therapeutically beneficial. We generated mice with medulloblastoma by crossing hGFAP-Cre and SmoM2 mouse lines. The resulting hGFAP-Cre/SmoM2 (G-Smo) mice developed medulloblastoma with 100% frequency and showed a median survival of 14.5 days (n=12). Treatment with 3 doses of resiquimod at postnatal days 10, 12 and 14 reduced tumor size and increased median survival to 37 days (n=10) (p=0.003508). Cellular studies showed that resiquimod altered TAM phenotype, rapidly inducing expression of the inflammatory marker VCAM1, and more slowly increasing TAM populations. Responses to the 3-dose regimen were ultimately limited by recurrence and all mice eventually died of tumor progression. Continued resiquimod therapy with every other day dosing was less effective than the 3-dose regimen, suggesting that TAM responses to resiquimod are dynamic and change with prolonged exposure. Our data show that innate immunity, mediated by TAMs and stimulated by TLR-7/8 agonist therapy, can produce a significant anti-tumor effect in medulloblastoma. The common expression of TLR-7/8 on TAMs in patient-derived medulloblastoma samples and in the mouse model suggests that resiquimod may produce similar anti-medulloblastoma effects in humans. Further studies are needed to define the mechanism of the anti-tumor effect in detail, to determine the optimal dose regimen, and to determine if resiquimod can combine effectively with additional adjuvant therapies to produce curative effects.
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- 2021
21. High-capacity poly(2-oxazoline) formulation of TLR 7/8 agonist extends survival in a chemo-insensitive, metastatic model of lung adenocarcinoma
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Alexander V. Kabanov, Chad V. Pecot, Marina Sokolsky-Papkov, Sloane Christian Fussell, Salma H. Azam, Elizabeth Wayne, Duhyeong Hwang, Natasha Vinod, and Amanda E.D. Van Swearingen
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Lung Neoplasms ,medicine.medical_treatment ,Adenocarcinoma of Lung ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Adjuvants, Immunologic ,Carcinoma, Non-Small-Cell Lung ,Tumor Microenvironment ,medicine ,Humans ,Health and Medicine ,Oxazoles ,Research Articles ,Cancer ,030304 developmental biology ,0303 health sciences ,Chemotherapy ,Tumor microenvironment ,Multidisciplinary ,business.industry ,SciAdv r-articles ,Immunotherapy ,respiratory system ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Immune checkpoint ,Imidazoquinoline ,Toll-Like Receptor 7 ,chemistry ,Toll-Like Receptor 8 ,030220 oncology & carcinogenesis ,Cancer research ,Adenocarcinoma ,Resiquimod ,business ,Research Article - Abstract
Polymeric micelle formulation of an immune modulator improves survival in a highly aggressive model of non–small cell lung cancer., About 40% of patients with non–small cell lung cancer (NSCLC) have stage IV cancer at the time of diagnosis. The only viable treatment options for metastatic disease are systemic chemotherapy and immunotherapy. Nonetheless, chemoresistance remains a major cause of chemotherapy failure. New immunotherapeutic modalities such as anti–PD-1 immune checkpoint blockade have shown promise; however, response to such strategies is highly variable across patients. Here, we show that our unique poly(2-oxazoline)–based nanomicellar formulation (PM) of Resiquimod, an imidazoquinoline Toll-like receptor (TLR) 7/8 agonist, had a superior tumor inhibitory effect in a metastatic model of lung adenocarcinoma, relative to anti–PD-1 therapy or platinum-based chemotherapy. Investigation of the in vivo immune status following Resiquimod PM treatment showed that Resiquimod-based stimulation of antigen-presenting cells in the tumor microenvironment resulted in the mobilization of an antitumor CD8+ immune response. Our study demonstrates the promise of poly(2-oxazoline)-formulated Resiquimod for treating metastatic NSCLC.
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- 2020
22. Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity
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Chaemin Lim, Taylor Dismuke, John R. Kagel, Andrey P. Tikunov, Elias P. Rosen, Jacob D. Ramsey, Alexander V. Kabanov, William C. Zamboni, Marina Sokolsky-Papkov, Timothy R. Gershon, and Duhyeong Hwang
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Central Nervous System ,Pyridines ,Pharmaceutical Science ,Medicine (miscellaneous) ,02 engineering and technology ,Mice ,0302 clinical medicine ,Drug Delivery Systems ,Medicine ,General Materials Science ,Anilides ,Oxazoles ,Micelles ,media_common ,0303 health sciences ,Drug Carriers ,021001 nanoscience & nanotechnology ,Hedgehog signaling pathway ,3. Good health ,030220 oncology & carcinogenesis ,Drug delivery ,Toxicity ,Molecular Medicine ,0210 nano-technology ,medicine.drug ,Protein Binding ,Drug ,media_common.quotation_subject ,Biomedical Engineering ,Brain tumor ,Vismodegib ,Biological Availability ,Bioengineering ,Article ,03 medical and health sciences ,Animals ,Basal cell carcinoma ,Particle Size ,Cerebellar Neoplasms ,Serum Albumin ,030304 developmental biology ,Medulloblastoma ,Tumor microenvironment ,business.industry ,medicine.disease ,Disease Models, Animal ,Cancer research ,Nanoparticles ,business - Abstract
We report a novel, nanoparticle formulation of the SHH pathway inhibitor vismodegib that improves efficacy for medulloblastoma treatment while reducing toxicity. Systemic therapies for brain tumors are complicated by restricted blood-brain barrier (BBB) permeability and dose-limiting extraneural toxicity, therefore improved delivery approached are needed. Here we show how a nanoparticle delivery system addresses these obstacles, bringing new efficacy to previously ineffective therapy. Vismodegib has been a promising agent for patients with SHH- subgroup medulloblastoma and is FDA-approved for basal cell carcinoma. However, vismodegib has limited benefit for patients with SHH-driven medulloblastoma, due to off-target toxicities and the development of resistance during therapy. We encapsulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo using transgenic mice engineered to develop endogenous medulloblastomas, testing the novel agent in a preclinical model with native vasculature and tumor microenvironment. POx-vismo showed improved CNS pharmacokinetics and reduced systemic and bone toxicity. Mechanistic studies show that POx nanoparticles did not enter the CNS, but rather acted within the vascular compartment to improve drug delivery by decreasing drug binding to serum proteins and reducing the volume of distribution. POx-vismo demonstrated improved efficacy, extending the survival of medulloblastoma-bearing mice. Our results show the potential for a simple, non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to enhance vismodegib therapy for SHH-driven cancers.
