Accumulation In Tumor Tissue Research Articles

Biogenic polymer-encapsulated diosgenin nanoparticles: Biodistribution, pharmacokinetics, cellular internalization, and anticancer potential in breast cancer cells and tumor xenograft

Diosgenin (DGN) is a natural bioactive steroidal saponin from therapeutic herbs and it exhibits potential anticancer efficacy. Here, we report the preparation of poly lactide-co-glycolide (PLGA)-encapsulated diosgenin nanoparticles (PLGA-DGN NPs) and characterization of their physicochemical nature, and morphology as well as inspect their drug-loading capability, in vitro drug release, pharmacokinetics, bio-distribution, safety profile. The in vitro and in vivo antineoplastic activities of PLGA-DGN NPs were also examined against the MCF-7 breast cancer cell line and in the Ehrlich ascites carcinoma (EAC) tumor xenograft model, respectively. The results displayed an appropriate size (∼147 nm), spherical shape, and a narrow polydispersity index. The nanoparticles showed a high encapsulation efficacy (78%), loading capacity (8%), good colloidal stability, and an initial burst release at an acidic medium. The nanoparticles exhibited significant cytotoxic activity at their IC50 dose compared to diosgenin. PLGA-DGN NPs facilitated cellular internalization of DGN in human breast cancer MCF-7 cells and extended the blood circulation time showing an excellent pharmacokinetic profile. Bio-distribution study revealed that PLGA-DGN NPs could significantly enhance DGN accumulation in tumor tissue. The safety profile of the PLGA-DGN NPs was confirmed in histopathologic, hematologic, and immunologic parameters of Swiss albino mice. At the same time, an effective antiangiogenic, and antiproliferative potential of PLGA-DGN NPs were exhibited in mice tumor xenograft model by showing tumor regression and down-regulating CD31 and Ki-67 expression. Therefore, PLGA-DGN NPs could be utilized as a promising anticancer drug, opening up a new avenue for further research.

PD1 blockade alters cell-cycle distribution and affects 3'-deoxy-3'-[18F]fluorothymidine uptake in a mouse CT26 tumor model.

We previously reported that alterations of the tumor microenvironment (TME) by programmed death receptor-1 (PD1) blockade affected tumor glucose metabolism and tumor 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake. In cancer cells, high glycolysis allows cells to sustain rapid proliferation since glycolysis is closely related to the proliferation of cancer cells. Therefore, imaging of cellular proliferation may provide more detail of TME alterations. In this study, we investigated how TME alterations by PD1 blockade affects the uptake of 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT), which is a 18F-radiolabeled thymidine derivative and is taken up by proliferating cells. Mice inoculated with murine colon carcinoma CT26 cells were intraperitoneally administered an anti-PD1 antibody on Day 0, when the tumor volume exceeded 50 mm3, and Day 5. [18F]FLT-PET imaging was performed pre-treatment (Day 0) and post treatment (Day 7). Tumor infiltrating lymphocytes (TILs) were identified by flow cytometry. [18F]FLT accumulation and localization in tumor tissue was evaluated by autoradiography and immunohistochemistry. The cell-cycle distribution of tumors and CT26 cells exposed to cytokines (interleukin-2, interferon [INF]-γ, and tumor necrosis factor [TNF]-α) was analyzed by flow cytometry. PD1 blockade increased CD8+ and CD4+ T cells in tumor tissue and significantly suppressed tumor proliferation; however, tumor [18F]FLT uptake remained unchanged. Autoradiography and immunohistochemistry showed that [18F]FLT was mainly taken up by cancer cells, but not TILs. Flow cytometric analysis demonstrated that the population of cells in G2/M phase increased after PD1 blockade. Moreover, INF-γ and TNF-α significantly increased cells in G2/M phase in vitro. PD1 blockade-induced alteration of the TME increased CT26 tumor cells in the G2/M phase, which have high thymidine kinase 1 activity. Therefore, [18F]FLT is taken up by tumor cells even if tumor proliferation is suppressed. This observation may be useful for evaluating the response to immunotherapy.

Hydrothermal Synthesis and In Vivo Fluorescent Bioimaging Application of Eu3+/Gd3+ Co-Doped Fluoroapatite Nanocrystals.

