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In this study, ROS-sensitive prodrug nanoassemblies composed of a single thioether bond bridged dihydroartemisinin-paclitaxel prodrug was constructed. The nanoassemblies with enhanced ferroptotic-chemotherapy promoted tumor cell death.

Liver-targeted ROS-scavenging liposomes loaded with oridonin and LY294002 (RLLs) was developed and modulated the “multiple crosstalk” in NAFLD via targeting PI3K–AKT–mTOR–NF-κB signaling.

The full-length AU-rich (63.14%) 2,794-nucleotide sequence of Rhizoctonia mitovirus K1 (RMV-K1) isolated from the binucleate AG-K strain FAS2909W was determined. The positive strand of RMV-K1 contains a large open reading frame (ORF) when the fungal mitochondrial genetic code is used. This ORF was predicted to encode an RdRp protein exhibiting the highest sequence identity (41.77%) to Rhizoctonia solani mitovirus 30. Phylogenetic analysis showed that RMV-K1 is a novel member of the genus Mitovirus, family Mitoviridae.

Strong infectivity enables coronavirus disease 2019 (COVID-19) to rage throughout the world. Moreover, the lack of drugs with definite therapeutic effects further aggravates the spread of the pandemic. Remdesivir is one of the most promising anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs. However, the limited clinical effects make its therapeutic effect controversial, which may result from the poor accumulation and activation of remdesivir in the lung. Therefore, we developed lyophilized remdesivir liposomes (Rdv-lips) which can be reconstituted as liposomal aerosol for pulmonary delivery to improve the in vivo behavior of existing remdesivir cyclodextrin conclusion compound (Rdv-cyc) injections. Liposome encapsulation endowed remdesivir with much higher solubility and better biocompatibility. The in vitro liposomal aerosol characterization demonstrated that Rdv-lips possessed a mass median aerodynamic diameter of 4.118 μm and fine particle fraction (, Graphical Abstract Image, graphical abstract

Co-delivery of chemotherapeutics and immunostimulant or chemoimmunotherapy is an emerging strategy in cancer therapy. The precise control of the targeting and release of agents is critical in this methodology. This article proposes the asynchronous release of the chemotherapeutic agents and immunostimulants to realize the synergistic effect between chemotherapy and immunotherapy. To obtain a proof-of-concept, a co-delivery system was prepared via a drug-delivering-drug (DDD) strategy for cytosolic co-delivery of Poly I:C, a synthetic dsRNA analog to activate RIG-I signaling, and PTX, a commonly used chemotherapeutics, in which pure PTX nanorods were sequentially coated with Poly I:C and mannuronic acid via stimulating the RIG-I signaling axis. The co-delivery system with a diameter of 200 nm enables profound immunogenicity of cancer cells, exhibiting increased secretion of cytokines and chemokines, pronounced immune response in vivo, and significant inhibition of tumor growth. Also, we found that intracellularly sustained release of cytotoxic agents could elicit the immunogenicity of cancer cells. Overall, the intracellular asynchronous release of chemotherapeutics and immunomodulators is a promising strategy to promote the immunogenicity of cancer cells and augment the antitumor immune response., Graphical abstract Cytosolic delivery of Poly I:C to cancer cells induces robust immunostimulation via activating RIG-I pathway. Intracellularly sustaining release of cytotoxic agent significantly promotes immunogenicity of cancer cells.Image 1

The interplay of liposome-protein corona hinders the clinical application of liposomes due to active macrophage sequestration and rapid plasma clearance. Here we showed that, CXCL10 as a therapeutic protein was coronated the thermosensitive liposomes to form stealth-like nanocarriers (CXCL10/TSLs). Decoration of the corona layer of CXCL10/TSLs by hyaluronic acid conjugated oridonin (ORD/CXCL10/TSLs), overcame the "fluid barrier" built by biological proteins, drastically reduced capture by leukocytes in whole blood, allowed the specific targeting of tumor sites. Multifunctional medicine ORD/CXCL10/TSLs with hyperthermia drove the sustained cytokine-CXCL10 inflammatory loop to switch macrophage phenotype to M1-like, expand tumor-infiltrating natural killer cells and induce intratumoral levels of interferon-γ. Oridonin synergized with CXCL10 during ORD/CXCL10/TSLs treatment, downregulated PI3K/AKT and Raf/MEK signaling for M1-like polarization and migration inhibition. Furthermore, ORD/CXCL10/TSLs potently synergized with anti-PD-L1 antibody in mice bearing metastatic melanoma, induced sustained immunological memory and controlled metastatic spread.

Invasive fungal infections (IFIs) represent a growing public concern for clinicians to manage in many medical settings, with substantial associated morbidities and mortalities. Among many current therapeutic options for the treatment of IFIs, amphotericin B (AmB) is the most frequently used drug. AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance. In this review, we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs. We have also discussed the mechanism of actions of AmB, rationale for treating IFIs, and recent advances in formulating AmB for clinical use. Finally, this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs., Graphical abstract Amphotericin B (AmB), placed in BCS class IV with low solubility and permeability, is a commonly used drug to combat Invasive fungal infections. In this review, research efforts on nanocarriers to improve AmB delivery are summarized.Image 1

Hepatic fibrosis remains a serious threat to human health globally and there are no effective antifibrotic pharmacotherapeutic strategies, to date. Upon the activation of hepatic stellate cells, excess deposition of the extracellular matrix occurs, acting as a trigger that generates reactive oxygen species and an inflammatory response, thereby exacerbating the development of hepatic fibrosis and inflammation. In this study, we incorporated an idea that targets key pathways for developing novel anti-fibrosis nanomedicine. Previous studies have reported the potential of LY294002 (LY) as a PI3K/Akt inhibitor that suppresses the HSC activation and fibrosis development; however, its poor water solubility impedes further investigation. Moreover, the proliferation of HSC, severe oxidative stress and inflammatory conditions could be undermined by oridonin (ORD) treatment. Herein, we developed an HA-ORD/LY-Lips nanocomplex, where LY294002 was encapsulated into liposomes to prepare LY-Lips while ORD was conjugated with a hyaluronic acid (HA) polymer acting as a prodrug HA-ORD. The complex exerts great potential in improving the liver-targeted drug release. We adopted a series of in vitro and in vivo evaluations which demonstrate that HA-ORD/LY-Lips can significantly avert activation of hepatic stellate cells via scavenging reactive oxygen species and suppressing an inflammatory response. Our work implements a proof of concept strategy for fibrosis treatment based on the dual antioxidative and anti-inflammatory mechanisms, which may be applicable to treat liver fibrosis associated with a dysregulated inflammatory microenvironment.