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- 2020
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23. High Capacity poly(2-oxazoline) formulation of TLR 7/8 agonist extends survival in a chemo-insensitive, metastatic model of Lung Adenocarcinoma
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Amanda E.D. Van Swearingen, Alexander V. Kabanov, Elizabeth Wayne, Duhyeong Hwang, Salma H. Azam, Chad V. Pecot, Natasha Vinod, Marina Sokolsky-Papkov, and Sloane Christian Fussell
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0303 health sciences ,Tumor microenvironment ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Cancer ,Immunotherapy ,medicine.disease ,Immune checkpoint ,3. Good health ,Imidazoquinoline ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Adenocarcinoma ,Resiquimod ,business ,030304 developmental biology - Abstract
About 40% of the NSCLC patients have Stage IV cancer at the time of diagnosis. The only viable treatment options for metastatic disease are systemic chemotherapy and immunotherapy. Nonetheless, chemoresistance remains a major cause of chemotherapy failure. New immunotherapeutic modalities such as anti-PD1 checkpoint blockade have shown promise; however, response to such strategies is highly variable across patients. Here, we show that our novel poly(2-oxazoline) (POx) based nanomicellar formulation of Resiquimod, an imidazoquinoline TLR 7/8 agonist, had a superior tumor inhibitory effect in a metastatic model of lung adenocarcinoma, relative to anti-PD1 immune checkpoint blockade therapy as well as platinum-based chemotherapy, which is the mainstay of treatment for NSCLC. Investigation of the in vivo immune status following Resiquimod PM (POx micellar formulation of Resiquimod) treatment showed that Resiquimod-based stimulation of antigen-presenting cells in the tumor microenvironment resulted in the mobilization of anti-tumor CD8+immune response. Our study demonstrates the promise of optimally delivered and nano-formulated Resiquimod as a new immunomodulating therapeutic strategy for the treatment of metastatic NSCLC.
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- 2019
24. SCIDOT-03. HYPERLOADED POLY(2-OXAZOLINE) MICELLES AS PERSONALIZED DRUG CARRIERS FOR BRAIN TUMORS
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Taylor Dismuke, William C. Zamboni, Duhyeong Hwang, Elias P. Rosen, Alexander V. Kabanov, Marina Sokolsky-Papkov, Timothy R. Gershon, John R. Kagel, and Chaemin Lim
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Cancer Research ,chemistry.chemical_compound ,Oncology ,Chemistry ,Abstracts from the 3rd Sno-Scidot Joint Conference on Therapeutic Delivery to the CNS ,Neurology (clinical) ,Oxazoline ,Drug carrier ,Micelle ,Combinatorial chemistry - Abstract
Systemic therapies for brain tumors are complicated by dose-limiting extraneural toxicity, serum protein binding and restricted blood-brain barrier (BBB) permeability. For patients with SHH-subgroup medulloblastoma, SHH-pathway inhibition may be more effective and less toxic than current non-targeted therapy. However, vismodegib, which effectively targets SHH-driven basal cell carcinoma, has limited benefit for patients with SHH-driven medulloblastoma. Formulating vismodegib in poly(2-oxazoline) micelles (POx-vismo) improved delivery and efficacy, using medulloblastoma-prone hGFAP-Cre/SmoM2 (G-Smo) mice for a preclinical model. Compared to conventional vismodegib (c-vismo), POx-vismo increased maximum tolerated dose (MTD), tumor:serum ratio and penetration to brain and tumor. Further studies have shown the ability of POx micelles to load CDK4/6 inhibitor. Loading into POx micelles improved MTD and efficacy of palbociclib. Taken together, our results show the potential for poly(2-oxazoline) micelles delivery to make failed brain tumor treatments newly effective. This work was supported by the NCI Alliance for Nanotechnology in Cancer (U54CA198999, Carolina Center of Cancer Nanotechnology Excellence), by NINDS (R01NS088219, R01NS102627) and by the St. Baldrick’s Foundation. References: 1 H. Bader et al. Angew. Macromol. Chem. 1984, 123/124:457; A. Kabanov et al. FEBS Lett. 1989, 258:343; M. Yokoyama et al. Cancer Res. 1990, 50:1693. 2 M. Yokoyama et al. J. Exp. Clin. Med. 2011, 3:8. 3 T. Lorson et al. Biomaterials. 2018, 178:204. 4 R. Luxenhofer et al. Biomaterials 2010, 31:4972; A. Schulz et al. ACS Nano 2014, 8 (3):2686; Z. He et al. Biomaterials 2016, 101:296
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- 2019
25. Drug‐Dependent Morphological Transitions in Spherical and Worm‐Like Polymeric Micelles Define Stability and Pharmacological Performance of Micellar Drugs