In this study, Eu3+/Gd3+ co-doped fluoroapatitååe (Eu/Gd:FAP) nanocrystals were synthesized by the hydrothermal method as a fluorescent bioimaging agent. The phase composition, morphology, fluorescence, and biosafety of the resulting samples were characterized. Moreover, the in vivo fluorescent bioimaging application of Eu/Gd:FAP nanocrystals was evaluated in mice with subcutaneously transplanted tumors. The results showed that the Eu/Gd:FAP nanocrystals were short rod-like particles with a size of 59.27 ± 13.34 nm × 18.69 ± 3.32 nm. With an increasing F substitution content, the Eu/Gd:FAP nanocrystals displayed a decreased size and enhanced fluorescence emission. Eu/Gd:FAP nanocrystals did not show hemolysis and cytotoxicity, indicating good biocompatibility. In vivo fluorescent bioimaging study demonstrated that Eu/Gd:FAP nanocrystals could be used as a bioimaging agent and displayed stable fluorescence emitting in tumors, indicating an accumulation in tumor tissue due to the passive targeting ability. In addition, any adverse effects of Eu/Gd:FAP nanocrystals on major organs were not observed. This study shows that biocompatible rare earth co-doped FAP nanocrystals have the potential to be used as a bioimaging agent in vivo.

Intrinsically Disordered Protein Micelles as Vehicles for Convection-Enhanced Drug Delivery to Glioblastoma Multiforme.

Lipid and micelle-based nanocarriers have been explored for anticancer drug delivery to improve accumulation and uptake in tumor tissue. As an experimental opportunity in this area, our lab has developed a protein-based micelle nanocarrier consisting of a hydrophilic intrinsically disordered protein (IDP) domain bound to a hydrophobic tail, termed IDP-2Yx2A. This construct can be used to encapsulate hydrophobic chemotherapeutics that would otherwise be too insoluble in water to be administered. In this study, we evaluate the in vivo efficacy of IDP-2Yx2A by delivering a highly potent but water-insoluble cancer drug, SN38, into glioblastoma multiforme (GBM) tumors via convection-enhanced delivery (CED). The protein carriers alone are shown to elicit minimal toxicity effects in mice; furthermore, they can encapsulate and deliver concentrations of SN38 that would otherwise be lethal without the carriers. CED administration of these drug-loaded micelles into mice bearing U251-MG GBM xenografts resulted in slowed tumor growth and significant increases in median survival times compared to nonencapsulated SN38 and PBS controls.

Metal-Free Radical Dendrimers as MRI Contrast Agents for Glioblastoma Diagnosis: Ex Vivo and In Vivo Approaches

Simultaneously being a nonradiative and noninvasive technique makes magnetic resonance imaging (MRI) one of the highly required imaging approaches for the early diagnosis and follow-up of tumors, specifically for brain cancer. Paramagnetic gadolinium (Gd)-based contrast agents (CAs) are the most widely used ones in brain MRI acquisitions with special interest when assessing blood–brain barrier (BBB) integrity, a characteristic of high-grade tumors. However, alternatives to Gd-based contrast agents (CAs) are highly required to overcome their established toxicity. Organic radicals anchored on a dendrimer macromolecule surface (radical dendrimers) are promising alternatives since they also exhibit paramagnetic properties and can act as T1 CAs like Gd-based CAs while being organic species (mitigating concerns about toxic metal accumulation). Here, we studied the third generation of a water-soluble family of poly(phosphorhydrazone) radical dendrimers, with 48 PROXYL radical units anchored on their branches, exploring their potential of ex vivo and in vivo contrast enhancement in brain tumors (in particular, of immunocompetent, orthotopic GL261 murine glioblastoma (GB)). Remarkably, this radical species provides suitable contrast enhancement on murine GL261 GB tumors, which was comparable to that of commercial Gd-based CAs (at standard dose 0.1 mmol/kg), even at its 4 times lower administered dose (0.025 mmol/kg). Importantly, no signs of toxicity were detected in vivo. In addition, it showed a selective accumulation in brain tumor tissues, exhibiting longer retention within the tumor, which allows performing imaging acquisition over longer time frames (≥2.5 h) as opposed to Gd chelates. Finally, we observed high stability of the radicals in biological media, on the order of hours instead of minutes, characteristic of the isolated radicals. All of these features allow us to suggest that the G3-Tyr-PROXYL-ONa radical dendrimer could be a viable alternative to metal-based MRI contrast agents, particularly on MRI analysis of GB, representing, to the best of our knowledge, the first case of organic radical species used for this purpose and one of the very few examples of these types of radical species working as MRI CAs in vivo.

