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The exemplary progress of silica nanotechnology has attracted extensive attention across a range of biomedical applications such as diagnostics and imaging, drug delivery, and therapy of cancer and other diseases. Ultrasmall silica nanoparticles (USNs) have emerged as a particularly promising class demonstrating unique properties that are especially suitable for and have shown great promise in translational and clinical biomedical research. In this review, we discuss synthetic strategies that allow precise engineering of USNs with excellent control over size and surface chemistry, functionalization, and pharmacokinetic and toxicological profiles. We summarize the current state-of-the-art in the biomedical applications of USNs with a particular focus on select clinical studies. Finally, we illustrate long-standing challenges in the translation of inorganic nanotechnology, particularly in the context of ultrasmall nanomedicines, and provide our perspectives on potential solutions and future opportunities in accelerating the translation and widespread adoption of USN technology in biomedical research.

Theranostic nanoparticles hold the potential to greatly improve cancer management by providing personalized medicine. Although many theranostic nanoconstructs have been successful in preclinical studies, clinical translation is still hampered by their limited targeting capability and lack of successful therapeutic efficacy. We report the use of novel ultrasmall porous silica nanoparticles (UPSN) with enhanced in vivo pharmacokinetics such as high target tissue accumulation (12% ID/g in the tumor) and evasion from the reticuloendothelial system (RES) organs. Herein, UPSN is conjugated with the isotopic pair (90/86)Y, enabling both noninvasive imaging as well as internal radiotherapy. In vivo PET imaging demonstrates prolonged blood circulation and excellent tumor contrast with (86)Y-DOTA-UPSN. Tumor-to-muscle and tumor-to-liver uptake values were significantly high (12.4 ± 1.7 and 1.5 ± 0.5, respectively), unprecedented for inorganic nanomaterials. (90)Y-DOTA-UPSN significantly inhibits tumor growth and increases overall survival, indicating the promise of UPSN for future clinical translation as a cancer theranostic agent.

Although immune-checkpoint inhibitors have improved the survival of patients with various types of metastatic tumor, intra- and inter-patient heterogeneities in the response of multiple tumors to the therapy have significantly limited clinical benefits. Understanding the specific driving forces behind these heterogeneities will facilitate a better understanding of therapeutic resistance. Research has revealed that tumors in patients and established cancer cell lines are composed of multiple clones with different phenotypes. Our goal is to dissect these complexities and decipher mechanisms of tumor heterogeneities and resistance to immunotherapy. We have established single cell-derived clonal populations from parental, polyclonal 4T1, murine breast cancer cells. In vitro studies, while parental cells formed the heterogeneous types of colonies in a clonogenic assay, established clones created clone dependent uniform colonies. Each clone showed different growth rates, response to chemotherapy, and produced different amounts of cytokines. Then, 4T1 parental cells, clone 1, or clone 16 cells were injected into the spleen of mice to create multiple experimental liver metastases. Seven days after the inoculation, tumor-bearing mice were implanted with the window chamber above the liver, intravenously (iv) injected with fluorescently labeled anti-PDL1 IgG, and delivery of the antibody to individual liver metastasis was imaged using intravital microscopy (IVM). Then, mice were imaged using IVM for 7 days to determine the therapeutic effect on individual tumor growth. In another set of tumor-bearing mice, either isotype IgG or anti-PDL1 IgG were iv injected and the effect on the survival was evaluated. We found that the delivery of fluorescently labeled anti-PDL1 IgG and therapeutic effect was heterogeneous among liver metastases originated from 4T1 parental cells. We also found that there was an inverse correlation between the amount of the anti-PDL1 IgG delivered to the tumor and individual tumor growth. Liver metastases originated from clone 16 cells accumulated significantly more amount of the anti-PDL1 IgG and most of the tumors disappeared within 7 days. On the other hand, the anti-PDL1 IgG delivery to clone 1 cell-derived tumor was significantly reduced than parental and clone 16 cell-derived tumors and none of the tumors responded to the therapy. Thus, limited therapeutic efficacy can be attributed to the limited anti-PDL1 IgG delivery to the tumor. The survival of the tumor-bearing mice was correlated with the level of anti-PDL1 IgG delivery. While the anti-PDL1 therapy could extend the survival of mice-bearing clone 16 derived tumors, mice-bearing parental cells, and clone 1 cells didn’t respond to the therapy. To elucidate the mechanism for the difference in anti-PDL1 Ab delivery, the effect of the therapeutics on tumor growth, and survival, we evaluated the expression of PDL1 protein in tumors by immunohistochemical analysis. PDL1 expression was higher in clone 16 tumors compared to parental and clone 1 tumor. Next, we evaluated the amount of blood vessels in tumors, because the difference in the antibody delivery can be attributed to the amount of angiogenesis. Interestingly, there was no significant difference in the amount of blood vessels, indicating the expression level of the target protein is crucial to determine the amount of the antibody delivery. Regarding the immune microenvironment, there was no difference in the amount of CD8 cells inside tumors. Thus, heterogeneity in anti-PDL1 IgG delivery and its therapeutic efficacy was explained by heterogeneous PDL1 expression in polyclonal tumors. Evaluation of heterogeneity in PDL1 expression in the patient’s tumor shall be considered for personalizing the therapy. Citation Format: Yan ting Liu, Shreya Goel, Megumi Kai, Thao Nguyen, Kenji Yokoi. Heterogeneous tumor microenvironment in metastatic breast cancer for insufficient anti-PDL1 IgG delivery and its efficacy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-42.