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Chi-Duen Poon, Chaemin Lim, Marina Sokolsky-Papkov, Jacob D. Ramsey, Susana C. M. Teixeira, Duhyeong Hwang, Elias P. Rosen, Alexander V. Kabanov, and Joshua D. Strauss
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Drug ,Drug Carriers ,Polymeric micelles ,Polymers ,Chemistry ,media_common.quotation_subject ,Antineoplastic Agents ,General Chemistry ,Micelle ,Tumor tissue ,Biomaterials ,Drug dependent ,Nanomedicine ,Pharmacokinetics ,Critical micelle concentration ,Biophysics ,General Materials Science ,Micelles ,Biotechnology ,media_common - Abstract
Significant advances in physicochemical properties of polymeric micelles enable optimization of therapeutic drug efficacy, supporting nanomedicine manufacturing and clinical translation. Yet, the effect of micelle morphology on pharmacological efficacy is not adequately addressed. This work addresses this gap by assessing pharmacological efficacy of polymeric micelles with spherical and worm-like morphologies. It is observed that poly(2-oxazoline)-based polymeric micelles can be elongated over time from a spherical structure to worm-like structure, with elongation influenced by several conditions, including the amount and type of drug loaded into the micelles. The role of different morphologies on pharmacological performance of drug loaded micelles against triple-negative breast cancer and pancreatic cancer tumor models is further evaluated. Spherical micelles accumulate rapidly in the tumor tissue while retaining large amounts of drug; worm-like micelles accumulate more slowly and only upon releasing significant amounts of drug. These findings suggest that the dynamic character of the drug-micelle structure and the micelle morphology play a critical role in pharmacological performance, and that spherical micelles are better suited for systemic delivery of anticancer drugs to tumors when drugs are loosely associated with the polymeric micelles.
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- 2021
26. IMMU-48. IMMUNOMODULATION WITH RESIQUIMOD REPOLARIZES THE IMMUNE MICROENVIRONMENT TO INHIBIT MEDULLOBLASTOMA PROGRESSION
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Duhyeong Hwang, Bhalchandra Mirlekar, Christopher Park, Rajeev Vibhakar, Yuliya Pylayeva-Gupta, Andrew M. Donson, Chaemin Lim, Coral Del Mar, Taylor Dismuke, Morrent Thang, Timothy R. Gershon, and Marina Sokolsky
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Medulloblastoma ,Cancer Research ,chemistry.chemical_compound ,Oncology ,chemistry ,business.industry ,Immune microenvironment ,medicine ,Cancer research ,Neurology (clinical) ,Resiquimod ,medicine.disease ,business - Abstract
BACKGROUND New, non-cytotoxic treatments may improve outcomes for medulloblastoma, the most common malignant pediatric brain tumor. Sonic hedgehog (SHH) subgroup medulloblastoma, which includes subtypes with poor prognosis, can be modeled in immunocompetent, transgenic mice. These models are ideal for preclinical testing of immunotherapies. Here, we show that immune stimulation using resiquimod, a small molecule agonist of Toll-like receptor 7 and 8 (TLR 7/8), alters myeloid populations in medulloblastoma and significantly reduces tumor growth. METHOD We generated mice with medulloblastoma by interbreeding the hGFAP-Cre and SmoM2 mouse lines. The resultant hGFAP-Cre/SmoM2 (G-Smo) mice develop SHH medulloblastoma with 100% frequency. We analyzed myeloid populations and demonstrated TLR7/8 expression patterns in G-Smo tumors. We then compared survival of untreated G-Smo mice versus G-Smo mice treated with three doses of resiquimod at postnatal days 10, 12, and 14. We also assessed pharmacodynamic effects at progressive intervals after a single dose. RESULTS Approximately 10% of cells in G-Smo medulloblastomas were myeloid cells, and these cells were the only cells that expressed TLR7/8. Resiquimod slowed tumor growth and increased the survival of mice with medulloblastoma. Untreated median survival was 14.5 days (n=12), compared to resiquimod-treated median survival of 37 days (n=10; p=0.0003). All treated mice eventually demonstrated tumor progression. Immunohistochemistry for IBA1, a pan-macrophage marker, demonstrated significant increase in myeloid cells within the tumor by 24 hours after treatment (p=0.0178), however the IGF1+ fraction of myeloid cells decreased (p=0.0275). CONCLUSION Resiquimod prolongs survival in mice with SHH-driven medulloblastoma, demonstrating the potential for therapies that target myeloid cells to produce significant anti-tumor effects. Myeloid-derived IGF-1 has been shown to support tumor progression and resiquimod may act by disrupting this paracrine signaling.