Tumor-microenvironment triggered signal-to-noise boosting nanoprobes for NIR-IIb fluorescence imaging guided tumor surgery and NIR-II photothermal therapy

High quantum yield quantum dots (QDs) with the emission in the sub-second near infrared window (NIR-IIb, 1500–1700 nm) can afford higher resolution, a deeper penetration depth and zero auto-fluorescence for bio-imaging. However, low tumor accumulation, the rapid renal clearance and potential toxicity impeding their biomedical applications. Here, we report a tumor microenvironment responsive hollowed virus-bionic MnO2 nanoshell with IR1061 loading in the cavity and QDs (PbS@CdS) anchoring on the surface for precise NIR-IIb fluorescence imaging guided tumor surgery and efficient NIR-II photothermal therapy. This QDs based nanoprobe could efficiently adhere on tumor cells to realize efficient tumor tissue accumulation. NIR-IIb fluorescence of tumor margin could be successfully delineating after extracellular weak acid triggered MnO2 biodegradation for IR1061 release with remarkable NIR-IIb signal-to-noise boosting. Then, it could facilitate complete dissection of various tumor models with the assistance of NIR-IIb fluorescence imaging. Moreover, the fascinating efficacy for micro-metastasis eradication via NIR-II photothermal effects can be achieved under NIR-IIb fluorescence imaging guidance. Specifically, in combination with negligible system toxicity, our nanoprobes showed great potential as a versatile NIR-IIb fluorescent imaging platform for precise tumor surgery and tumor therapy guidance for future clinical translation.

Abstract 2456: Mass spectrometry imaging reveals distinct differences in glycogen accumulation in lung tumors from Appalachian patients

Abstract Lung cancer is the leading cause of cancer related death in the United States, with patients from rural Appalachia having drastically higher incidence and mortality rates, driven by largely unknown mechanisms. Identifying molecular features that contribute to this health disparity is a critical step in lung cancer research that could lead to predictive biomarkers and personalized therapy for the Appalachia population. Recently, aberrant glycogen accumulation in lung tumors has been reported to promote lung cancer progression. However, the full clinical implications of dysregulated glycogen metabolism and its role in lung cancer health disparities has yet to be explored. Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) is a new and innovative technique that combines mass spectrometry with high resolution imaging, enabling the detection of hundreds of analytes with spatial distribution. We recently developed an advanced method to analyze glycogen content in formalin-fixed paraffin-embedded tissues using MALDI-MSI. With this technique, we analyzed glycogen chain length and glycogen phosphate content from tissue microarrays containing over 100 lung cancer patient samples banked at the University of Kentucky. Our patient cohort included adenocarcinoma and squamous cell carcinoma patients from Appalachian and non-Appalachian counties, with diverse cytopathological features. We found significant glycogen accumulation and higher glycogen phosphate content in lung tumor tissue compared to match normal lung across all patients. Further, we found glycogen accumulation is markedly high in adenocarcinoma patients compared to other lung cancer subtypes. Interestingly, Appalachian adenocarcinoma patients exhibit increased glycogen accumulation and higher glycogen phosphate content than patients from non-Appalachian counties. These data suggest differential glycogen accumulation is a unique feature of lung tumors from Appalachian adenocarcinoma patients. Our study highlights the potential clinical applications of MALDI-MSI for digital pathology, biomarker applications, and reveals molecular features that contribute to the health disparity in Appalachian lung cancer patients that warrant further molecular analysis. Citation Format: Michael D. Buoncristiani, Lindsey R. Conroy, Harrison Clarke, Lyndsay E. Young, Ramon C. Sun. Mass spectrometry imaging reveals distinct differences in glycogen accumulation in lung tumors from Appalachian patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2456.

Targeting CXCL5 in Pancreatic Cancer Cells Inhibits Cancer Xenograft Growth by Reducing Proliferation and Inhibiting EMT Progression.

Pancreatic cancer (PC) is the most lethal malignant tumor, with average survival period of about 10 months. C-X-C ligand 5 (CXCL5), an important chemokine for immune cell accumulation in tumor tissues, has been reported to be involved in a variety of human cancers. However, the exact role of CXCL5 in PC progression has not been well defined. The expression of CXCL5 in PC was analyzed based on online databases and clinical specimens immunohistochemical staining, and Western blotting of CXCL5 in PC cell lines and patient samples. The correlation between CXCL5 expression and prognosis in PC was explored. The role of CXCL5 in PC was investigated through in vitro and in vivo experiments. The expression of CXCL5 was significantly increased in PC tissues compared with that in pancreas tissues, and CXCL5 high expression predicts poor prognosis in PC patients. Further analyses demonstrated that overexpression of CXCL5 in PC cells was positively related to higher proliferation rate, higher migration ability, and higher EMT markers including SNAI2 and TWIST1 of tumor cells in vitro. Consistently, the knockdown of CXCL5 in PC cells harmed the proliferation rate, migration ability, and expression of EMT indexes of tumor cells in vitro. Importantly, knockdown of CXCL5 inhibited the growth of xenograft tumors in vivo. CXCL5 high expression predicts poor prognosis in PC patients. CXCL5 promotes PC cell growth and EMT process. Inhibition of CXCL5 may be a potential therapeutic approach for PC.