The incidence of lung cancer has been increasing in the recent years. Bronchial cytology using Papanicolaou society of cytopathology (PSC) system is an effective method for triaging patients. The present study attempts to evaluate the bronchial cytological diagnosis with histopathological correlation of lung lesions.i. To study the cytological features of lung lesions. ii. To assess the sensitivity, specificity, and diagnostic accuracy of bronchial cytology of lung lesions in comparison with histopathology.Prospective study at the tertiary care hospital.It included 63 cases of lung lesions, evaluated using the PSC system for reporting respiratory cytology. The cytological diagnosis was correlated with the final histopathological diagnosis. The study was conducted between January 2019 and June 2020.SPSS 20.0 software.The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of bronchial cytology was 60%, 89%, 90%, 58.62%, and 71.42%, respectively.Bronchial cytology including bronchial wash, bronchial brush, endobronchial ultrasound/transbronchial needle aspiration, and computerized tomography-guided fine needle aspiration cytology can be used to increase the sensitivity and specificity for definitive diagnosis and better management.

Adrenal hemangiomas are rare vascular tumors. These are benign, mostly nonfunctioning and asymptomatic. Cavernous adrenal hemangiomas are more common in the elderly, with female preponderance. A computed tomography (CT) scan can diagnose their benign nature. Most cases are managed surgically, and laparoscopy is the most common approach followed nowadays.A young female presented with nausea, pain, and a vague mass palpable in the right abdomen. With CT findings favoring benign lesion or nonfunctioning adenoma but symptomatic, the patient had to undergo diagnostic laparoscopy and adrenalectomy. Adrenal hemangiomas are rare lesions. Moreover, involving a young female further makes their diagnosis difficult. Hence, they must be kept as one of the differential diagnosis in evaluation of adrenal mass in young females.

Recently, drug delivery systems based on nanotechnology have received great attention in cancer therapeutics and diagnostics since they can not only improve the treatment efficacy but also reduce the side effects. Among them, mesoporous silica nanoparticles (MSNs) with large surface area, high pore volume, tunable pore size, abundant surface chemistry, and acceptable biocompatibility exhibit unique advantages and are considered as promising candidates for cancer diagnosis and therapy. In this review, we update the recent progress on MSN-based systems for cancer treatment purposes. We also discuss the drug loading mechanism of MSNs, stimuli-responsive drug release, and surface modification strategies for improving biocompatibility, and targeting functionalities. STATEMENT OF SIGNIFICANCE: The development of MSN-based delivery systems that can be used in both diagnosis and treatment of cancer has attracted tremendous interest in the past decade. MSN-based delivery systems can improve therapeutic efficacy and reduce cytotoxicity to normal tissue. To further improve the in vivo properties of MSNs and potential translation to the clinics, it is critical to design MSNs with appropriate surface engineering and desirable cancer targeting. This review is intended to provide the readers a comprehensive background of the vast literature till date on silica-based drug delivery systems, and to inspire further innovations in silica nanomedicine in the future.

We sought to determine if Stephen Paget’s “seed and soil” hypothesis of organ-preference patterns of cancer metastasis can explain the development of heterogeneity in a tumor microenvironment (TME) as well as immunotherapeutic delivery and efficacy. We established single-cell-derived clones (clones 1 and 16) from parental 4T1 murine breast cancer cells to create orthotopic primary and liver metastasis models to deconvolute polyclonal complexity cancer cells and the difference in TME-derived heterogeneities. Tumor-bearing mice were treated with anti-PD-L1 IgG or a control antibody, and immunofluorescent imaging and quantification were then performed to evaluate the therapeutic efficacy on tumor growth, the delivery of therapy to tumors, the development of blood vessels, the expression of PD-L1, the accumulation of immune cells, and the amount of coagulation inside tumors. The quantification showed an inverse correlation between the amount of delivered therapy and therapeutic efficacy in parental-cell-derived tumors. In contrast, tumors originating from clone 16 cells accumulated a significantly greater amount of therapy and responded better than clone-1-derived tumors. This difference was greater when tumors grew in the liver than the primary site. A similar trend was found in PD-L1 expression and immune cell accumulation. However, the change in the number of blood vessels was not significant. In addition, the amount of coagulation was more abundant in clone-1-derived tumors when compared to others. Thus, our findings reconfirmed the seed- and soil-dependent differences in PD-L1 expression, therapeutic delivery, immune cell accumulation, and tumor coagulation, which can constitute a heterogeneous delivery and response of immunotherapy in polyclonal tumors growing in different organs.

Siliceous nanomaterials are attractive candidates for applications in cancer theranostics due to their precise synthesis control, ease of surface functionalization, accuracy of characterization, controllable release of cargo, and predictable pharmacokinetics. However, the inorganic silica core inherent to these nanomaterials has colloidal instability and can be cytotoxic, presenting notable challenges for their clinical translation. Surface coatings may be used to overcome this hurdle, by improving their stability, safety, and biological activity and thereby supporting their development for various biomedical applications. Out of the various surface coatings tested to date, lipid-based coatings have shown notable potential due to their biocompatibility and low immunogenicity, where lipids have demonstrated clinical success in the form of liposomal drug delivery systems. In this chapter, we will discuss lipid-coated siliceous nanomaterials, with an emphasis on the principles of lipid coating, the enhanced biocompatibility brought about by the lipid shell, and the use of lipid-coated silica nanoparticles in cancer therapy.