A matrix metalloproteinases (MMPs) triggered multifunctional micellar system loading traditional chemotherapeutic agent paclitaxel (PTX) and marimastat (MATT), an inhibition of matrix metalloproteinases, was established to prevent tumor growth and metastasis. The micelles were self-assembled by the conjugate synthesized with an MMPs sensitive peptide as the bridge between PTX and poly(ethylene glycol) (PEG). 4T1 cell line derived from a murine breast tumor was selected as the cell model due to its high metastasis. The cytotoxicity assay and cell apoptosis analysis revealed that the sensitive micelles increased the toxicity and cell apoptosis compared with the insensitive micelles. In addition, this system also exhibited high penetration ability in tumor spheroids and significant invasion inhibition with the method of Transwell invasion assay. In the BALB/c mice bearing 4T1 tumors, this system inhibited the growth of the metastatic tumor and prevented the incidence of lung metastasis with low systemic toxicity. And the expression of MMP-2 and MMP-9, which are important in the process of tumor metastasis, was down-regulated. Generally, the data obtained from the in vitro and in vivo studies confirmed that the codelivery of PTX and MATT by the MMPs sensitive micelles achieved not only significant antitumor effect but also obvious inhibition effect of tumor metastasis, which are the leading cause of cancer deaths. This functional particle system may provide a promising strategy for metastatic breast cancer therapy.

Despite the remarkable success of immunotherapies over the past decade, their effectiveness against triple-negative breast cancer (TNBC) is limited to a small subset of patients, mainly due to the low immunogenicity and unfavorable tumor microenvironment. In this study, we successfully constructed a programmed site-specific delivery nanosystem for the combined delivery of transforming growth factor beta (TGF-β) receptor inhibitor LY3200882 (LY) and PD-L1 siRNA (siPD-L1) to boost anti-tumor immunotherapy. As expected, LY in the outer layer of the nanosystem was released by stimulation of MMP2, and dramatically down-regulated the expression of extracellular matrix (ECM) in the tumor-associated fibroblasts (TAFs), and thus promoted the infiltration of effector T cells and penetration of nanomedicines. Simultaneously, the blockade of TGF-β by LY also triggered immunogenic cell death (ICD) of tumor cells and induced the maturation of dendritic cells. Moreover, the programmed design provided the siPD-L1/protamine cationic inner core with easier access to tumor cells and TAFs after MMP2-stimulated breakup of the outer layer, down-regulating the expression of PD-L1 in both types of cells. Notably, the synergistic effect of LY and siPD-L1 remarkably enhanced the tumor antigen presentation and immunosuppressive microenvironment remodeling, thus efficiently inhibiting the TNBC growth, metastasis, and recurrence. Therefore, the programmed site-specific delivery nanosystem is a promising drug delivery platform for boosting anti-tumor immunotherapy efficacy for TNBC.

Hepatic fibrosis remains a serious threat to human health globally and there are no effective antifibrotic pharmacotherapeutic strategies, to date. Upon the activation of hepatic stellate cells, excess deposition of the extracellular matrix occurs, acting as a trigger that generates reactive oxygen species and an inflammatory response, thereby exacerbating the development of hepatic fibrosis and inflammation. In this study, we incorporated an idea that targets key pathways for developing novel anti-fibrosis nanomedicine. Previous studies have reported the potential of LY294002 (LY) as a PI3K/Akt inhibitor that suppresses the HSC activation and fibrosis development; however, its poor water solubility impedes further investigation. Moreover, the proliferation of HSC, severe oxidative stress and inflammatory conditions could be undermined by oridonin (ORD) treatment. Herein, we developed an HA-ORD/LY-Lips nanocomplex, where LY294002 was encapsulated into liposomes to prepare LY-Lips while ORD was conjugated with a hyaluronic acid (HA) polymer acting as a prodrug HA-ORD. The complex exerts great potential in improving the liver-targeted drug release. We adopted a series of

The co-delivery of chemotherapeutic agents and immune modulators to their targets remains to be a great challenge for nanocarriers. Here, we developed a hybrid thermosensitive nanoparticle (TMNP) which could co-deliver paclitaxel-loaded transferrin (PTX@TF) and marimastat-loaded thermosensitive liposomes (MMST/LTSLs) for the dual targeting of cancer cells and the microenvironment. TMNPs could rapidly release the two payloads triggered by the hyperthermia treatment at the site of tumor. The released PTX@TF entered cancer cells via transferrin-receptor-mediated endocytosis and inhibited the survival of tumor cells. MMST was intelligently employed as an immunomodulator to improve immunotherapy by inhibiting matrix metalloproteinases to reduce chemokine degradation and recruit T cells. The TMNPs promoted the tumor infiltration of CD3+ T cells by 2-fold, including memory/effector CD8+ T cells (4.2-fold) and CD4+ (1.7-fold), but not regulatory T cells. Our in vivo anti-tumor experiment suggested that TMNPs possessed the highest tumor growth inhibitory rate (80.86%) compared with the control group. We demonstrated that the nanoplatform could effectively inhibit the growth of tumors and enhance T cell recruitment through the co-delivery of paclitaxel and marimastat, which could be a promising strategy for the combination of chemotherapy and immunotherapy for cancer treatment.