Construction of hyperbranched polysiloxane-based multifunctional fluorescent prodrug for preferential cellular uptake and dual-responsive drug release.

Hyperbranched polymers hold great promise in nanomedicine for their controlled chemical structures, sizes, multiple terminal groups and enhanced stability than linear amphiphilic polymer assemblies. However, the rational design of hyperbranched polymer-based nanomedicine with low toxic materials, selective cellular uptake, controlled drug release, as well as real-time drug release tracking remains challenging. In this work, a hyperbranched multifunctional prodrug HBPSi-SS-HCPT is constructed basing on the nonconventional aggregation-induced emission (AIE) featured hyperbranched polysiloxanes (HBPSi). The HBPSi is a biocompatible AIE macromolecule devoid of conjugates, showing a high quantum yield of 17.88% and low cytotoxicity. By covalently grafting the anticancer drug, 10-hydroxycamptothecin (HCPT), to the HBPSi through 3,3'-dithiodipropionic acid, HBPSi-SS-HCPT is obtained. The HBPSis demonstrate obvious AIE features and it turned to aggregation-caused quenching (ACQ) after grafting HCPT owing to the FRET behavior between HBPSi and HCPT in HBPSi-SS-HCPT. In addition to on-demand HCPT release in response to changes in environmental pH and glutathione, a series of in vitro and in vivo studies revealed that HBPSi-SS-HCPT exhibits enhanced accumulation in tumor tissues through the enhanced permeation and retention (EPR) effect and preferential cancer cell uptake by charge reversal, thus resulting in apoptotic cell death subsequently. This newly developed multifunctional HBPSi-SS-HCPT prodrug provides a biocompatible strategy for controlled drug delivery, preferential cancer cell uptake, on-demand drug release and enhanced antitumor efficacy.

MP06-19 ANTI-TUMOR EFFECT IN BLADDER CANCER MODEL OF TUMOR VASCULATURE-TARGETED 10 B DELIVERY MEDIATED BORON NEUTRON CAPTURE THERAPY

