Bioresponsive nanocomplex integrating cancer-associated fibroblast deactivation and immunogenic chemotherapy for rebuilding immune-excluded tumors.

Cancer-associated fibroblasts (CAFs) play a crucial role in creating an immunosuppressive environment and remodeling the extracellular matrix within tumors, leading to chemotherapy resistance and limited immune cell infiltration. To address these challenges, integrating CAFs deactivation into immunogenic chemotherapy may represent a promising approach to the reversal of immune-excluded tumor. We developed a tumor-targeted nanomedicine called the glutathione-responsive nanocomplex (GNC). The GNC co-loaded dasatinib, a CAF inhibitor, and paclitaxel, a chemotherapeutic agent, to deactivate CAFs and enhance the effects of immunogenic chemotherapy. Due to the modification with hyaluronic acid, the GNC preferentially accumulated in the tumor periphery and responsively released cargos, mitigating the tumor stroma as well as overcoming chemoresistance. Moreover, GNC treatment exhibited remarkable immunostimulatory efficacy, including CD8+ T cell expansion and PD-L1 downregulation, facilitating immune checkpoint blockade therapy. In summary, the integration of CAF deactivation and immunogenic chemotherapy using the GNC nanoplatform holds promise for rebuilding immune-excluded tumors.

Red blood membrane camouflaging Bismuth nanoflowers designed for radio-photothermal therapy in lung cancer.

Radio-photothermal therapy is an effective modality for cancer treatment. To overcome the radio-resistance in the hypoxic microenvironment and improve the sensitivity of radiotherapy, metal nanoparticles, and radio-photothermal therapy are widely used in the research of improving the curative effect and reducing the side effects of radiotherapy. Here, we developed red blood membrane camouflaging bismuth nanoflowers (RBCM-BNF) with outstanding physiological stability and biodegradability for lung tumours. In vitro data proved that the RBCM-BNF had the greatest cancer cell-killing ability combined with X-ray irradiation and photo-thermal treatment. Meanwhile, in vivo studies revealed that RBCM-BNF can alleviate the hypoxic microenvironment and promote tumour cell apoptosis by inhibiting HIF-1α expression and increasing caspase-3 expression. Therefore, RBCM-BNF had a good radio-sensitising effect and might be a promising biomimetic nanoplatform as a therapeutic target for cancer.

Sensitization Strategies of Lateral Flow Immunochromatography for Gold Modified Nanomaterials in Biosensor Development.

Gold nanomaterials have become very attractive nanomaterials for biomedical research due to their unique physical and chemical properties, including size dependent optical, magnetic and catalytic properties, surface plasmon resonance (SPR), biological affinity and structural suitability. The performance of biosensing and biodiagnosis can be significantly improved in sensitivity, specificity, speed, contrast, resolution and so on by utilizing multiple optical properties of different gold nanostructures. Lateral flow immunochromatographic assay (LFIA) based on gold nanoparticles (GNPs) has the advantages of simple, fast operation, stable technology, and low cost, making it one of the most widely used in vitro diagnostics (IVDs). However, the traditional colloidal gold (CG)-based LFIA can only achieve qualitative or semi-quantitative detection, and its low detection sensitivity cannot meet the current detection needs. Due to the strong dependence of the optical properties of gold nanomaterials on their shape and surface properties, gold-based nanomaterial modification has brought new possibilities to the IVDs: people have attempted to change the morphology and size of gold nanomaterials themselves or hybrid with other elements for application in LFIA. In this paper, many well-designed plasmonic gold nanostructures for further improving the sensitivity and signal output stability of LFIA have been summarized. In addition, some opportunities and challenges that gold-based LFIA may encounter at present or in the future are also mentioned in this paper. In summary, this paper will demonstrate some feasible strategies for the manufacture of potential gold-based nanobiosensors of post of care testing (POCT) for faster detection and more accurate disease diagnosis.