Highlights Nanosized cytotoxic drug could combat against the autophagy induced by the drug. The drug nanorods enabled efficient intracellular delivery of the nucleic acid and the resultant autophagy inhibition in vitro and in vivo, which in turn sensitized the cancer cells to the anti-tumor nanorods. Electronic supplementary material The online version of this article (10.1007/s40820-019-0310-0) contains supplementary material, which is available to authorized users., Autophagy is closely related to the drug resistance and metastasis in cancer therapy. Nanoparticle-mediated co-delivery of combinatorial therapy with small-molecular drugs and nucleic acids is promising to address drug resistance. Here, a drug-delivering-drug (DDD) platform consisting of anti-tumor-drug nanorods as a vehicle for cytosol delivery of nucleic acid (miR-101) with potent autophagic-inhibition activity is reported for combinatorial therapy. The developed 180-nm nanoplatform, with total drug loading of up to 66%, delivers miR-101 to cancer cells, with threefold increase in intracellular level compared to conventional gene carriers and inhibits the autophagy significantly, along with above twofold reduction in LC3II mRNA and approximately fivefold increase in p62 mRNA over the control demonstrated in the results in vivo. And in turn, the delivery of miR-101 potentiates the drug’s ability to kill cancer cells, with a threefold increase in apoptosis over that of chemotherapy alone. The anti-tumor study in vivo indicates the combined therapy that enables a reduction of 80% in tumor volume and > twofold increase in apoptosis than of the single-drug strategy. In summary, via the carrier-free strategy of DDD, this work provides a delivery platform that can be easily customized to overcome drug resistance and facilitates the delivery of combined therapy of small-molecular drugs and nucleic acids. Electronic supplementary material The online version of this article (10.1007/s40820-019-0310-0) contains supplementary material, which is available to authorized users.

The objective of this research is to study the taste masking efficiency of Amberlite IRP88 in sildenafil citrate chewable tablets. Amberlite IPR88 was complexed with sildenafil citrate using the batch method. Formulation with sildenafil citrate/Amberlite IPR88 in a ratio of 2:1 by weight showed higher Drug complexation efficiency and drug-loaded, and furthermore the results from SEM, DSC, XRD, and FT-IR of selected complex indicated that the salt bridge between sildenafil and citrate was replaced by salt bridge between NH groups of sildenafil and the sulfonate group of the resin. Different chewable tablets containing the complex were prepared with various ingredients as well. Then, dissolution tests, in vivo performance assessment as well as palatability evaluation of chewable tablets were performed. The dissolution behaviors, in vivo performances and taste profiles of the prepared chewable tablets with lactose monohydrate, CMC-Na were similar to those of Nipatra Chewable Tablets, which was one of selling sildenafil citrate chewable tablet. Overall, the pH-dependent process of ion exchange by weak cationic resins opens a promising approach to mask the bitter taste of cationic drug for oral fast disintegrating formulation such as sildenafil citrate.

Multidrug resistance (MDR) is a common intractable barrier in success of clinical cancer chemotherapy. Codelivery of two drugs using nanocarriers is a commonly used approach to treat the MDR cancer. However, the drug payload in the conventional nanocarriers is low and thus compromises the treatment outcomes. Disulfiram (DSF) is promising to reverse MDR and increases the sensitivity of cancer cells to chemotherapy. While, paclitaxel (PTX) is one of the frequently used anticancer drug. Here, by using a drug-delivering-drug (DDD) strategy based on nanocrystals, hybrid PTX-DSF nanocrystals (PTX-DSF Ns) were developed for codelivery of PTX and DSF to reverse MDR in cancer. The 160-nm PTX-DSF Ns with rod-like morphology had drug-loading up to 43% at mass ratio of 5:1. Interestingly, the nanoparticles entered cells via caveolar endocytosis. By reducing intracellular ATP level and GST activity, PTX-DSF Ns killed the Taxol resistant A549 cells with higher efficiency than PTX alone, exhibiting as 6-fold increase of apoptosis in MDR tumor. The nanoparticles circulated in blood over time, accumulated in tumor efficiently and reduced the tumor volume by 12-fold in MDR tumor-bearing BALB/c nude mice and allowed 12-fold apoptosis in tumor. Additionally, the immunohistochemical examination demonstrated the safety of the nanoparticles. Overall, the DDD strategy-based PTX-DSF Ns have promising potential for the treatment of MDR cancer.

Multidrug resistance (MDR) remains a major obstacle to ensure effective chemotherapy in cancer patients. Several factors could be associated with cancer cells' drug resistance such as overexpression of P-glycoprotein (P-gp), cancer stem cells (CSCs), defect in apoptosis, mutation and alteration in DNA repair pathways, angiogenesis, autophagy, and modulation in metabolic enzymes. Until now, drug efflux by ABC transporters has been a univocal and well-established mechanism of chemotherapeutic associated drug resistance. To explore the mechanics involved in ABC transporter associated drug resistance, many crucial studies have been conducted from identification of drug binding sites to elucidation of their structure. Due to our continuous battle with drug resistance, several strategies have been employed to combat MDR, including P-gp modulators, siRNAs, antibodies, as well as peptides. Furthermore, various nanoparticle and different effective combination nanomedicine strategies also suggest some exciting results. Thus, to improve nanomedicine approaches to overcome MDR, in this evolutionary review, we have focused on fundamentals of possible strategies as well as the latest accomplishments to reverse MDR.