You have accessJournal of UrologyCME1 May 2022MP06-19 ANTI-TUMOR EFFECT IN BLADDER CANCER MODEL OF TUMOR VASCULATURE-TARGETED 10B DELIVERY MEDIATED BORON NEUTRON CAPTURE THERAPY Tohru Yoneyama, Shingo Hatakeyama, Mihoko Sutoh Yoneyama, Taku Yoshiya, Tsuyoshi Uemura, Takehiro Ishizu, Minoru Suzuki, Shingo Hachinohe, Shintaro Ishiyama, Motohiro Nonaka, Michiko N. Fukuda, and Chikara Ohyama Tohru YoneyamaTohru Yoneyama More articles by this author , Shingo HatakeyamaShingo Hatakeyama More articles by this author , Mihoko Sutoh YoneyamaMihoko Sutoh Yoneyama More articles by this author , Taku YoshiyaTaku Yoshiya More articles by this author , Tsuyoshi UemuraTsuyoshi Uemura More articles by this author , Takehiro IshizuTakehiro Ishizu More articles by this author , Minoru SuzukiMinoru Suzuki More articles by this author , Shingo HachinoheShingo Hachinohe More articles by this author , Shintaro IshiyamaShintaro Ishiyama More articles by this author , Motohiro NonakaMotohiro Nonaka More articles by this author , Michiko N. FukudaMichiko N. Fukuda More articles by this author , and Chikara OhyamaChikara Ohyama More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002523.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: p-Boronophenylalanine (10BPA) is a powerful 10B drug used in current clinical trials of BNCT. For BNCT to be successful, a high (500 mg/kg) dose of 10BPA must be administered over a few hours. Here, we report BNCT efficacy after rapid, ultralow-dose administration of either tumor vasculature-specific annexin A1-targeting IFLLWQR (IF7)-conjugated 10BPA or borocaptate sodium (10BSH). METHODS: IF7 conjugates of either 10B drugs intravenously injected into MBT2 bladder tumor-bearing mice and biodistribution of 10B in tumors and normal organs analyzed by prompt gamma-ray analysis. Therapeutic effect of IF7-10B drug-mediated BNCT was assessed by either MBT2 bladder tumor bearing C3H/He mice and YTS-1 tumor bearing nude mice. RESULTS: Intravenous injection of IF7C conjugates of either 10B drugs into MBT2 bladder tumor-bearing mice promoted rapid 10B accumulation in tumor tissues and suppressed tumor growth. Moreover, multiple treatments at ultralow (10–20 mg/kg) doses of IF7-10B drug-mediated BNCT significantly suppressed tumor growth in a mouse model of human YTS-1 bladder cancer, with increased Anxa1 expression in tumors and infiltration by CD8-positive lymphocytes. Our findings suggest BNCT treatment induces an immune response by the host against tumor cells, triggering a strong cytotoxic reaction and also inflammatory and immune responses that increase after BNCT upregulate Anxa1 expression in tumor tissues. Moreover, we hypothesize that if the first BNCT treatment upregulates Anxa1 in tumor tissues due to an inflammatory response or induced immunogenicity, more effective 10B accumulation in tumor tissues might occur following the second injection of IF7-10B drugs. Thus, multiple ultralow doses of IF7-10B drug-mediated BNCT likely boost BNCT therapeutic potential. CONCLUSIONS: We conclude that IF7 serves as an efficient 10B delivery vehicle by targeting bladder tumor tissues via the tumor vasculature and could serve as a relevant vehicle for BNCT drugs. Source of Funding: This study was supported by a Center of Innovation program grant for the young scientist collaborative research fund project (no. R02W16) from the Japan Science and Technology Agency and supported by the Japan Society for the Promotion of Science KAKENHI (grants nos. 17K11119, 20K09517, and 19H05556). The study was also supported by the Kobayashi Foundation for Cancer Research and by the Aomori Prefecture Quantum Science Center © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e84 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tohru Yoneyama More articles by this author Shingo Hatakeyama More articles by this author Mihoko Sutoh Yoneyama More articles by this author Taku Yoshiya More articles by this author Tsuyoshi Uemura More articles by this author Takehiro Ishizu More articles by this author Minoru Suzuki More articles by this author Shingo Hachinohe More articles by this author Shintaro Ishiyama More articles by this author Motohiro Nonaka More articles by this author Michiko N. Fukuda More articles by this author Chikara Ohyama More articles by this author Expand All Advertisement PDF DownloadLoading ...

Mass Spectrometry Imaging Reveals Distinct Differences in Glycogen Accumulation in Lung Tumors from Appalachian Patients

Lung cancer is the leading cause of cancer related death in the United States, with patients from rural Appalachia having drastically higher incidence and mortality rates, driven by largely unknown mechanisms. Identifying molecular features that contribute to this health disparity is a critical step in lung cancer research that could lead to predictive biomarkers and personalized therapy for the Appalachia population. Recently, aberrant glycogen accumulation in lung tumors has been reported to promote lung cancer progression. However, the full clinical implications of dysregulated glycogen metabolism and its role in lung cancer health disparities has yet to be explored. Matrix‐assisted laser desorption/ionization‐mass spectrometry imaging (MALDI‐MSI) is a new and innovative technique that combines mass spectrometry with high resolution imaging, enabling the detection of hundreds of analytes with spatial distribution. We recently developed an advanced method to analyze glycogen content in formalin‐fixed paraffin‐embedded tissues using MALDI‐MSI. With this technique, we analyzed glycogen chain length and glycogen phosphate content from tissue microarrays containing over 100 lung cancer patient samples banked at the University of Kentucky. Our patient cohort included adenocarcinoma and squamous cell carcinoma patients from Appalachian and non‐Appalachian counties, with diverse cytopathological features. We found significant glycogen accumulation and higher glycogen phosphate content in lung tumor tissue compared to match normal lung across all patients. Further, we found glycogen accumulation is markedly high in adenocarcinoma patients compared to other lung cancer subtypes. Interestingly, Appalachian adenocarcinoma patients exhibit increased glycogen accumulation and higher glycogen phosphate content than patients from non‐Appalachian counties. These data suggest differential glycogen accumulation is a unique feature of lung tumors from Appalachian adenocarcinoma patients. Our study highlights the potential clinical applications of MALDI‐MSI for digital pathology, biomarker applications, and reveals molecular features that contribute to the health disparity in Appalachian lung cancer patients that warrant further molecular analysis.