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- 2021
27. Bioequivalence assessment of high-capacity polymeric micelle nanoformulation of paclitaxel and Abraxane® in rodent and non-human primate models using a stable isotope tracer assay
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Stephanie A. Montgomery, Stephan T. Stern, Duhyeong Hwang, Sarah L. Skoczen, Mengzhe Wang, Natasha Vinod, Jacob D. Ramsey, Jonathan E. Frank, Chaemin Lim, Kelsie S. Snapp, Zibo Li, Marina Sokolsky-Papkov, Hong Yuan, and Alexander V. Kabanov
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Drug ,Paclitaxel ,media_common.quotation_subject ,Biophysics ,Rodentia ,Bioengineering ,Bioequivalence ,Pharmacology ,Biomaterials ,chemistry.chemical_compound ,Isotopes ,Pharmacokinetics ,In vivo ,Cell Line, Tumor ,Animals ,Micelles ,media_common ,Drug Carriers ,Antineoplastic Agents, Phytogenic ,Macaca mulatta ,Rats ,Therapeutic Equivalency ,chemistry ,Mechanics of Materials ,Pharmacodynamics ,Ceramics and Composites ,Nanomedicine ,Albumin-Bound Paclitaxel ,Nanocarriers - Abstract
The in vivo fate of nanoformulated drugs is governed by the physicochemical properties of the drug and the functionality of nanocarriers. Nanoformulations such as polymeric micelles, which physically encapsulate poorly soluble drugs, release their payload into the bloodstream during systemic circulation. This results in three distinct fractions of the drug-nanomedicine: encapsulated, protein-bound, and free drug. Having a thorough understanding of the pharmacokinetic (PK) profiles of each fraction is essential to elucidate mechanisms of nanomedicine-driven changes in drug exposure and PK/PD relationships pharmacodynamic activity. Here, we present a comprehensive preclinical assessment of the poly (2-oxazoline)-based polymeric micelle of paclitaxel (PTX) (POXOL hl-PM), including bioequivalence comparison to the clinically approved paclitaxel nanomedicine, Abraxane®. Physicochemical characterization and toxicity analysis of POXOL hl-PM was conducted using standardized protocols by the Nanotechnology Characterization Laboratory (NCL). The bioequivalence of POXOL hl-PM to Abraxane® was evaluated in rats and rhesus macaques using the NCL's established stable isotope tracer ultrafiltration assay (SITUA) to delineate the plasma PK of each PTX fraction. The SITUA study revealed that POXOL hl-PM and Abraxane® had comparable PK profiles not only for total PTX but also for the distinct drug fractions, suggesting bioequivalence in given animal models. The comprehensive preclinical evaluation of POXOL hl-PM in this study showcases a series of widely applicable standardized studies by NCL for assessing nanoformulations prior to clinical investigation.
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- 2021
28. ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation
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Joel S. Parker, Duhyeong Hwang, Gouri Nanjangud, Christine Shaw, Marina Sokolsky-Papkov, Patrick Y. Lang, Timothy R. Gershon, and Alexander V. Kabanov
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Male ,0301 basic medicine ,Cerebellum ,Programmed cell death ,Cell cycle checkpoint ,Developmental Disabilities ,Neurogenesis ,Apoptosis ,Ataxia Telangiectasia Mutated Proteins ,Biology ,Nervous System Malformations ,medicine.disease_cause ,Mice ,03 medical and health sciences ,Chromosomal Instability ,medicine ,Animals ,Cerebellar Neoplasms ,Molecular Biology ,Mice, Knockout ,Neurons ,Gene Expression Regulation, Developmental ,Cerebellar Neoplasm ,Isoxazoles ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Cell Transformation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Animals, Newborn ,Pyrazines ,Cancer research ,Female ,Cerebellar hypoplasia (non-human) ,biological phenomena, cell phenomena, and immunity ,Carcinogenesis ,Gene Deletion ,Medulloblastoma ,Research Article ,Developmental Biology - Abstract
Microcephaly and medulloblastoma may both result from mutations that compromise genomic stability. We report that ATR, which is mutated in the microcephalic disorder Seckel syndrome, sustains cerebellar growth by maintaining chromosomal integrity during postnatal neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis and cerebellar hypoplasia in mice. Co-deletions of either p53 or Bax and Bak prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. ATR-deficient CGNPs had impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to ATR-deficient proliferation was highly p53 dependent and markedly attenuated by p53 co-deletion. Acute ATR inhibition in vivo by nanoparticle-formulated VE-822 reproduced the developmental disruptions seen with Atr deletion. Genetic deletion of Atr blocked tumorigenesis in medulloblastoma-prone SmoM2 mice. Our data show that p53-driven apoptosis and cell cycle arrest – and, in the absence of p53, non-apoptotic cell death – redundantly limit growth in ATR-deficient progenitors. These mechanisms may be exploited for treatment of CGNP-derived medulloblastoma using ATR inhibition.