Synchronous targeted delivery of TGF-ß siRNA to stromal and tumor cells elicits robust antitumor immunity against triple-negative breast cancer by comprehensively remodeling the tumor microenvironment.

The poor permeability of therapeutic drugs, limited T-cell infiltration, and strong immunosuppressive tumor microenvironment of triple-negative breast cancer (TNBC) acts as a prominent barrier to the delivery of drugs and immunotherapy including programmed cell death ligand-1 antibody (anti-PD-L1). Transforming growth factor (TGF)-ß, an important cytokine produced by cancer-associated fibroblasts (CAFs) and tumor cells contributes to the pathological vasculature, dense tumor stroma and strong immunosuppressive tumor microenvironment (TME). Herein, a nanomedicine platform (HA-LSL/siTGF-ß) employing dual-targeting, alongside hyaluronidase (HAase) and glutathione (GSH) triggered release was elaborately constructed to efficiently deliver TGF-ß small interference RNA (siTGF-ß). It was determined that this system was able to improve the efficacy of anti-PD-L1. The siTGF-ß nanosystem efficiently silenced TGF-ß-related signaling pathways in both activated NIH 3T3 cells and 4T1 cells in vitro and in vivo. This occurred firstly, through CD44-mediated uptake, followed by rapid escape mediated by HAase in endo/lysosomes and release of siRNA mediated by high GSH concentrations in the cytoplasm. By simultaneous silencing of TGF-ß in stromal and tumor cells, HA-LSL/siTGF-ß dramatically reduced stroma deposition, promoted the penetration of nanomedicines for deep remodeling of the TME, improved oxygenation, T cells infiltration and subsequent anti-PD-L1 deep penetration. The double suppression of TGF-ß has been demonstrated to promote blood vessel normalization, inhibit an epithelial-to-mesenchymal transition (EMT), and further modify the immunosuppressive TME, which was supported by an overall increase in the proportion of dendritic cells and cytotoxic T cells. Further, a reduction in the proportion of immunosuppression cells such as regulatory T cells and myeloid-derived suppressor cells was also observed in the TME. Based on the comprehensive remodeling of the tumor microenvironment by this nanosystem, subsequent anti-PD-L1 therapy elicited robust antitumor immunity. Specifically, this system was able to suppress the growth of both primary and distant tumor while preventing tumor metastasis to the lung. Therefore, the combination of the dual-targeted siTGF-ß nanosystem, alongside anti-PD-L1 may serve as a novel method to enhance antitumor immunotherapy against stroma-rich TNBC.

Enhancing chemotherapy for pancreatic cancer through efficient and sustained tumor microenvironment remodeling with a fibroblast-targeted nanosystem.

Pancreatic cancer (PC) carries a poor prognosis among all malignancies and poses great challenges to clinical drug accessibility due to the severely fibrotic and hypoxic tumor microenvironment (TME). Therein, cancer-associated fibroblasts (CAFs), which are extremely abundant in PC, play a key role in forming the complex PC microenvironment. Therefore, a highly efficient TME reprogramming therapeutic paradigm that can specifically inhibit CAF function is urgently needed. Herein, we successfully developed a novel CAF-tailored nanosystem (Dex-GP-DOCA, DPD) loaded with a potent anti-fibrosis flavonoid compound (Quercetin, QUE), which possesses biological responsiveness to fibroblast activation protein alpha (FAP-α), prolonged TME remodeling and enhancement of clinical chemotherapeutics. Specifically, DPD/QUE allowed for extracellular matrix (ECM) reduction, vessel normalization, hypoxia-induced drug resistance reversal, and blockade of Wnt16 paracrine in CAFs. More importantly, this chemotherapy conducive microenvironment persisted for at least 8 days following treatment with DPD/QUE. It should also be noted that the effective and prolonged microenvironment modulation induced by DPD/QUE significantly improved the chemotherapy sensitivity of Abraxane and gemcitabine, the first-line chemotherapeutic drugs for PC, with inhibition rates increasing from 37.5% and 40.0% to 87.5% and 85.2%, respectively. Overall, our CAFs-targeted nanosystem showed promising prospects for remodeling the TME and facilitating chemotherapy for refractory pancreatic cancer.