CD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor for which there are no screening methods sensitive enough to facilitate early, effective intervention. We propose targeting the neuroendocrine tumor neoantigen CD133 via antibody-based early detection and PET (immunoPET) to facilitate earlier and more accurate detection of SCLC. Methods: RNA sequencing datasets, immunohistochemistry, flow cytometry, and Western blots were used to quantify CD133 expression in healthy and SCLC patients. CD133 was imaged invivo using near-infrared fluorescence (NIRF) immunoimaging, and 89Zr immunoPET. Anti(α)-CD133 autoantibody levels were measured in SCLC patient plasma using antibody microarrays. Results: Across 6 publicly available datasets, CD133 messenger RNA was found to be higher in SCLC tumors than in other tissues, including healthy or normal adjacent lung and non-SCLC samples. Critically, the upregulation of CD133 messenger RNA in SCLC was associated with a significant increase (hazard ratio, 2.62) in death. CD133 protein was expressed in primary human SCLC, in SCLC patient-derived xenografts, and in both SCLC cell lines tested (H82 and H69). Using an H82 xenograft mouse model, we first imaged CD133 expression with NIRF. Both invivo and ex vivo NIRF clearly showed that a fluorophore-tagged αCD133 homed to lung tumors. Next, we validated the noninvasive visualization of subcutaneous and orthotopic H82 xenografts via immunoPET. An αCD133 antibody labeled with the positron-emitting radiometal 89Zr demonstrated significant accumulation in tumor tissue while producing minimal uptake in healthy organs. Finally, plasma αCD133 autoantibodies were found in subjects from cohort studies up to 1 year before SCLC diagnosis. Conclusion: In light of these findings, we conclude that the presence of αCD133 autoantibodies in a blood sample followed by CD133-targeted 89Zr-immunoPET could be an effective early detection screening strategy for SCLC.

Cell Membrane-Camouflaged Nanocarriers with Biomimetic Deformability of Erythrocytes for Ultralong Circulation and Enhanced Cancer Therapy.

Despite considerable advancements in cell membrane-camouflaged nanocarriers to leverage natural cell functions, artificial nanocarriers that can accurately mimic both the biological and physical properties of cells are urgently needed. Herein, inspired by the important effect of the stiffness and deformability of natural red blood cells (RBCs) on their life span and flowing through narrow vessels, we report the construction of RBC membrane-camouflaged nanocarriers that can mimic RBCs at different life stages and study how the deformability of RBC-derived nanocarriers affects their biological behaviors. RBC membrane-coated elastic poly(ethylene glycol) diacrylate hydrogel nanoparticles (RBC-ENPs) simulating dynamic RBCs exhibited high immunocompatibility with minimum immunoglobulin adsorption in the surface protein corona, resulting in reduced opsonization in macrophages and ultralong circulation. Furthermore, RBC-ENPs can deform like RBCs and achieve excellent diffusion in tumor extracellular matrix, leading to improved multicellular spheroid penetration and tumor tissue accumulation. In mouse cancer models, doxorubicin-loaded RBC-ENPs demonstrated superior antitumor efficacy to the first-line chemotherapeutic drug PEGylated doxorubicin liposomes. Our work highlights that tuning the physical properties of cell membrane-derived nanocarriers may offer an alternative approach for the bionic design of nanomedicines in the future.

Application of Approved Cisplatin Derivatives in Combination Therapy against Different Cancer Diseases.

The problems with anticancer therapy are resistance and toxicity. From 3000 Cisplatin derivatives tested as antitumor agents, most of them have been rejected, due to toxicity. The aim of current study is the comparison of therapeutic combinations of the currently applied in clinical practice: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin, Lobaplatin, Heptaplatin, and Satraplatin. The literature data show that the strategies for the development of platinum anticancer agents and bypassing of resistance to Cisplatin derivatives and their toxicity are: combination therapy, Pt IV prodrugs, the targeted nanocarriers. The very important strategy for the improvement of the antitumor effect against different cancers is synergistic combination of Cisplatin derivatives with: (1) anticancer agents—Fluorouracil, Gemcitabine, Cytarabine, Fludarabine, Pemetrexed, Ifosfamide, Irinotecan, Topotecan, Etoposide, Amrubicin, Doxorubicin, Epirubicin, Vinorelbine, Docetaxel, Paclitaxel, Nab-Paclitaxel; (2) modulators of resistant mechanisms; (3) signaling protein inhibitors—Erlotinib; Bortezomib; Everolimus; (4) and immunotherapeutic drugs—Atezolizumab, Avelumab, Bevacizumab, Cemiplimab, Cetuximab, Durvalumab, Erlotinib, Imatinib, Necitumumab, Nimotuzumab, Nivolumab, Onartuzumab, Panitumumab, Pembrolizumab, Rilotumumab, Trastuzumab, Tremelimumab, and Sintilimab. An important approach for overcoming the drug resistance and reduction of toxicity of Cisplatin derivatives is the application of nanocarriers (polymers and liposomes), which provide improved targeted delivery, increased intracellular penetration, selective accumulation in tumor tissue, and enhanced therapeutic efficacy. The advantages of combination therapy are maximum removal of tumor cells in different phases; prevention of resistance; inhibition of the adaptation of tumor cells and their mutations; and reduction of toxicity.