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- 2016
29. Antiapoptotic Bcl-2 family proteins BCL-xL and MCL-1 integrate neural progenitor survival and proliferation during postnatal cerebellar neurogenesis
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Duhyeong Hwang, Benjamin Babcock, Marina Sokolsky-Papkov, Timothy R. Gershon, You-Wen He, Katherine Veleta, and Abigail H. Cleveland
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0301 basic medicine ,Neurogenesis ,Bcl-xL ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Animals ,Humans ,Progenitor cell ,Cerebellar Neoplasms ,Molecular Biology ,Progenitor ,Cell Proliferation ,biology ,Bcl-2 family ,Cell Biology ,Cell cycle ,Cell biology ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,Apoptosis ,030220 oncology & carcinogenesis ,biology.protein ,Myeloid Cell Leukemia Sequence 1 Protein ,Neural development ,Signal Transduction - Abstract
The tendency of brain cells to undergo apoptosis in response to exogenous events varies across neural development, with apoptotic threshold dependent on proliferation state. Proliferative neural progenitors show a low threshold for apoptosis, while terminally differentiated neurons are relatively refractory. To define the mechanisms linking proliferation and apoptotic threshold, we examined the effect of conditionally deleting Bcl2l1, the gene that codes the antiapoptotic protein BCL-xL, in cerebellar granule neuron progenitors (CGNPs), and of co-deleting Bcl2l1 homologs, antiapoptotic Mcl-1, or pro-apoptotic Bax. We found that cerebella in conditional Bcl2l1-deleted (Bcl-xL(cKO)) mice were severely hypoplastic due to the increased apoptosis of CGNPs and their differentiated progeny, the cerebellar granule neurons (CGNs). Apoptosis was highest as Bcl-xL(cKO) CGNPs exited the cell cycle to initiate differentiation, with proliferating Bcl-xL(cKO) CGNPs relatively less affected. Despite the overall reduction in cerebellar growth, SHH-dependent proliferation was prolonged in Bcl-xL(cKO) mice, as more CGNPs remained proliferative in the second postnatal week. Co-deletion of Bax rescued the Bcl-xL(cKO) phenotype, while co-deletion of Mcl-1 enhanced the phenotype. These findings show that CGNPs require BCL-xL to regulate BAX-dependent apoptosis, and that this role can be partially compensated by MCL-1. Our data further show that BCL-xL expression regulates MCL-1 abundance in CGNPs, and suggest that excessive MCL-1 in Bcl-xL(cKO) mice prolongs CGNP proliferation by binding SUFU, resulting in increased SHH pathway activation. Accordingly, we propose that BCL-xL and MCL-1 interact with each other and with developmental mechanisms that regulate proliferation, to adjust the apoptotic threshold as CGNPs progress through postnatal neurogenesis to CGNs.
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- 2019
30. Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells
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Mitsuharu Aga, Anjali Bheda-Malge, Marina Sokolsky, Julia Shakelford, Duhyeong Hwang, Satoru Kondo, Eiji Kobayashi, Alexander V. Kabanov, Christopher B. Whitehurst, Tomokazu Yoshizaki, and Joseph S. Pagano
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0301 basic medicine ,Herpesvirus 4, Human ,Indoles ,Exosomes ,lcsh:Chemistry ,0302 clinical medicine ,Cell Movement ,Nasopharynx ,Tumor Virus ,Oximes ,markers of invasion and metastasis ,lcsh:QH301-705.5 ,Oxazoles ,Spectroscopy ,Micelles ,Drug Carriers ,Chemistry ,General Medicine ,3. Good health ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Ubiquitin Thiolesterase ,Cell Survival ,Antineoplastic Agents ,Catalysis ,Virus ,Article ,Inorganic Chemistry ,Gene product ,Viral Matrix Proteins ,03 medical and health sciences ,Cell Line, Tumor ,Cell Adhesion ,Humans ,Secretion ,Physical and Theoretical Chemistry ,Molecular Biology ,Cell Proliferation ,Mouth ,poly (2-oxazoline) micelle ,Organic Chemistry ,Epithelial Cells ,nanoformulation ,In vitro ,Microvesicles ,Squamous carcinoma ,de-ubiquitination ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cell culture ,Cancer research ,Nanoparticles - Abstract
Normally ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in the central nervous and reproductive systems of adults, but its de novo expression has been detected in many human cancers. There is a growing body of evidence that UCH-L1 de-ubiquitinating (DUB) activity plays a major pro-metastatic role in certain carcinomas. Here we tested anti-metastatic effects of the small-molecule inhibitor of UCH-L1 DUB activity, LDN-57444, in cell lines from advanced oral squamous cell carcinoma (OSCC) as well as invasive nasopharyngeal (NP) cell lines expressing the major pro-metastatic gene product of Epstein&ndash, Barr virus (EBV) tumor virus, LMP1. To overcome the limited aqueous solubility of LDN-57444 we developed a nanoparticle formulation of LDN-57444 by incorporation of the compound in polyoxazoline micellear nanoparticles (LDN-POx). LDN-POx nanoparticles were equal in effects as the native compound in vitro. Our results demonstrate that inhibition of UCH-L1 DUB activity with LDN or LDN-POx inhibits secretion of exosomes and reduces levels of the pro-metastatic factor in exosomal fractions. Both forms of UCH-L1 DUB inhibitor suppress motility of metastatic squamous carcinoma cells as well as nasopharyngeal cells expressing EBV pro-metastatic Latent membrane protein 1 (LMP1) in physiological assays. Moreover, treatment with LDN and LDN-POx resulted in reduced levels of pro-metastatic markers, a decrease of carcinoma cell adhesion, as well as inhibition of extra-cellular vesicle (ECV)-mediated transfer of viral invasive factor LMP1. We suggest that soluble inhibitors of UCH-L1 such as LDN-POx offer potential forms of treatment for invasive carcinomas including EBV-positive malignancies.