Cancer-associated fibroblasts (CAFs) are the majority cell population of tumor stroma, and they not only play important roles in tumor growth and metastasis, but they also form a protective physical barrier for cancer cells. Herein, we designed a fibroblast activation protein-α (FAP-α)-adaptive polymeric micelle based on hyaluronic acid and curcumin conjugates. The polymeric micelle is composed of a CD44-targeting shell and a FAP-α-cleavable polyethylene glycol (PEG) coating. When FAP-α is encountered on the surface of CAFs in the tumor microenvironment, the PEG layer is released, hyaluronic acid is recovered on the surface of nanoparticles, and the nanoparticles effectively inhibit the growth of tumor cells and CAFs through CD44-mediated endocytosis. The FAP-α-adaptive polymeric micelle exhibited potent anti-cancer efficacy by enhancing CAF apoptosis and reducing collagen in tumor tissues. Collectively, FAP-α-adaptive nanoparticles may be a promising method for antitumor anticancer treatments via reprogramming of stroma fibrosis.

During the process of cancer metastasis, various enzymes, cytokines, and factors were involved, and upregulated cyclooxygenase-2(COX-2) in tumor cells led to proliferation and invasion of various tumors. Many nonsteroidal anti-inflammatory drugs (NSAIDs) were used as an anticancer adjuvant in chemotherapy, such as ibuprofen (BF) and celecoxib. NSAIDs could effectively inhibit local inflammation and decreased COX-2 expression. However, most of them have serious toxicity issues due to their limit selectivity against cancer and poor water solubility. Thus hyaluronic acid-ibuprofen (HA-ss-BF), which was sensitive to the reducing environment, was prepared by binding ibuprofen (BF) to the hyaluronic acid backbone through a disulfide bond, and the HA-ss-BF polymer could self-assemble into micelles and serve as carriers to delivery doxorubicin. These redox-sensitive prodrug polymeric micelles hold multiple therapeutic advantages, including on-demand BF release and disassembling micelles responding to redox stimuli, as well as desirable cellular uptake and favorable biodistribution. These advantages indicated the redox-responsive hyaluronic acid-ibuprofen prodrug could be a promising delivery system for metastatic breast cancer treatment.

We report the development of a small interfering RNA (siRNA) delivery vector based on cationic perfluorocarbon nanoemulsions. We have prepared perfluorodecalin (PFD) emulsions with a positive surface charge provided by a fluorinated poly(ethylenimine) (F-PEI). The fluorinated emulsion (F-PEI@PFD) reduced cytotoxicity of F-PEI and demonstrated effective binding with siRNAs to form nanosized emulsion polyplexes. The prepared emulsion polyplexes enhanced cellular uptake and improved endosomal escape of the siRNA. In addition to increased reporter gene silencing in multiple cancer cell lines, when compared with control F-PEI and PEI polyplexes, the siRNA emulsion polyplexes showed an excellent resistance to serum deactivation and maintained high activity, even in high-serum conditions. The F-PEI@PFD emulsion polyplexes carrying an siRNA to silence the expression of Bcl2 gene induced apoptosis and inhibited tumor growth in a melanoma mouse model in vivo and showed potential for in vivo ultrasound imaging. This study demonstrates the potential of F-PEI@PFD emulsions as a multifunctional theranostic nanoplatform for safe siRNA delivery, with integrated ultrasound imaging functionality.

Protein therapeutics is playing an increasingly critical role in treatment of human diseases. However, current vectors are captured by the digestive endo-lysosomal system, which results in an extremely low fraction (60% apoptosis, implying significant antitumor activities. Conclusions: This platform gains cellular entry without entrapment in the endo-lysosomes and enables efficient intracellular protein delivery and resultant profound cancer treatment. This platform, with extremely high drug-loading, is a valuable platform for combined cancer therapy with small-molecule drugs and proteins. More importantly, this work offers a robust and safe approach for protein therapeutics and intracellular delivery of other functional peptides, as well as gene-based therapy.

The tumor microenvironment (TME) plays a critical role in tumor initiation, progression, invasion, and metastasis. Therefore, a therapy that combines chemotherapeutic drugs with a TME modulator could be a promising route for cancer treatment. This paper reports a nanoplatform self-assembled from a hyaluronic acid (HA)-paclitaxel (PTX) (HA-PTX) prodrug and marimastat (MATT)-loaded thermosensitive liposomes (LTSLs) (MATT-LTSLs) for the dual targeting of the TME and cancer cells. Interestingly, the prodrug HA-PTX can self-assemble on both positively and negatively charged liposomes, forming hybrid nanoparticles (HNPs, 100 nm). Triggered by mild hyperthermia, HA-PTX/MATT-LTSLs HNPs rapidly release their payloads into the extracellular environment, and the released HA-PTX quickly enters 4T1 cells through a CD44-HA affinity. The HNPs possess promoted tumor accumulation (1.6-fold), exhibit deep tumor penetration, and significantly inhibit the tumor growth (10-fold), metastasis (100%), and angiogenesis (10-fold). Importantly, by targeting the TME and maintaining its integrity via inhibiting the expression and activity of matrix metalloproteinases (>5-fold), blocking the fibroblast activation by downregulating the TGF-β1 expression (5-fold) and suppressing the degradation of extracellular matrix, the HNPs allow for significant metastasis inhibition. Overall, these findings indicate that a prodrug of an HA-hydrophobic-active compound and liposomes can be self-assembled into a smart nanoplatform for the dual targeting of the TME and tumor cells and efficient combined treatment; additionally, the co-delivery of MATT and HA-PTX with the HNPs is a promising approach for the treatment of metastatic cancer. This study creates opportunities for fabricating multifunctional nanodevices and offers an efficient strategy for disease therapy.