Spatiotemporal decomposition methods for nanobubble contrast-enhanced ultrasound

Nanobubble ultrasound contrast agents (NBs) offer enhanced access to deep tumor tissue by extrapolation from vasculature. When combined with targeting moieties, shell-stabilized nanobubbles can outperform other agents used in molecular ultrasound imaging due to their small size. The visualization and decoupling of extravasated and intravascular NBs is critical to furthering nanobubble molecular imaging with ultrasound. Spatiotemporal processing of echo data, usually via singular value decomposition (SVD), enables enhanced decoupling of signals of stationary from moving scatterers and therefore provides a novel tool for analysis of NB extravasation into the parenchyma. Instead of trivial solutions, we have developed non-negative SVD (nnSVD) methods applicable to most commercial scanners without requiring the raw data. Additionally, our formulation allows addition of proper regularizers, such as sparsity, to further expand the decomposition dimensions. We validate these methods in phantom models and present how the suggested decompositions can distinctly decouple flowing from extravasated NBs in in vivo tumour models with enhanced permeability. Our results show the successful tracking of nanobubble accumulation in tumour tissue and can serve as a relative metric for molecular targeting of prostate cancer. Further exploration of these methods could be used to improve long-term imaging and drug delivery capabilities of NBs.

GSH-Responsive Metal-Organic Framework for Intratumoral Release of NO and IDO Inhibitor to Enhance Antitumor Immunotherapy.

Immunotherapy brings great benefits for tumor therapy in clinical treatments but encounters the severe challenge of low response rate mainly because of the immunosuppressive tumor microenvironment. Multifunctional nanoplatforms integrating effective drug delivery and medical imaging offer tremendous potential for cancer treatment, which may play a critical role in combinational immunotherapy to overcome the immunosuppressive microenvironment for efficient tumor therapy. Here, a nanodrug (BMS-SNAP-MOF) is prepared using glutathione (GSH)-sensitive metal-organic framework (MOF) to encapsulate an immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) inhibitor BMS-986205, and the nitric oxide (NO) donor s-nitrosothiol groups. The high T1 relaxivity allows magnetic resonance imaging to monitor nanodrug distribution in vivo. After the nanodrug accumulation in tumor tissue via the EPR effect and subsequent internalization into tumor cells, the enriched GSH therein triggers cascade reactions with MOF, which disassembles the nanodrug to rapidly release the IDO-inhibitory BMS-986205 and produces abundant NO. Consequently, the IDO inhibitor and NO synergistically modulate the immunosuppressive tumor microenvironment with increase CD8+ T cells and reduce Treg cells to result in highly effective immunotherapy. In an animal study, treatment using this theranostic nanodrug achieves obvious regressions of both primary and distant 4T1 tumors, highlighting its application potential in advanced tumor immunotherapy.

The effect of AS1411 surface density on the tumor targeting properties of PEGylated silver nanotriangles.

Aim: To determine the optimal AS1411 density on polyethylene glycol (PEG)ylated silver nanotriangles (PNTs) for targeting breast cancer cells. Methods: PNTs modified with different AS1411 densities (ANTs) were constructed, characterized and evaluated for their targeting properties in breast cancer cells and a mouse model of breast cancer. Results: AS1411 was successfully conjugated to PNTs. The accumulation and cellular uptake of 10-ANTs were the highest. 10-ANTs plus near-IR laser irradiation displayed the greatest inhibitory effect on cell viability. However, 5-ANTs had the highest accumulation in tumor tissues. When combined with NIR laser, 5-ANTs exhibited the best in vivo photothermal therapy effect. Conclusion: The optimal AS1411 densities at the cellular and animal levels were 10% and 5%, respectively.

Autophagy-inhibiting biomimetic nanodrugs enhance photothermal therapy and boost antitumor immunity.