The design of effective nanoformulations that target metastatic breast cancers is challenging due to a lack of competent imaging and image analysis protocols that can capture the interactions between the injected nanoparticles and metastatic lesions. Here, we describe the integration of in vivo whole-body PET-CT with high temporal resolution, ex vivo whole-organ optical imaging and high spatial resolution confocal microscopy to deconstruct the trafficking of injectable nanoparticle generators encapsulated with polymeric doxorubicin (iNPG-pDox) in pulmonary metastases of triple-negative breast cancer. We describe the details of image acquisition and analysis in a step-wise manner along with the development of a mouse model for metastatic breast cancer. The methods described herein can be easily adapted to any nanoparticle or disease model, allowing a standardized pipeline for in vivo preclinical studies that focus on delineating nanoparticle kinetics and interactions within metastases.

Photodynamic therapy (PDT) by near-infrared (NIR) irradiation is a promising technique for treating various cancers. Here, we reported the development of free-standing wafer-scale Au nanosheets (NSs) that exhibited an impressive PDT effect. The Au NSs were synthesized by ionic layer epitaxy at the air-water interface with a uniform thickness in the range from 2 to 8.5 nm. These Au NSs were found very effective in generating singlet oxygen under NIR irradiation. In vitro cellular study showed that the Au NSs had very low cytotoxicity and high PDT efficiency due to their uniform 2D morphology. Au NSs could kill cancer cells after 5 min NIR irradiation with little heat generation. This performance is comparable to using 10 times mass loading of Au nanoparticles (NPs). This work suggests that two-dimensional (2D) Au NSs could be a new type of biocompatible nanomaterial for PDT of cancer with an extraordinary photon conversion and cancer cell killing efficiency.

We report a translational toolbox of multiscale imaging and mathematical modeling exploring nanoscale drug transport in metastases., It is challenging to design effective drug delivery systems (DDS) that target metastatic breast cancers (MBC) because of lack of competent imaging and image analysis protocols that suitably capture the interactions between DDS and metastatic lesions. Here, we integrate high temporal resolution of in vivo whole-body PET-CT, ex vivo whole-organ optical imaging, high spatial resolution of confocal microscopy, and mathematical modeling, to systematically deconstruct the trafficking of injectable nanoparticle generators encapsulated with polymeric doxorubicin (iNPG-pDox) in pulmonary MBC. iNPG-pDox accumulated substantially in metastatic lungs, compared to healthy lungs. Intratumoral distribution and retention of iNPG-pDox varied with lesion size, possibly induced by locally remodeled microenvironment. We further used multiscale imaging and mathematical simulations to provide improved drug delivery strategies for MBC. Our work presents a multidisciplinary translational toolbox to evaluate transport and interactions of DDS within metastases. This knowledge can be recursively applied to rationally design advanced therapies for metastatic cancers.

In the research article, “Molecular targeting of FATP4 transporter for oral delivery of therapeutic peptide” ( 1 ), we reported development of a chitosan nanoparticle-coated liposome …

While plasma concentration kinetics has traditionally been the predictor of drug pharmacological effects, it can occasionally fail to represent kinetics at the site of action, particularly for solid tumors. This is especially true in the case of delivery of therapeutic macromolecules (drug‐loaded nanomaterials or monoclonal antibodies), which can experience challenges to effective delivery due to particle size‐dependent diffusion barriers at the target site. As a result, disparity between therapeutic plasma kinetics and kinetics at the site of action may exist, highlighting the importance of target site concentration kinetics in determining the pharmacodynamic effects of macromolecular therapeutic agents. Assessment of concentration kinetics at the target site has been facilitated by non‐invasive in vivo imaging modalities. This allows for visualization and quantification of the whole‐body disposition behavior of therapeutics that is essential for a comprehensive understanding of their pharmacokinetics and pharmacodynamics. Quantitative non‐invasive imaging can also help guide the development and parameterization of mathematical models for descriptive and predictive purposes. Here, we present a review of the application of state‐of‐the‐art imaging modalities for quantitative pharmacological evaluation of therapeutic nanoparticles and monoclonal antibodies, with a focus on their integration with mathematical models, and identify challenges and opportunities. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseDiagnostic Tools > in vivo Nanodiagnostics and ImagingNanotechnology Approaches to Biology > Nanoscale Systems in Biology, Pharmacological evaluation of nanoparticles and antibodies performed through quantitative imaging‐guided mathematical models.

Targeting the FATP4 transporter is an effective way to transport peptides and enhance oral bioavailability of peptide drugs., Low oral bioavailability of peptide drugs has limited their application to parenteral administration, which suffers from poor patient compliance. Here, we show that molecular targeting of the FATP4 transporter is an effective approach to specifically transport long-chain fatty acid (LCFA)–conjugated peptides across the enterocytic membrane and, thus, enables oral delivery of drug peptides. We packaged LCFA-conjugated exendin-4 (LCFA-Ex4) into liposomes and coated with chitosan nanoparticles to form an orally deliverable Ex4 (OraEx4). OraEx4 protected LCFA-Ex4 from damage by the gastric fluid and released LCFA-Ex4 in the intestinal cavity, where LCFA-Ex4 was transported across the enterocyte membrane by the FAPT4 transporter. OraEx4 had a high bioavailability of 24.8% with respect to subcutaneous injection and exhibited a substantial hypoglycemic effect in murine models of diabetes mellitus. Thus, molecular targeting of the FATP4 transporter enhances oral absorption of therapeutic peptides and provides a platform for oral peptide drug development.