Treatment for metastatic cancer is a great challenge throughout the world. Commonly, directed inhibition of extracellular matrix metalloproteinases (MMPs) secreted by cancer cells can reduce metastasis. Here, a novel nanoplatform (HPMC NPs) assembled from hyaluronic acid (HA)-paclitaxel (PTX) prodrug and marimastat (MATT)/β-casein (CN) complexes was established to cure a 4T1 metastatic cancer model via targeting CD44 and intracellular, rather than extracellular, MMPs. Methods: HPMC NPs were prepared by assembling the complexes and prodrug under ultrasonic treatment, which the interaction between them was evaluated by förster resonance energy transfer, circular dichroism and fluorescence spectra. The developed nanoplatform was characterized via dynamic light scattering and transmission electron microscopy, and was evaluated in terms of MMP-sensitive release and stability. Subsequently, the cellular uptake, trafficking, and in vitro invasion were studied by flow cytometry, confocal laser microscopy and transwell assay. MMP expression and activity was determined by western blotting and gelatin zymography. Finally, the studies of biodistribution and antitumor efficacy in vivo were performed in a mouse 4T1 tumor breast model, followed by in vivo safety study in normal mouse. Results: The interaction between the prodrug and complexes is strong with a high affinity, resulting in the assembly of these two components into hybrid nanoparticles (250 nm). Compared with extracellular incubation with MATT, HPMC NP treatment markedly reduced the expression (100%) and activity (50%) of MMPs in 4T1 cells and in the tumor. HPMC NPs exhibited 1.4-fold tumor accumulation, inhibited tumor-growth by >8-fold in volume with efficient apoptosis and proliferation, and suppressed metastasis (>5-fold) and angiogenesis (>3-fold). Overall, HPMC NPs were efficient in metastatic cancer therapy. Conclusions: According to the assembly of polymer prodrug and protein-drug complexes, this study offers a new strategy for constructing nanoparticles for targeted drug delivery, biomedical imaging, and combinatorial treatment. Importantly, via inhibition of intracellular MMPs, metastasis and angiogenesis can be potently blocked, benefiting the rational design of nanomedicine for cancer treatment.

High-density lipoprotein (HDL) is an outstanding biocompatible nanovector for tumor-targeted delivery of multimodel drugs in cancer therapy. However, this seemingly promising delivery platform demonstrates an adverse accumulation in liver and adrenal due to the primary expression of natural target scavenger receptor class B type I (SR-BI), which overexpressed in malignant cells as well. Therefore, we endowed native HDLs with rerouting capacity, that is, enabling HDLs to get away from natural receptors (SR-BI) to selectively alternate tumor-rich receptors. The αvβ3-integrin specific cyclic-RGDyk peptide was conjugated with HDL-protein component apolipoprotein A-I (apoA-I), demonstrating high substitution degree of 26.2%. Afterward, RGD-modified apoA-I was introduced to fabricate cholesterol siRNA-loaded HDL nanoparticles (RGD-HDL/Ch-siRNA) for specific affinity with tumor angiogenesis and αvβ3 integrin on tumor surface. After preparation, RGD-HDL/Ch-siRNA shared desirable particle size, efficient siRNA pro...

The effective combination of drugs promoting antiangiogenesis and apoptosis effects has proven to be a promising collaborative tumor antidote; and the codelivery of small interfering RNA (siRNA) and chemotherapy agents within one efficient vehicle has gained more attention over single regimen administration. Herein, vascular endothelial growth factor specific siRNA (siVEGF) and paclitaxel (PTX) were introduced as therapeutic companions and coencapsulated into naturally mimic high-density lipoproteins (rHDL/siVEGF-PTX), so that various mechanisms of treatment can occur simultaneously. The terminal nanoparticles share capacity of specific-targeting to tumor cells overexpressed scavenger receptor class B type I (SR-BI) and deliver siVEGF and PTX into cytoplasm by a nonendocytosis mechanism. By exchanging HDL core lipids with hydrophobic therapeutics, rHDL/siVEGF-PTX possessed particle size of ∼160 nm, surface potential of ∼-20 mV, and desirable long-term storage stability. In vitro results confirmed that the parallel activity of siVEGF and PTX displayed enhanced anticancer efficacy. The half-maximal inhibitory concentration (IC

We describe here a novel lyophilized nanosuspension technology in order to improve the dissolution rate and oral bioavailability of the insoluble drug P2X7 receptor antagonist (PRA), which is an effective antagonist to P2X7 receptor for non-steroidal anti-inflammatory. PRA-lyophilized nanosuspension (PRA-LNS) was fabricated by anti-solvent precipitation in combination with high pressure homogenization, and then lyophilized for prolonged storage. After preparations, various characterization experiments were performed including particle size, zeta potential, surface morphology, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), in vitro dissolution study, and in vivo pharmacokinetic study. The re-dissolved particle size of PRA-LNS was about 180~250 nm with uniform distribution, confirmed by TEM image. The drug PRA in nanosuspensions possessed crystalline form evaluated via XRPD and DSC analysis. The solubility of PRA-LNS in water was 1.52 times larger than PRA raw drug; in vitro dissolution tests showed that PRA-LNS could dissolve completely within 5 min, which is a significant improvement compared to the raw drug. The relative bioavailability of PRA-LNS is 290.70% compared to the raw drug and 177.94% compared to the physical mixture. PRA-LNS could easily re-disperse in water with increased solubility, enhanced oral bioavailability, and controllable production process.

Many lead compounds have a low solubility in water, which substantially hinders their clinical application. Nanosuspensions have been considered a promising strategy for the delivery of water-insoluble drugs. Here, denatured soy protein isolate (SPI)-coated docetaxel nanosuspensions (DTX-NS) were developed using an anti-solvent precipitation-ultrasonication method to improve the water-solubility of DTX, thus improving its intracellular delivery. DTX-NS, with a diameter of 150-250nm and drug-loading up to 18.18%, were successfully prepared by coating drug particles with SPI. Interestingly, the drug state of DTX-NS was alterable. Amorphous drug nanoparticles were obtained at low drug-loading, whereas at a high drug-loading, the DTX-NS drug was mainly present in the crystalline state. Moreover, DTX-NS could be internalized at high levels by cancer cells and enter the cytosol by lysosomal escape, enhancing cell cytotoxicity and apoptosis compared with free DTX. Taken together, denatured SPI has a strong stabilization effect on nanosuspensions, and the drug state in SPI-coated nanosuspensions is alterable by changing the drug-loading. Moreover, DTX-NS could achieve cytosolic delivery, generating enhanced cell cytotoxicity against cancer cells.