The instinctive protective stress responses of tumor cells hamper low-temperature photothermal therapy (LTPTT), resulting in tumor recurrence and metastasis. The rapid blood clearance and low-efficiency tumor enrichment of nanomedicines also decrease the efficacy of LTPTT. In this study, we fabricated coassembled photothermal agents (indocyanine green, ICG) and autophagy inhibitors (chloroquine, CQ) and red blood cell and cancer cell hybrid membrane (RCm)-camouflaged ICGCQ@RCm nanoparticles (ICGCQ@RCm NPs) to enhance tumor LTPTT. The ICGCQ@RCm NPs exhibited prolonged blood drug circulation and markedly enhanced drug accumulation in tumor tissues. The ICGCQ@RCm NPs reduced the thermal tolerance of tumor cells to sensitize ICG-mediated LTPTT by inhibiting protective autophagy. The ICGCQ@RCm NPs exerted strong immunogenic cell death (ICD) after efficient LTPTT to activate antitumor immunity. In addition, ICGCQ@RCms optimized the therapeutic efficacy by imaging-guided LTPTT, taking advantage of the near-infrared (NIR) fluorescence of ICG. Consequently, the ICGCQ@RCm NPs effectively inhibited tumors under mild LTPTT, significantly suppressed tumor metastasis and prolonged the survival time of tumor-bearing mice. Furthermore, the ICGCQ@RCm NPs showed high biosafety in vitro and in vivo. The ICGCQ@RCm NPs demonstrated tumor-targeting and imaging-guided autophagy inhibition-sensitized LTPTT using two Food and Drug Administration (FDA)-approved drugs, which have great potential for clinical application.

A Nanogel with Effective Blood-Brain Barrier Penetration Ability through Passive and Active Dual-Targeting Function

Clinically, surgery assisted by chemotherapy is the most effective treatment of cancer. But from our clinical observation, the median survival of patients with glioblastoma is still not so good with only 15-16 months. The low therapeutic index is mainly due to the blood-brain barrier (BBB) which significantly hindered the chemotherapeutic drug accumulation in tumor tissue. One main composition of the BBB is astrocyte, which contains a lipophilic cell membrane, which prevents more than 98% of small-molecule drugs from entering the brain. Previously, we found that the nanogel with passive targeting function can increase the BBB penetration ability, which indicates that it could be used to overcome the above mentioned in vivo obstacles which promoted drug accumulation in the tumor. In this study, thermosensitive targeted nanogel delivery systems (DPPC) with cell-penetrating peptides (CPP) are introduced onto the particle surface for active astrocyte breaking. The hydrodynamic radius of DPPC is around 300 nm, the potential is about 0-5 mV, and the TEM and DLS studies further confirm its well spherical morphology and uniform distribution. The DPPC is verified as the biocompatible carriers for further application by cell viability tests. The in vitro-constructed BBB model successfully proves that DPPC can efficiently penetrate the BBB, which is attributed to both the temperature-sensitive passive targeting and the active CPP penetration. Consequently, the intracellular doxorubicin (DOX) promotes such functional DPPC at the relatively high temperature inside tumor microenvironment (TME) (~42°C), which obviously improves intratumor drug accumulation and tumor cell-killing effects. The dual-targeted nanogel delivery systems designed in this study provides a more effective strategy for the treatment of glioma.

Double hit strategy using pH-sensitive liposomes containing doxorubicin and pheophorbide-a for combination tumor therapy

For successful combination therapy using nanoparticles, stable loading and targeted delivery of different drugs are important. Herein, we prepared pH-sensitive liposomes with hydrophilic doxorubicin (Dox) in the core and hydrophobic pheophobide-a (Pba) in the lipid membrane (pH-lipo-Dox-Pba). The liposomes provided high drug accumulation in tumor tissue, with an enhanced permeability and retention (EPR) effect and enhanced binding to tumor cells by cyclic Arg-Gly-Asp peptide (cRGD). After cellular uptake, Dox was released in response to the endo-lysosomal acidic pH and moved into the nucleus, while Pba remained in the cytosol. Therefore, a double hit strategy composed of a simultaneous attack on nucleus and cytosol could be achieved by chemo- and photodynamic therapy. High tumor accumulation of pH-lipo-Dox-Pba was observed after intravenous injection into 4T1 tumor-bearing mice. Effective suppression of tumor growth in the same mouse model demonstrated a synergetic effect of combination therapy enabled by the double hit strategy using pH-lipo-Dox-Pba.