Porphyrin-based nanomaterials can inherently integrate multiple contrast imaging functionalities with phototherapeutic capabilities. We dispersed pheophytin (Pheo) into Pluronic F127 and carried out low-temperature surfactant-stripping to remove the bulk surfactant. Surfactant-stripped Pheo (ss-Pheo) micelles exhibited a similar size, but higher near-infrared fluorescence, compared to two other nanomaterials also with high porphyrin density (surfactant-stripped chlorophyll micelles and porphysomes). Singlet oxygen generation, which was higher for ss-Pheo, enabled photodynamic therapy (PDT). ss-Pheo provided contrast for photoacoustic and fluorescence imaging, and following seamless labeling with (64)Cu, was used for positron emission tomography. ss-Pheo had a long blood circulation and favorable accumulation in an orthotopic murine mammary tumor model. Trimodal tumor imaging was demonstrated, and PDT resulted in delayed tumor growth.

The present work explores the possible applications of co-sputtered titania(Ti)-zinc(Zn)-oxide nanocomposite-(nC) thin films to improve the bonding of metallic fixture with bone. As a proof of principle study, the nC-titania-zinc-oxide thin films have been deposited on Si-(100) substrates by reactive magnetron co-sputtering at various substrate temperatures. In vitro, static immersion test in Hanks Balanced Salt Solution reveals the ability of the composite films to encourage the formation of bone-like apatite. Results of the cytocompatibility tests with MG-63 human osteoblast and L929 mouse fibroblast cell lines demonstrate superior adhesion and proliferation ability on the nC-titania-zinc-oxide coated substrates as compared to uncoated ones. The developed films material was observed to strongly inhibit the growth of both Staphylococcus aureus and Escherichia coli. The microstructural, morphological and surface properties of the films were studied, using various characterization techniques. Overa...

Silica nanoparticles have been one of the most promising nanosystems for biomedical applications due to their facile surface chemistry and non-toxic nature. However, it is still challenging to effectively deliver them into tumor sites and noninvasively visualize their in vivo biodistribution with excellent sensitivity and accuracy for effective cancer diagnosis. In this study, we design a yolk/shell-structured silica nanosystem 64Cu-NOTA-QD@HMSN-PEG-TRC105, which can be employed for tumor vasculature targeting and dual-modality PET/optical imaging, leading to superior targeting specificity, excellent imaging capability and more reliable diagnostic outcomes. By combining vasculature targeting, pH-sensitive drug delivery, and dual-modality imaging into a single platform, as-designed yolk/shell-structured silica nanosystems may be employed for the future image-guided tumor-targeted drug delivery, to further enable cancer theranostics.

Radiolabeled nanoprobes for positron emission tomography (PET) imaging has received special attention over the past decade, allowing for sensitive, non-invasive, and quantitative detection of different diseases. The rapidly renal clearable nanomaterials normally suffer from a low accumulation in the tumor through the enhanced permeability and retention (EPR) effect due to the rapidly reduced concentration in the blood circulation after renal clearance. It is highly important to design radiolabeled nanomaterials which can meet the balance between the rapid renal clearance and strong EPR effect within a suitable timescale. Herein, renal clearable polyoxometalate (POM) clusters of ultra-small size (∼1 nm in diameter) were readily radiolabeled with the oxophilic 89Zr to obtain 89Zr-POM clusters, which may allow for efficient staging of kidney dysfunction in a murine model of unilateral ureteral obstruction (UUO). Furthermore, the as-synthesized clusters can accumulate in the tumor through EPR effect and self-assemble into larger nanostructures in the acidic tumor microenvironment for enhanced tumor accumulation, offering an excellent balance between renal clearance and EPR effect.

Multifunctional yolk/shell-structured hybrid nanomaterials have attracted increasing interest as theranostic nanoplatforms for cancer imaging and therapy. However, because of the lack of suitable surface engineering and tumor targeting strategies, previous research has focused mainly on nanostructure design and synthesis with few successful examples showing active tumor targeting after systemic administration. In this study, we report the general synthetic strategy of chelator-free zirconium-89 (89Zr)-radiolabeled, TRC105 antibody-conjugated, silica-based yolk/shell hybrid nanoparticles for in vivo tumor vasculature targeting. Three types of inorganic nanoparticles with varying morphologies and sizes were selected as the internal cores, which were encapsulated into single hollow mesoporous silica nanoshells to form the yolk/shell-structured hybrid nanoparticles. As a proof-of-concept, we demonstrated successful surface functionalization of the nanoparticles with polyethylene glycol, TRC105 antibody (specific forCD105/endoglin), and 89Zr (a positron-emitting radioisotope), and enhanced in vivo tumor vasculature-targeted positron emission tomography imaging in 4T1murine breast tumor-bearing mice. This strategy could be applied to the synthesis of other types of yolk/shell theranostic nanoparticles for tumor-targeted imaging and drug delivery.

Manganese-based nanoparticles (NPs) have recently attracted much attention in the field of biomedical imaging due to their impressive enhanced T1 contrast ability. Although the reported manganese-based NPs have exhibited good imaging capabilities as contrast agents, it is still urgent to develop novel multifunctional manganese-based imaging probes for future biomedical imaging, especially PET/MRI probes. Herein, we present chelator-free zirconium-89 (89Zr, t1/2: 78.4 h) labeling of manganese oxide NPs (Mn3O4@PEG) with ~78% labeling yield and good stability. Serial positron emission tomography (PET) and magnetic resonance imaging (MRI) studies non-invasively assessed the biodistribution patterns of the NPs and the feasibility of in vivo dual-modality imaging and lymph-node mapping. Since Mn3O4 NPs exhibited desirable properties for enhanced T1 imaging and the simplicity of chelator-free radiolabeling, [89Zr]Mn3O4@PEG NPs offer a novel, simple, safe and accurate nanoplatforms for future precise cancer imaging and diagnosis.