Tyroservatide (YSV) is a tripeptide that has been approved for clinical testing, as a new anticancer drug. In the current study, YSV-stearic acid (YSV-SA) was inserted into the surface of d-alpha-tocopheryl polyethylene glycol 1000 succinate monoester (TPGS)-modified paclitaxel (PTX) liposomes (TP-Lip) to form YSV-conjugated TP-Lip (TYP-Lip). Both in vivo imaging and in vitro cell uptake analysis indicated that these modifications could increase tumor-targeting and cell uptake of the liposomes. Optimal antitumor effects were achieved via tail vein injections of TYP-Lip in MB-231 tumor-bearing nude mice. Overall, the formed TYP-Lip not only achieved a synergistic anticancer effect through YSV and PTX, but also improved tumor-targeting and exhibited further antitumor capabilities. These results indicated that combining biological (YSV) and chemotherapeutic (PTX) agents is an efficient combinatorial delivery strategy for enhanced tumor targeting and synergistic antitumor effects.

Nanosuspensions of drugs are nanosized colloidal dispersions of pure particles. In contrast to conventional nanoparticles, the particles in nanosuspensions feature 100% drug loading. Stiripentol (STP) is an effective drug for severe myoclonic epilepsy of infancy (SMEI); however, because of its low water solubility, high oral doses of STP, up to 50 mg per kg per day in two or three divided doses, must be administered to patients, compromising therapy outcomes. Here, we report STP nanosuspensions (STP-Ns) stabilized with denatured soybean protein isolate (SPI) as a stabilizer to promote the absorption of STP and thus improve therapeutic outcomes. STP-Ns with a drug loading of up to 50% (w/w) and a diameter of 150 nm were successfully prepared. Importantly, in the presence of denatured SPI as a stabilizer, the drug state in the nanosuspensions was tunable by drug loading: low drug loading resulted in the formation of amorphous drug nanoparticles while high drug loading greater than 3.22% (w/w) in formulation induced the formation of nanosuspensions with the coexistence of amorphous and crystalline drug. This new nanosuspension formulation was related to the fact that the protein-drug complex exhibited a much stronger affinity for the drug particles over the protein itself. Interestingly, via the transcytosis pathway, the STP-Ns penetrated across the intestinal barrier into the systemic circulation, with the duodenum as the predominant absorption site. The bioavailability of the STP-Ns was 4-fold as great as that of raw crystals. The discovery of this mechanism for the use of globular protein as a stabilizer for nanosuspensions provides a new route for the preparation of amorphous drug nanoparticles. This work offers a new strategy to widen the application of globular protein and nanosuspensions of insoluble active compounds in drug delivery.

Celecoxib (CLX) is a selective cyclooxygenase-2 (COX-2) inhibitor; however, the application of CLX is compromised due to its poor aqueous solubility and low oral bioavailability. This study aims to develop a nanotechnology to overcome these issues. Celecoxib nanosuspensions (CLX-NS) were formulated using D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as stabilizer via high pressure homogenization (HPH) and then freeze-dried to solid powder. Transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) were employed to characterize the physicochemical and pharmaceutical properties of CLX-NS lyophilization. In vitro dissolution, an in situ single-pass intestinal perfusion study, and in vivo pharmacokinetic studies were performed for further investigation. Particles of the nanosuspensions were short-rod shaped (∼388 nm) and remained in the same crystalline state as CLX coarse powder. In the test of in vitro dissolution, CLX-NS displayed a higher dissolution amount (90.8% during 60 minutes) compared to groups of CLX coarse powder (47.9%) and physical mixture (52.9%). Moreover, in situ single-pass intestinal perfusion study indicated that CLX-NS could be well absorbed in the whole intestine with the main absorption site being the duodenum. Significant improvements in Cmax and AUC0–t of CLX-NS were obtained in pharmacokinetic analyses with a 245.8% increase in relative bioavailability compared to CLX coarse powder. This study showed that nanosuspension preparations could be a promising strategy in influencing CLX absorption in gastrointestinal tract, and improving dissolution and oral bioavailability of poorly water-soluble drugs.

Co-delivery systems capable of transporting hydrophobic chemotherapeutics and hydrophilic siRNA to the same cell population with simultaneous burst release of both drugs to maximize synergistic anticancer efficacy remains elusive. In this light, a multifunctional nanoparticle (HA-PSR) consisting of a redox-sensitive core and detachable crosslinked hyaluronic acid (HA) shell was developed. Octyl modified PEI containing disulfide linkages (PSR) were synthesized as the core materials for co-encapsulation of chemotherapeutics and siRNA, while a HAase-sensitive thiolated HA (HA-SH) was collaboratively assembled to the anionic shell for CD44-mediated active targeting along with enhanced and detachable protection for drug loaded inner cores. Resultantly, HA de-protected redox-sensitive inner cores achieved co-burst release of both cargoes when triggered by glutathione (GSH) rich environments in cytoplasm. Results of in-vivo and in-vitro testing indicated successful co-encapsulation of hydrophobic drugs and hydrophilic siRNA with adjustable ratios. Selective delivery to CD44 overexpressing tumors was achieved through passive and active targeting, followed by HAase-triggered HA de-shielding and GSH-triggered burst release of both cargos. Rapid intracellular trafficking maximized synergistic cytotoxicities of chemotherapeutics and siRNA for remarkable tumor inhibition in a xenograft animal tumor model. Consequently, the HA-PSR nanoparticle holds great potential for combined chemotherapeutics/siRNA treatment in cancer with maximized synergistic antitumor efficacy.