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- 2019
31. Cheminformatics-driven discovery of polymeric micelle formulations for poorly soluble drugs
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Duhyeong Hwang, Carolina Horta Andrade, Ekaterina V. Varlamova, Alexander Tropsha, Vinicius M. Alves, Natasha Vinod, Marina Sokolsky-Papkov, Alexander V. Kabanov, Eugene N. Muratov, and Chaemin Lim
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Drug ,Simvastatin ,Polymers ,Chemistry, Pharmaceutical ,media_common.quotation_subject ,02 engineering and technology ,010402 general chemistry ,Designing drug ,01 natural sciences ,Micelle ,Drug Delivery Systems ,medicine ,Health and Medicine ,Particle Size ,Solubility ,Research Articles ,Micelles ,Podophyllotoxin ,media_common ,Virtual screening ,Multidisciplinary ,Polymeric micelles ,Chemistry ,Cheminformatics ,SciAdv r-articles ,Water ,021001 nanoscience & nanotechnology ,Combinatorial chemistry ,0104 chemical sciences ,3. Good health ,0210 nano-technology ,Research Article ,medicine.drug - Abstract
Computer-assisted strategy for drug delivery leads to discovery of polymeric micelle formulations for poorly soluble drugs., Many drug candidates fail therapeutic development because of poor aqueous solubility. We have conceived a computer-aided strategy to enable polymeric micelle-based delivery of poorly soluble drugs. We built models predicting both drug loading efficiency (LE) and loading capacity (LC) using novel descriptors of drug-polymer complexes. These models were employed for virtual screening of drug libraries, and eight drugs predicted to have either high LE and high LC or low LE and low LC were selected. Three putative positives, as well as three putative negative hits, were confirmed experimentally (implying 75% prediction accuracy). Fortuitously, simvastatin, a putative negative hit, was found to have the desired micelle solubility. Podophyllotoxin and simvastatin (LE of 95% and 87% and LC of 43% and 41%, respectively) were among the top five polymeric micelle-soluble compounds ever studied experimentally. The success of the strategy described herein suggests its broad utility for designing drug delivery systems.
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- 2019
32. Novel poly(2-oxazoline) block copolymer with aromatic heterocyclic side chains as a drug delivery platform
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Naoki Makita, Rainer Jordan, Jacob D. Ramsey, Clemens Sachse, Alexander V. Kabanov, Duhyeong Hwang, and Marina Sokolsky-Papkov
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Polymers ,Pharmaceutical Science ,Antineoplastic Agents ,02 engineering and technology ,Oxazoline ,Micelle ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Drug Delivery Systems ,Cell Line, Tumor ,Side chain ,Copolymer ,Moiety ,Animals ,Humans ,Oxazoles ,Micelles ,030304 developmental biology ,0303 health sciences ,Hydrogen bond ,Nuclear magnetic resonance spectroscopy ,021001 nanoscience & nanotechnology ,Combinatorial chemistry ,Drug Liberation ,chemistry ,Drug delivery ,0210 nano-technology - Abstract
Here we report a novel poly(2-oxazoline)-based block copolymer with the aromatic heterocyclic side chains in one block, poly(2-methyl-2-oxazoline)-b-poly(2-N,N-dimethyl-1,3,5-triazine-2,4-diamine-6-ethyl-2-oxazoline) (PMeOx-PcBOx), and demonstrate its potential application as a drug delivery platform. The copolymer was synthesized via the condensation of N,N-dimethylbiguanide with the methyl ester side chain in poly(2-methoxycarboxyethyl-2-oxazoline) block (PMestOx) of the PMeOx-PMestOx diblock copolymer. We confirmed the N,N-dimethylbiguanide condensation with PMestOx and the complete conversion of the side chain to the N,N-dimethyl-1,3,5-triazine-2,4-diamine-6-ethyl moiety by NMR spectroscopy, MALDI-TOF mass spectroscopy, UV-Vis spectroscopy, and titration analysis. The PMeOx-PcBOx copolymer self-assemble into polymeric micelles in aqueous solution. Successful encapsulation into these micelles has been demonstrated for 1) several poorly soluble drugs, such as bruceantin and LY2109761, and 2) dichloro(1,2-diaminocyclohexane)platinum(II) (DachPt). The first class of drugs is incorporated possibly via hydrogen bonding and pi-pi interactions with the PcBOx side groups, while the second one is likely forms coordination bonds with the same side groups. The capability of this new copolymer to solubilize a uniquely diverse set of active pharmaceutical ingredients suggests potential applications in drug delivery.
- Published
- 2019
33. CADD-06. VISMODEGIB LOADED POLYOXAZOLINE (POx) MICELLES ENHANCE EFFICACY OF VISMODEGIB AND PROLONG MICE SURVIVAL, EMPHASIZE POTENTIAL OF POx MICELLES TO IMPROVE DRUG DELIVERY TO BRAIN TUMORS
- Author
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Duhyeong Hwang, Alexander V. Kabanov, Marina Sokolsky-Papkov, Timothy R. Gershon, Chaemin Lim, Hedi Liu, and Yuling Zhao
- Subjects
Medulloblastoma ,Cancer Research ,Glial fibrillary acidic protein ,biology ,Chemistry ,Vismodegib ,medicine.disease ,Blood–brain barrier ,Micelle ,Abstracts ,medicine.anatomical_structure ,Oncology ,Drug delivery ,Cancer research ,medicine ,biology.protein ,Basal cell carcinoma ,Neurology (clinical) ,Signal transduction ,medicine.drug - Abstract
For the roughly 30% of medulloblastoma patients with SHH-subgroup tumors, drugs that disrupt SHH signaling offer the potential of improved efficacy with reduced toxicity compared to current, non-targeted treatment. The FDA-approved SMO inhibitor vismodegib, has been shown to be safe and effective for the treatment of basal cell carcinoma. In SHH-subgroup medulloblastomas, however, initial responses to vismodegib, have been followed by resistance that develops during treatment. We hypothesized that improving the delivery of the drug across the blood-brain barrier would forestall the development of resistance. We developed a novel, nanoparticle formulation of vismodegib, encapsulated in polyoxazoline micelles (POx-vismo). These nanoparticles showed high drug loading, and consistent, nanometer-scale particle size. We treated medulloblastoma bearing GFAP-cre/SmoM2 (G-Smo) mice with either POx-vismo or conventional vismodegib, administered by IP injection at postnatal days 12 and 13 (P12, P13) and then every other day. Both formulations induced an initial response. However, G-Smo mice treated with conventional vismodegib quickly progressed despite therapy. In contrast, POx-vismo-treated mice survived significantly longer than untreated mice or mice treated with conventional vismodegib. Our results show the superiority of POx-vismo and highlight the potential for POx micelles drug delivery to increase the efficacy of approved and experimental agents for brain tumor therapy. The anti-tumor effect of vismodegib, optimized in POx-vismo is significant and may, in combination with additional treatments such as radiation, lead to new treatment approaches.