Mesoporous silica nanoshell (MSN) coating has been demonstrated as a versatile surface modification strategy for various kinds of inorganic functional nanoparticles , such as gold nanorods (GNRs), to achieve not only improved nanoparticle stability but also concomitant drug loading capability. However, limited drug loading capacity and low tumor accumulation rate in vivo are two major challenges for the biomedical applications of MSN-coated GNRs (GNR@MSN). In this study, by coating uniformly sized GNRs with MSN in an oil-water biphase reaction system, we have successfully synthesized a new bacteria-like GNR@MSN (i.e., bGNR@MSN) with a significantly enlarged pore size (4–8 nm) and surface area (470 m 2 /g). After PEGylation and highly efficient loading of doxorubicin (DOX, 40.9%, w/w), bGNR@MSN were used for positron emission tomography (PET, via facile and chelator-free 89Zr-labeling) and photoacoustic imaging-guided chemo-photothermal cancer therapy in vivo. PET imaging showed that 89Zr-labeled bGNR@MSN(DOX)-PEG can passively target to the 4T1 murine breast cancer-bearing mice with high efficiency (∼10 %ID/g), based on enhanced permeability and retention effect. Significantly enhanced chemo-photothermal combination therapy was also achieved due to excellent photothermal effect and near-infrared-light-triggered drug release by bGNR@MSN(DOX)-PEG at the tumor site. The promising results indicate great potential of bGNR@MSN-PEG nanoplatforms for future cancer diagnosis and therapy.

Background: Cervical cancer is amongst the leading causes of deaths due to cancer in developing countries. Moreover, preinvasive lesions of the cervix have a long latency period for conversion into malignancy and are also detectable by screening techniques. Hence, colposcopy in addition to cytology should be carried out wherever facility is available to ensure early detection and timely management.Methods: Simultaneous cytology and colposcopy was done for 80 women with symptomatic cervical erosion followed by a colposcopic directed biopsy in women with MRCI >3. Finally, correlation between cytology, colposcopy and histopathological results was done.Results: 65/80 women were biopsied. 12/80 women had MRCI >6 amongst which 10/80 were confirmed to have a high grade lesion on histopathology. 13/80 had lesser abnormalities (ASCUS and LSIL) amongst which 3/80 had CIN1 on histopathology. Only 2/80 had HSIL on cytology as compared to 8/80 on histopathology that had CIN 2/3. Lastly, only 1/80 had SCC on cytology compared to 2/80 on histopathology. The sensitivity, specificity, PPV and NPV of cytology and colposcopy for diagnosing cervical dysplasia was 46.1%, 83.5%, 35.2%, 88.8% and 84.6%, 86.5%, 55%, 96.6% respectively making colposcopy a better screening tool than cytology for evaluating cervical malignancy.Conclusions: Colposcopic examination should ideally be carried out in all women with symptomatic cervical erosion in addition to cytology. Moreover, suspicious areas should be biopsied even if cytology is normal to exclude malignancy.

Radiotherapy is a vitally important strategy for clinical treatment of malignant cancers. Therefore, rational design and development of radiosensitizers that could enhance radiotherapeutic efficacy has attracted tremendous attention. Antiangiogenic therapy could be a potentially effective strategy to regulate tumor growth and metastasis since angiogenesis plays a pivotal role in tumor growth, invasion and metastasis to other organs. Herein, we have rationally designed a smart and effective nanosystem by combining ultrasmall selenium nanoparticles and bevacizumab (Avastin™, Av), for simultaneous radiotherapy and antiangiogenic therapy of cancer. The nanosystem was further coated with red blood cell (RBC) membranes to develop the final construct, RBCs@Se/Av. The RBC membrane coating effectively prolongs the blood circulation time and reduces the elimination of the nanosystem by autoimmune responses. As expected, RBCs@Se/Av, when irradiated with X-rays demonstrated potent anticancer and antiangiogenic responses in vitro and in vivo, as evidenced by the strong inhibition of A375 tumor growth in nude mice, without causing any obvious histological damage to the non-target major organs. Taken together, this study demonstrates an effective strategy for the design of a smart Se-based nanosystem decorated with the RBC membrane for simultaneous cancer radiosensitization and precise antiangiogenesis.

Doxorubicin (Dox)-loaded stealth liposomes (similar to those in clinical use) can incorporate small amounts of porphyrin–phospholipid (PoP) to enable chemophototherapy (CPT). PoP is also an intrinsic and intrabilayer 64Cu chelator, although how radiolabeling impacts drug delivery has not yet been assessed. Here, we show that 64Cu can radiolabel the stable bilayer of preformed Dox-loaded PoP liposomes with inclusion of 1% ethanol without inducing drug leakage. Dox-PoP liposomes labeled with intrabilayer copper behaved nearly identically to unlabeled ones in vitro and in vivo with respect to physical parameters, pharmacokinetics, and CPT efficacy. Positron emission tomography and near-infrared fluorescence imaging visualized orthotopic mammary tumors in mice with passive liposome accumulation following administration. A single CPT treatment with 665 nm light (200 J/cm2) strongly inhibited primary tumor growth. Liposomes accumulated in lung metastases, based on NIR imaging. These results establish the feasib...