Metastasis is a major cause of chemotherapeutic failure and death. Degradation of a specific component of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) affects the physical barrier of the tumor microenvironment (TME) and induces metastasis. Here, lysolipid-containing thermosensitive liposomes (LTSLs) were prepared to deliver an MMP inhibitor, marimastat (MATT), to the TME to inhibit MMP activity and expression. LTSLs rapidly released their payloads at 42 °C. Compared with the saline control, MATT-LTSLs exhibited enhanced accumulation in the tumor and a 20-fold decrease in tumor growth in 4T1 tumor-bearing mice; moreover, MATT-LTSLs reduced MMP-2 and MMP-9 activity by 50% and 43%, respectively, and downregulated MMP-2 and MMP-9 expression in vivo by 30% and 43%, respectively. Most importantly, MATT-LTSL treatment caused a 7-fold decrease in metastatic lung nodules and a 6-fold reduction in microvessels inside the tumor. We believe this study provides an effective approach for the suppression of metastasis, and the use of a cytotoxic agent in combination with MATT is a potential strategy for metastatic cancer treatment.

The treatment of metastatic cancer is a great challenging issue throughout the world. Conventional chemotherapy can kill the cancer cells and, whereas, would exacerbate the metastasis and induce drug resistance. Here, a new combinatorial treatment strategy of metastatic cancer was probed via subsequentially dosing dual nanomedicines, marimastat‐loaded thermosensitive liposomes (MATT‐LTSLs) and paclitaxel nanocrystals (PTX‐Ns), via intravenous and intratumoral injection. First, the metastasis was blocked and cancer cells were locked in the tumor microenvironment (TME) by delivering the matrix metalloproteinase (MMP) inhibitor, MATT, to the tumor with LTSLs, downregulating the MMPs by threefold and reducing the degradation of the extracellular matrix. And then, the “locked” cancer cells were efficiently killed via intratumoral injection of the other cytotoxic nanomedicine, PTX‐Ns, along with no metastasis and 100% inhibition of tumor growth. This work highlights the importance of the TME's integrity in the chemotherapy duration. We believe this is a generalized strategy for cancer treatment and has potential guidance for the clinical administration.

Ineffective drug delivery and poor prognosis are two major challenges in the treatment of pancreatic ductal adenocarcinoma (PDAC). While there is significant downregulation of tumor suppressor microRNA-34a (miR-34a), which targets many oncogenes related to proliferation, apoptosis, and invasion, high expression level of Polo-like kinase 1 (PLK1) is closely associated with short survival rates of pancreatic cancer patients. Therefore, the objective is to codeliver miR-34a mimic and small molecule PLK1 inhibitor volasertib (BI6727) using poly(ethylene glycol)–poly[aspartamidoethyl(p-boronobenzyl)diethylammonium bromide] (PEG-B-PAEBEA). This polymer could self-assemble into micelles of ~100 nm with 10% drug loading of volasertib and form a complex with miR-34a at the N/P ratio of 18 and higher. Combination treatment of volasertib and miR-34a displayed the synergistic effect and superior antiproliferative activity along with an enhanced G(2)/M phase arrest and suppression of colony formation, leading to cell death due to potential c-myc targeting therapeutics. Orthotopic pancreatic tumor bearing NSG mice were scanned for fluorescence by IVIS after systemic administration of micelles encapsulating volasertib and miR-34a at doses of 5 and 1 mg/kg, respectively. Cy5.5 concentration in plasma and major organs was determined by measuring fluorescence intensity. There was significant reduction in tumor volume, and histological examination of major organs suggested negligible systemic toxicity. In conclusion, PEG-B-PAEBEA micelles carrying volasertib and miR-34a mimic have the potential to treat pancreatic cancer.

The drug nanocrystals (NCs) with unique physicochemical properties are now considered as a promising drug delivery system for poorly water-soluble drugs. So far >20 formulations of NCs have been approved in the market. In this review, we summarized recent advances of NCs with emphasis on their therapeutic applications based on administration route and disease states. At the end, we present a brief description of the future perspectives of NCs and their potential role as a promising drug delivery system. As a strategy for solubilization and bioavailability enhancement, the NCs have gained significant success. Besides this, the function of NCs is still far from developed. The emerging NC-based drug delivery approach would widen the applications of NCs in drug delivery and bio-medical field. Their in vitro and in vivo fate is extremely unclear; and the development of hybrid NCs with environment-sensitive fluorophores may assist to extend the scope of bio-imaging and provide better insight to their intracellular uptake kinetics, in vitro and in vivo.

A redox-sensitive micellar system constructed from an O,N-hydroxyethyl chitosan-octylamine (HECS-ss-OA) conjugate with disulfide linkages between the hydrophobic alkyl chains and hydrophilic chitosan backbone was synthesized for triggered intracellular delivery of hydrophobic paclitaxel (PTX). In aqueous environments, conjugates formed micelles with high PTX loading (30%). Mechanistically, the sensitivity of HECS-ss-OA micelles to reducing environments was investigated using the parameters of in vitro release and particle size. Intracellular release of nile red fluorescence alongside cytotoxicity studies further confirmed the potency of redox-sensitive micelles for intracellular drug delivery compared with redox-insensitive micelles. Additionally, an in vivo study confirmed the efficacy of PTX-loaded micelles in tumor-bearing mice with superior antitumor efficacy and diminished systemic toxicity when compared with the redox-insensitive micelles and a PTX solution. These results demonstrate the potential of redox-sensitive HECS-ss-OA micelles for intracellular trafficking of lipophilic anticancer drugs.