- Published
- 2018
34. MBRS-53. ENHANCED EFFICACY OF NANO-FORMULATED VISMODEGIB SHOWS THE POTENTIAL FOR POLYOXAZOLINE MICELLES TO IMPROVE DRUG DELIVERY TO BRAIN TUMORS
- Author
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Duhyeong Hwang, Yuling Zhao, Marina Sokolsky, Timothy R. Gershon, Hedi Liu, and Alexander V. Kabanov
- Subjects
0301 basic medicine ,Medulloblastoma ,Cancer Research ,Chemistry ,Vismodegib ,Blood–brain barrier ,medicine.disease ,Micelle ,Cell membrane ,03 medical and health sciences ,Abstracts ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Drug delivery ,medicine ,Biophysics ,Basal cell carcinoma ,Neurology (clinical) ,Signal transduction ,medicine.drug - Abstract
For the roughly 30% of medulloblastoma patients with SHH-subgroup tumors, drugs that disrupt SHH signaling offer the potential of improved efficacy with reduced toxicity compared to current, non-targeted treatment. The FDA-approved SMO inhibitor vismodegib, which targets SHH signaling at the cell membrane, has been shown to be safe and effective for the treatment of basal cell carcinoma. In SHH-subgroup medulloblastomas, however, initial responses to vismodegib, have been followed by resistance that develops during treatment. We hypothesized that improving the delivery of the drug across the blood-brain barrier would forestall the development of resistance. To test this hypothesis, we developed a novel, nanoparticle formulation of vismodegib, encapsulated in polyoxazoline micelles (POx-vismo). These nanoparticles showed high drug loading, and small, consistent particle size. We then compared the efficacy of POx-vismo to conventional vismodegib in mice genetically-engineered to develop medulloblastoma. We treated GFAP-cre/SmoM2 (G-Smo) mice with either POx-vismo or conventional vismodegib, administered by IP injection at postnatal days 12 and 13 and then every other day. Both formulations induced an initial response. However, POx-vismo-treated mice survived significantly longer than mice treated with conventional vismodegib. While no mice were cured by either formulation, our results show the superiority of POx-vismo and highlight the potential for polyoxazoline micelle drug delivery to increase the efficacy of approved and experimental agents for brain tumor therapy. The anti-tumor effect of vismodegib, optimized in POx-vismo is significant and may, in combination with additional treatments such as radiation, lead to new treatment approaches.
- Published
- 2018
35. MB-37ATR INHIBITION INDUCES DNA DAMAGE AND APOPTOSIS IN MEDULLOBLASTOMA AND ATTENUATES TUMORIGENESIS
- Author
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Duhyeong Hwang, Alexander V. Kabanov, Patrick Y. Lang, Jaclyn Wu, Marina Sokolsky-Papkov, and Timothy R. Gershon
- Subjects
Medulloblastoma ,Cancer Research ,DNA damage ,business.industry ,Biology ,medicine.disease_cause ,medicine.disease ,Abstracts ,Text mining ,Oncology ,Apoptosis ,medicine ,Cancer research ,Neurology (clinical) ,Carcinogenesis ,business - Published
- 2016
36. A novel solid dispersion system for natural product-loaded medicine: silymarin-loaded solid dispersion with enhanced oral bioavailability and hepatoprotective activity
- Author
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Jong Oh Kim, Dong Wuk Kim, Bijay Kumar Poudel, Young-Jun Shin, Duhyeong Hwang, Chul Soon Yong, Yong-Il Kim, Abid Mehmood Yousaf, Ju Yeon Choi, Kwan Hyung Cho, Ok-Nam Bae, and Han-Gon Choi
- Subjects
Drug ,Materials science ,media_common.quotation_subject ,Pharmaceutical Science ,Administration, Oral ,Biological Availability ,Polysorbates ,Bioengineering ,Antioxidants ,Crystallinity ,Surface-Active Agents ,Colloid and Surface Chemistry ,medicine ,Pharmaceutic Aids ,Animals ,Physical and Theoretical Chemistry ,Solubility ,Dissolution ,media_common ,Chromatography ,Polyvinylpyrrolidone ,Carbon Tetrachloride Poisoning ,Organic Chemistry ,Povidone ,Bioavailability ,Rats ,Hepatoprotection ,Dispersion (chemistry) ,medicine.drug ,Silymarin - Abstract
A surface-attached silymarin-loaded solid dispersion with improved dissolution profile and enhanced oral bioavailability was formulated using silymarin, polyvinylpyrrolidone (PVP) and Tween 80 in water. In this solid dispersion, hydrophilic PVP was adhered onto the surface of crystalline drug rendering silymarin hydrophilic without changing its crystallinity. The drug solubility from the optimised solid dispersion prepared with silymarin/PVP/Tween 80 at the weight ratio of 5/2.5/2.5 increased by almost 650-fold compared to drug powder. The drug was physically and chemically stable in the solid dispersion for at least 6 months. Moreover, the solid dispersion enhanced the oral bioavailability of the drug in rats by almost 3-fold compared to the commercial product. The silymarin-loaded solid dispersion also exhibited advanced hepatoprotective bioactivity against CCl4-induced liver damage compared to silymarin or the commercial product. Thus, this silymarin-loaded solid dispersion would be useful for the enhancement of oral bioavailability and hepatoprotective activity of poorly water-soluble silymarin.