Radiolabeling of molecules or nanoparticles to form imaging probes is critical for positron emission tomography (PET) imaging, which, with high sensitivity and the ability for quantitative imaging, has been widely used in the clinic. While conventional radiolabeling often employs chelator molecules, a general method for chelator-free radiolabeling of a wide range of materials remains to be developed. Herein, we uncovered that ten different types of metal oxide (MxOy, M=Gd, Ti, Te, Eu, Ta, Er, Y, Yb, Ce, or Mo, x=1–2, y=2–5) nanomaterials with polyethylene glycol (PEG) modification could be labeled with 89Zr, a PET tracer, via a simple yet general chelator-free radiolabeling method upon simple mixing. High labeling yields and good serum stabilities are achieved with this method, owing to the strong bonding between oxyphilic 89Zr4+ with oxygen atoms on the MxOy surface. Selecting 89Zr-Gd2O3-PEG as a multimodal imaging probe, we have successfully demonstrated in vivo PET imaging of draining lymph nodes, which are also visualized under magnetic resonance imaging, showing advantages over free 89Zr in the mapping of draining lymph node networks. Our work describes a general and simple method for chelator-free radiolabeling of metal oxide nanostructures, which is promising for the development of multifunctional nanoprobes in biomedical imaging.

Increased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely applicable target for targeted radioimmunotherapy. The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with DTPA for radiolabeling with 177Lu (t 1/2 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: 177Lu only, TRC105 only, 177Lu-DTPA-IgG (a nonspecific antibody), 177Lu-DTPA-TRC105 low-dose, and 177Lu-DTPA-TRC105 high-dose. Toxicity of the agent was monitored by body weight measurements and analysis of blood markers. Biodistribution studies of 177Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after injection of high-dose 177Lu-DTPA-TRC105. Biodistribution studies indicated steady uptake of 177Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days after injection (14.3 ± 2.3%ID/g and 11.6 ± 6.1%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high-dose group, with a corresponding significant increase in survival (p

Rapid sequestration and prolonged retention of intravenously injected nanoparticles by the liver and spleen (reticuloendothelial system (RES)) presents a major barrier to effective delivery to the target site and hampers clinical translation of nanomedicine. Inspired by biological macromolecular drugs, synthesis of ultrasmall (diameter ~12 −15 nm) porous silica nanoparticles (UPSNs), capable of prolonged plasma half-life, attenuated RES sequestration, and accelerated hepatobiliary clearance, is reported. The study further investigates the effect of tumor vascularization on uptake and retention of UPSNs in two mouse models of triple negative breast cancer (TNBC) with distinctly different microenvironments. A semi-mechanistic mathematical model is developed to gain mechanistic insights into the interactions between the UPSNs and the biological entities of interest, specifically the RES. Despite similar systemic pharmacokinetic (PK) profiles, UPSNs demonstrate strikingly different tumor responses in the two models. Histopathology confirmed the differences in vasculature and stromal status of the two models, and corresponding differences in the microscopic distribution of UPSNs within the tumors. The studies demonstrate the successful application of multidisciplinary and complementary approaches, based on laboratory experimentation and mathematical modeling, to concurrently design optimized nanomaterials, and investigate their complex biological interactions, in order to drive innovation and translation.

Cancer continues to be among the leading healthcare problems worldwide, and efforts continue not just to find better drugs, but also better drug delivery methods. The need for delivering cytotoxic agents selectively to cancerous cells, for improved safety and efficacy, has triggered the application of nanotechnology in medicine. This effort has provided drug delivery systems that can potentially revolutionize cancer treatment. Nanocarriers, due to their capacity for targeted drug delivery, can shift the balance of cytotoxicity from healthy to cancerous cells. The field of cancer nanomedicine has made significant progress, but challenges remain that impede its clinical translation. Several biophysical barriers to the transport of nanocarriers to the tumor exist, and a much deeper understanding of nano-bio interactions is necessary to change the status quo. Mathematical modeling has been instrumental in improving our understanding of the physicochemical and physiological underpinnings of nanomaterial behavior in biological systems. Here, we present a comprehensive review of literature on mathematical modeling works that have been and are being employed towards a better understanding of nano-bio interactions for improved tumor delivery efficacy.

Introduction: Assessing the tumor vasculature in models of pancreatic tumors can improve the characterization of these models, which can then support the eventual assessments of anti-cancer treatments. In this study, we sought to relate hypoxia, vascular perfusion, and vascular patency using synergistic imaging methods. In vivo Multispectral Optoacoustic Tomography (MSOT; also known as photoacoustic imaging) can measure %sO2 a relative measurement of oxy- vs. deoxy-hemoglobin in tumors. In vivo Dynamic Contrast Enhanced (DCE) MSOT can measure vascular perfusion. CryoVizTM imaging, a serial-sectioning-and-block-face-imaging technique, provides high-resolution 3D microscopic color anatomy and sensitive fluorescence making it ideal for assessing vascular perfusion by imaging ICG uptake and vascular patency by imaging Dylight488 lectin uptake. Methods: We performed MSOT and CryoVizTM imaging with subcutaneous tumor mouse models of SU.86.86 and MIA PaCa-2 pancreatic cancer. We performed MSOT with 21% O2 and 100% O2 carrier gas, which measures %sO2 (% oxyhemoglobin/total hemoglobin) as a biomarker of hypoxia. We performed DCE MSOT with 50 nmol indocyanine green (ICG), which measures Kapp (uptake rate from blood to tumor tissue) - a biomarker of vascular perfusion. To assess microvessel patency, we injected Dylight488 lectin via retro-orbital injection into the mice 3 min before euthanasia to enable CryoVizTM visualization of functional blood vessels. Subsequently, mice were euthanized, embedded in optimal cutting temperature (OCT) gel and flash-frozen in liquid nitrogen, and then imaged on the CryoVizTM. We acquired brightfield color anatomy, Dylight488 lectin (visible) fluorescence (ex: 460-490 nm, em>510nm) and ICG (NIR) fluorescence images (ex: 747/11 nm, em: >790nm) with an in-plane resolution of 10.232µm and a section thickness of 40 µm. Results: The in vivo MSOT analysis indicated that the MIA PaCa-2 model was more hypoxic than the SU.86.86 model, based on lower %sO2 measurements with both carrier gases. The in vivo DCE MSOT analysis indicated that the MIA PaCa-2 model had greater vascular perfusion than SU.86.86, based on a higher Kapp value. CryoVizTM images showed higher levels of lectin and ICG fluorescence in MIA PaCa-2 as compared to SU.86.86, indicating greater vascular patency and perfusion in the former. A strong lectin signal was observed in the injection site (retro-orbital sinuses), and in the renal medulla. ICG was also found to be retained in the axillary lymph node in both MIA PaCa-2 and SU.86.86, and in the kidney/adrenal glands of the MIA PaCa-2 mouse. Conclusion: Together, these results confirmed that the MIA PACa-2 model had higher hypoxia, vascular perfusion, and vascular patency, demonstrating the relationship between hypoxia and angiogenesis. This study reveals the power of 3D CryoVizTM imaging as a gold standard validation tool in cancer imaging. Citation Format: Madhusudhana Gargesha, Shreya Goel, Bryan Scott, Mark D. Pagel, Debashish Roy. CryoVizTM and photoacoustic imaging for assessment of tumor vasculature in mouse models of pancreatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB239.