Deoxypodophyllotoxin (DPT) is a new potential anti-tumor drug with nearly no water solubility and low permeability. Hence, we prepared a poly (ethylene glycol)-distearoylphosphatidylethanolamine (PEG-DSPE) modified long-circulation liposomes for enhanced solubility and anti-tumor capacity of DPT with clinical expectation. DPT-loaded long-circulation liposomes (DPT-LCLPs) were prepared by thin-film dispersion method, and characteristics including particle size, zeta potential and entrapment efficiency of re-dissolution after lyophilization were 110.5 ± 4.5 nm, −15.06 ± 1.14 mV, and 92.45 ± 5.21 %, respectively. TEM images showed that DPT-LCLPs appeared as spherical or ellipsoidal in shape with multilayer membrane. Moreover, sensitive liquid chromatography method was developed for quantification of DPT concentration in rat plasma with diazepam as internal standard (IS), and the results revealed that two-compartment intravenous model analysis was better with respect to data fitted by Kinetica 4.4 program. The terminal phase half-life (T 1/2β) of DPT-LCLPs group was estimated to be approximately 155 min; AUC0−τ was more than three times higher than that of control group, demonstrating a prolonged circulation time due to PEG modification. In vivo investigation on Heps tumor-xenografted mice, DPT-LCLPs group indicated higher anti-tumor efficacy with dose-dependence, comparing to Etoposide and control group. PEG-modified liposomes highly improved the solubility and blood circulation of DPT with simple preparation for potentially enhanced anti-cancer therapy.

Docetaxel (DTX) has profound effects on several hepatic cancer (HC) cells, but shows unsatisfactory clinical efficacy due to the lack of tumor specificity and p-gp mediated drug efflux. Herein, a novel targeted drug delivery nanosystem based on hyaluronic acid (HA) and quercetin (QU) was designed to improve the in vivo therapeutic efficacy of DTX on HC through HA-CD44 mediated targeting and QU-based p-gp efflux inhibition. DTX-loaded HA–QU polymeric micelles (DTX/HA–QU PMs) displayed a mean particle size of 176.8 ± 3.4 nm with a low polydispersity index (

PEG coating was regarded as one effective method to improve the tumor-targeting efficiency of hyaluronic acid-based nanoparticles (HBN). However, the research of interaction between PEG coating and different receptors such as stabilin-2 and CD44 was limited. Herein, we synthesized a series of PEGylated hyaluronic acid with Curcumin (PHCs) to evaluate the role of PEG coating density in the interaction between HA and its receptors, which influenced tissues targeting activity, pharmacokinetic profiles and therapeutic efficacy of HBN. Compared with other counterparts, PHC HBN with about 5% PEG coating density preferably accumulated in the tumor mass, rather than in the liver, and hold desirable anti-cancer effect. These results indicated that to obtain optimized anticancer effect of HBN, the cellular uptake efficiency between different types of the cells should be carefully balanced by different PEG densities.

Cold is a global common infectious disease accompanied by symptoms such as headache and stuffy nose. Ibuprofen (IBU) and phenylephrine hydrochloride (PE) were commonly used for common cold due to their different effects in relieving fever and the main symptoms such as nasal congestion and high sinus pressure. However, the commercial tablets of IBU and PE have to be administered 2 to 3 times per day due to their short half-life, with inconvenience for patient and fluctuations of plasma concentration. Bilayer tablet technology was utilized to design the IBU-PE sustained release tablets because of the significantly different solubility of IBU and PE in release media. The formulations of IBU layer and PE layer contain different viscosity grades of hydroxypropyl methylcellulose (HPMC) as sustained-release matrix, hydrophilic diluent, and traditional glidant and lubricant. The sustained release bilayer tablet exhibited satisfying sustained release performance with the mechanisms of diffusion and matrix erosion. Compared with the conventional tablets, the IBU-PE sustained release bilayer tablet expressed significantly sustained-release behavior with decreased Cmax and prolonged Tmax in fasted conditions for IBU and PE. Though IBU of IBU-PE sustained release bilayer tablet was bioequivalent to the commercial IBU tablet, the relative bioavailability of PE from the bilayer tablets was 87.49 ± 20.00% (90% confidence interval was 72.3 to 102.5%), indicating bioinequivalence probably due to the “first pass” effect.

The present study intended to prepare orally disintegrating film (ODF) containing donepezil (DP) for the treatment of mild to moderate alzheimer disease. HPMC and HPC, glycerine were used as film forming agents, plasticizer, respectively. The ODFs were prepared by solvent casting method. The method was optimized with full factorial design considering the amount of film forming agents, the proportion of HPMC: HPC, amount of plasticizer as independent variables and tensile strength, elongation, folding endurance and disintegration time as dependent variables. Furthermore the studies of mechanical, drug release and bioavailability of the optimized DP-loading ODF formulation were performed. The results indicated the prepared film hold uniform, smooth film surface, non-sticky and disintegrated within 30 s, and over 85% of the drug dissolved in the first 5 min. And there was no significant difference between the optimized ODF formulation and the marketed one in cmax, tmax and AUC0-t.Current study suggested the optimized ODF formulation will be an effective alternative for commercially available dosage forms for the treatment of Alzheimer's diseases.

Nanoparticle drug delivery system improves the therapeutic efficacy of a drug; however, achieving sustained release from nanoparticles is challenging, owing to the increase of surface area and pronounced burst release. In this study, by incorporating an organogel of 12-hydroxystearic acid (12-HSA) into lipid-bilayers, a gel-liposomal formulation was developed to sustain drug release over time. The lipid-bilayer-coated nanogels (LBCNs) with a particle size of approximately 200 nm and with a core-shell structure had an entrapment efficiency of up to 80% for paclitaxel. LBCNs could continually release both hydrophobic and water-soluble drugs over time. Interestingly, the incorporation of organogel enhanced the cellular uptake of liposomes significantly and, accordingly, enabled improved cytotoxicity of chemotherapy agent against the cancer cells. In conclusion, by formulating the organogel into the lipid bilayers, gel-liposomes were developed, allowing for sustained drug release, improved internalization and the resultant enhancement of cytotoxicity of chemotherapy agent to cancer cells.