- Published
- 2014
37. Silymarin-loaded solid nanoparticles provide excellent hepatic protection: physicochemical characterization and in vivo evaluation
- Author
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Chul Soon Yong, Han-Gon Choi, Young-Jun Shin, Dong Wuk Kim, Jong Oh Kim, Duhyeong Hwang, Kwan Yeol Yang, Ok-Nam Bae, Abid Mehmood Yousaf, and Yong-II Kim
- Subjects
Male ,Shirasu porous glass membrane ,Materials science ,silymarin ,Treatment outcome ,Biophysics ,Pharmaceutical Science ,Nanoparticle ,Biological Availability ,Bioengineering ,enhanced oral bioavailability ,Pharmacology ,Porous glass ,Protective Agents ,Nanocapsules ,Biomaterials ,Diffusion ,Rats, Sprague-Dawley ,In vivo ,International Journal of Nanomedicine ,Drug Discovery ,Animals ,Desiccation ,Membrane emulsification ,Carbon Tetrachloride ,hepatoprotective activity ,Original Research ,Chromatography ,nanoparticle ,Organic Chemistry ,General Medicine ,Bioavailability ,Rats ,Treatment Outcome ,Emulsions ,Chemical and Drug Induced Liver Injury ,Biological availability - Abstract
Kwan Yeol Yang,1,* Du Hyeong Hwang,1,* Abid Mehmood Yousaf,2 Dong Wuk Kim,2 Young-Jun Shin,2 Ok-Nam Bae,2 Yong-II Kim,1 Jong Oh Kim,1 Chul Soon Yong,1 Han-Gon Choi2 1College of Pharmacy, Yeungnam University, Dae-Dong, Gyongsan, 2College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Sangnok-gu, Ansan, South Korea *These authors contributed equally to this work Background: The purpose of this study was to develop a novel silymarin-loaded solid nanoparticle system with enhanced oral bioavailability and an ability to provide excellent hepatic protection for poorly water-soluble drugs using Shirasu porous glass (SPG) membrane emulsification and a spray-drying technique. Methods: A silymarin-loaded liquid nanoemulsion was formulated by applying the SPG membrane emulsification technique. This was further converted into solid state nanosized particles by the spray-drying technique. The physicochemical characteristics of these nanoparticles were determined by scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. Their dissolution, bioavailability, and hepatoprotective activity in rats were assessed by comparison with a commercially available silymarin-loaded product. Results: Formulation of a silymarin-loaded nanoemulsion, comprising silymarin, castor oil, polyvinylpyrrolidone, Transcutol HP, Tween 80, and water at a weight ratio of 5/3/3/1.25/1.25/100 was accomplished using an SPG membrane emulsification technique at an agitator speed of 700 rpm, a feed pressure of 15 kPa, and a continuous phase temperature of 25°C. This resulted in generation of comparatively uniform emulsion globules with a narrow size distribution. Moreover, the silymarin-loaded solid nanoparticles, containing silymarin/castor oil/polyvinylpyrrolidone/Transcutol HP/Tween 80 at a weight ratio of 5/3/3/1.25/1.25, improved about 1,300-fold drug solubility and retained a mean size of about 210 nm. Silymarin was located in unaltered crystalline form in the nanoparticles. The drug dissolved rapidly from the nanoparticles, reaching nearly 80% within 15 minutes, indicating three-fold better dissolution than that of the commercial product. Further, the nanoparticles showed a considerably shorter time to peak concentration, a greater area under the concentration-time curve, and a higher maximum concentration of silymarin compared with the commercial product (P < 0.05). In particular, the area under the concentration-time curve of the drug provided by the nanoparticles was approximately 1.3-fold greater than that of the commercial product. In addition, the silymarin-loaded nanoparticles significantly reduced carbon tetrachloride-induced hepatotoxicity, indicating improved bioactivity compared with silymarin powder and the commercial product. Conclusion: Silymarin-loaded nanoparticles developed using SPG membrane emulsification and spray-drying techniques could be a useful system for delivery of poorly water-soluble silymarin while affording excellent hepatic protection. Keywords: silymarin, nanoparticle, hepatoprotective activity, Shirasu porous glass membrane, enhanced oral bioavailability
- Published
- 2013
38. Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib.
- Author
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Chaemin Lim, Dismuke, Taylor, Malawsky, Daniel, Ramsey, Jacob D., Duhyeong Hwang, Godfrey, Virginia L., Kabanov, Alexander V., Gershon, Timothy R., and Sokolsky-Papkov, Marina
- Subjects
- *
COPOLYMER micelles , *CYCLIN-dependent kinase inhibitors , *POLYMERSOMES , *MEDULLOBLASTOMA - Abstract
The article presents a study that explores enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq–guided combination with sapanisertib . It mentions the potential of nanoparticle formulation and scRNA-seq analysis of resistance to improve brain tumor treatment and identify CDK4/6 inhibitor palbociclib (POx-Palbo) Sapanisertib as effective combinatorial therapy for SHH medulloblastoma.
- Published
- 2022
- Full Text
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