Heterogeneities in the response of tumors to immunotherapies have significantly limited clinical benefits. Understanding the specific driving forces behind the heterogeneities will facilitate a better understanding of therapeutic resistance. Research has revealed that tumors in patients and established cancer cell lines are composed of multiple clones. Therefore, we established single cell-derived clonal populations from parental, polyclonal 4T1 murine breast cancer cells. Our goal is to dissect these complexities and decipher mechanisms of tumor heterogeneities. We injected 4T1 parental, clone1, or clone 16 cells into the spleen to create multiple liver metastases. Tumor-bearing mice were treated with anti-PDL1 Ab or isotype control Ab, then the therapeutic effect on tumor size and survival were evaluated. In another set of mice, the window chamber was installed above the liver to image the tumors utilizing intravital microscopy. Also, fluorescently labeled anti-PDL1 Ab or control Ab was injected intravenously (iv) to image the accumulation of Ab into the individual tumor. Anti-PDL1 Ab therapy significantly inhibited clone 16 tumor growth and extended survival of the tumor-bearing mice compared to isotype control Ab. On the other hand, parental and clone 1 tumors did not respond to the anti-PDL1 Ab. Using IVM, we monitored individual tumor response to anti-PLD1 Ab for 7 days and correlated the response with the amount of fluorescently labeled anti-PDL1 Ab delivered to the tumor. The amount of iv injected anti-PDL1 Ab delivery was heterogeneous among the tumors originated from 4T1 parental cells. We found an inverse correlation between the amount of the Ab delivered to the tumor and tumor growth, indicating drug delivery dependent tumor response. Metastases originated from clone 16 cells accumulated more amount of the Ab with most tumors disappeared. While the amount of Ab delivered to clone 1 tumor was significantly lower than parental and clone 16 tumors, none of the clone 1 tumors responded. Thus, limited therapeutic efficacy can be attributed to the insufficient anti-PDL1 Ab delivery to the tumor. Immunohistochemical analysis of resected liver revealed that the expression of PDL1 in clone 16 tumors was significantly higher than parental and clone 1 tumor. On the other hand. The amount of immune cells (CD8 & F4/80) were slightly higher in clone 16 than parental and clone 1 tumors. Finally, we compared the amount of coagulation inside the tumor by imaging fibrinogen, which can reduce therapeutics delivery to tumors. Interestingly, the clone 1 tumor showed significantly more amount of coagulation. Evaluation of heterogeneity in PDL1 expression, tumor coagulation, and the immune microenvironment in the patient's tumor shall be considered for personalizing the therapy. Citation Format: Yan Ting Liu, Thao Nguyen, Shreya Goel, Megumi Kai, Haifa Shen, Kenji Yokoi. Effect of clone dependent difference in the metastatic tumor microenvironment of 4T1 breast cancer on anti-PDL1 antibody delivery & therapeutic efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2810.

Lateral aberrant ectopic thyroid is very rare, comprising only 1%–3% of all the ectopic thyroid tissue. Clinically, these lesions are mistaken for lymph node swelling or metastatic tumour. Primary carcinoma in lateral aberrant ectopic thyroid with normal active native thyroid is very uncommon. We report a case of papillary carcinoma in lateral aberrant ectopic thyroid tissue, with a completely normal native thyroid gland in a 53-year-old man, who presented with a massive swelling in the lateral aspect of the neck clinically and radiologically diagnosed as a malignant soft tissue tumour with differential diagnosis of malignant lymphoma. Fine needle aspiration cytology revealed metastatic papillary carcinoma. In toto excision of the soft tissue mass along with subtotal thyroidectomy was performed. Histology of the mass revealed papillary carcinoma of lateral aberrant ectopic thyroid, while the thyroid gland did not show evidence of malignancy. The postsurgical period was uneventful, and the patient underwent radioiodine ablation.

Traditional photodynamic therapy (PDT) requires external light to activate photosensitizers for therapeutic purposes. However, the limited tissue penetration of light is still a major challenge for this method. To overcome this limitation, we report an optimized system that uses Cerenkov radiation for PDT by using radionuclides to activate a well-known photosensitizer (Chlorin e6, Ce6). By taking advantage of hollow mesoporous silica nanoparticles (HMSNs) that can intrinsically radiolabel oxophilic zirconium-89 (89Zr, t1/2 = 78.4 h) radionuclide, as well as possess great drug loading capacity, Ce6 can be activated by Cerenkov radiation from 89Zr in the same nanoconstruct. In vitro cells viability experiments demonstrated dose-dependent cell deconstructions as a function of concentration of Ce6 and 89Zr. In vivo studies show inhibition of tumor growth when mice were subcutaneously injected with [89Zr]HMSN-Ce6 and histological analysis of tumor section showed damage to tumor tissues, implying that reactive oxygen species mediated the destruction. This study offers a way to use internal radiation source to achieve deep-seated tumor therapy without using any external light source for future applications.

While position emission tomography (PET) is an important molecular imaging technique for both preclinical research and clinical disease diagnosis/prognosis, chelator-free radiolabeling has emerged as a promising alternative approach to label biomolecules or nanoprobes in a facile way. Herein, starting from bottom-up synthesized WS2 nanoflakes, this study fabricates a unique type of WS2/WOx nanodots, which can function as inherent hard oxygen donor for stable radiolabeling with Zirconium-89 isotope (89Zr). Upon simply mixing, 89Zr can be anchored on the surface of polyethylene glycol (PEG) modified WS2/WOx (WS2/WOx-PEG) nanodots via a chelator-free method with surprisingly high labeling yield and great stability. A higher degree of oxidation in the WS2/WOx-PEG sample (WS2/WOx (0.4)) produces more electron pairs, which would be beneficial for chelator-free labeling of 89Zr with higher yields, suggesting the importance of surface chemistry and particle composition to the efficiency of chelator-free radiolabeling. Such 89Zr-WS2/WOx (0.4)-PEG nanodots are found to be an excellent PET contrast agent for in vivo imaging of tumors upon intravenous administration, or mapping of draining lymph nodes after local injection.

A gut imaging contrast agent would benefit from the following: 1) being edible and generally regarded as safe; 2) transiting stably through the intestine; and 3) activity in multiple modalities. We found that Chlorophyll-a (Chl), a plant pigment that is ubiquitous in human diets, was amenable to formulation in surfactant-stripped induced frozen micelles (ss-InFroMs). However, Chl ss-InFroM stability was limited in gastric conditions in vitro and in vivo. By demetallating Chl to generate pheophytin-a (Pheo), more stable ss-InFroms were obtained which exhibited complete fecal excretion following oral gavage without systemic absorption. Because ss-InFroms could be concentrated to high concentration during the low-temperature stripping of the loose Pluronic surfactant, Pheo ss-InFroMs were used for non-invasive photoacoustic computed tomography of the gut of mice. Unexpectedly, Pheo (but not Chl) ss-InFroms exhibited strong near infrared fluorescence, further enabling non-invasive fluorescence gut imaging. Since Pheo (but not Chl) could be chelated with exogenous metals, Pheo ss-InFroMs could be seamlessly post-labeled with 64Cu for whole body positron emission tomography. Taken together, these results underscore the potential for Pheo, as an edible material, to be re-formulated for higher-order multimodal gut imaging.

This paper shows the synopsis of digital watermarking, an important solution used for ensuring and assisting data authentication, security of digital media and protection of copyright. The Least Significant Bit (LSB) algorithm is used for Image Watermarking. LSB embeds the image into the original image. In this paper, the original image is compared with the watermarked image using two parameters that areMean Square Error (MSE) & Peak Signal to Noise Ratio (PSNR) . Further the image after watermarking is distorted with the Gaussian noise and then watermark is detected. Its analysis is done using MATLAB.

Pleomorphic carcinoma is a very rare subtype of pulmonary sarcomatoid carcinoma. It is an aggressive primary lung carcinoma that accounts for about

Endometriosis is a disease seen in 10-15% of reproductive age women, which involves the pelvic cavity. The urinary tract is affected in 1% cases of pelvic endometriosis, while 0.1-0.4% of ureteric endometriosis which is extremely rare. Ureteric endometriosis poses a diagnostic challenge, as it can be asymptomatic or can present as renal colic. It can lead to a severe burden on kidneys like hydroureteronephrosis, renal atrophy, and irreversible renal failure. Authors report an extremely rare case of ureteric endometriosis in a postmenopausal female, who presented with complaints of lower backache. Radiologically diagnosed as neoplastic ureteric stricture.

Multifunctional yolk/shell-structured hybrid nanomaterials have attracted increasing interest as theranostic nanoplatforms for cancer imaging and therapy. However, because of the lack of suitable surface engineering and tumor targeting strategies, previous research has focused mainly on nanostructure design and synthesis with few successful examples showing active tumor targeting after systemic administration. In this study, we report the general synthetic strategy of chelator-free zirconium-89 ((89)Zr)-radiolabeled, TRC105 antibody-conjugated, silica-based yolk/shell hybrid nanoparticles for in vivo tumor vasculature targeting. Three types of inorganic nanoparticles with varying morphologies and sizes were selected as the internal cores, which were encapsulated into single hollow mesoporous silica nanoshells to form the yolk/shell-structured hybrid nanoparticles. As a proof-of-concept, we demonstrated successful surface functionalization of the nanoparticles with polyethylene glycol, TRC105 antibody (specific forCD105/endoglin), and (89)Zr (a positron-emitting radioisotope), and enhanced in vivo tumor vasculature-targeted positron emission tomography imaging in 4T1murine breast tumor-bearing mice. This strategy could be applied to the synthesis of other types of yolk/shell theranostic nanoparticles for tumor-targeted imaging and drug delivery.