A biocompatible nano-barium sulfonate system for quad-modal imaging-guided photothermal radiotherapy of tumors.

Integration of multi-modal imaging techniques and various cancer treatments based on their respective characteristics would be beneficial for enhancing anticancer efficacy. Exploiting an "all-in-one" nanoparticle with high biocompatibility has attracted widespread attention. Herein, two clinically proven modalities, human serum albumin (HSA) and indocyanine green (ICG), were selected to create HSA-stable barium sulfonate nanoparticles (HSA@ICG-Ba) through the reaction of a sulfonic acid group with barium ions. Our nano-probe showed excellent optical properties and X-ray absorption capacity, which can be applied in tumor theranostics. Utilizing the rich tumor accumulation of HSA@ICG-Ba, this nanoparticle can obtain multifaceted tumor information through fluorescence (FL), computerized tomography (CT), photoacoustic (PA) imaging, and single photon emission computed tomography (SPECT) imaging. Additionally, radiation sensitization therapy and photothermal therapy based on HSA@ICG-Ba were evaluated using both in vitro and in vivo models. The efficacy of tumor radiotherapy can be further improved by mild hyperthermia owing to the relieved tumor hypoxia. Finally, the favorable safety profile of HSA@ICG-Ba is confirmed by blood index analysis and tissue section observation. Therefore, this study explored an "all-in-one" barium sulfonate nanoparticle with high biocompatibility for FL/CT/PA/SPECT imaging-guided synergetic photothermal-radiotherapy of tumors, providing a new approach and potential pathway for tumor theranostics.

Dextran 40 hybrid biomimetic bismuth-nanoflower designed for NIR II-triggered hypoxic tumor thermoradiotherapy via macrophage escape.

At present, NIR-II-triggered photothermal biomedical applications are limited by complex synthesis reactions, mediocre photothermal conversion efficiency, and difficult degradation. Herein, we prepared biodegradable Bi flower-like nanoparticles (phospholipid-modified Bi nanoflowers, BNFs) with high photothermal conversion efficiency (∼33.52 %) in NIR-II by a simple method and then modified them with the red blood cell membrane and dextran 40 (DRBCM) to improve their in vitro stability, to escape macrophages clearance and to enhance tumor accumulation. Dextran coating onto the surface of particles as a dispersant shell stabilizes inorganic particles by maintaining the surface charges and creating steric repulsions upon compression of neighboring polymer chains. In vitro and in vivo experiments proved that combined thermoradiotherapy of DRBCM-BNFs exhibited significantly enhanced tumor inhibition efficacy than monotherapy with good biocompatibility and low toxicity due to its biodegradability. Furthermore, the mechanism studies demonstrated that DRBCM-BNFs could serve as a nano sensitizer to promote the thermoradiotherapy under NIR-II illumination and X-ray irradiation, by downregulating heat shock protein 70 (HSP70) and phosphorylated-p65 (p-p65) to reduce the thermal resistance and radioresistance of tumor cells and increasing the expression of apoptosis-related protein cleaved caspase-3. In conclusion, DRBCM-BNFs could be a promising green delivery platform for the sensitization of synergistic thermoradiotherapy.

A pHe sensitive nanodrug for collaborative penetration and inhibition of metastatic tumors.

Current chemotherapies for metastatic tumors are seriously restricted by limited drug infiltration and deficient disturbance of metastasis-associated complex pathways involving tumor cell autocrine as well as paracrine loops in the microenvironment (TME). Of note, cancer-associated fibroblasts (CAFs) play a predominant role in shaping TME favoring drug resistance and metastasis. Herein, we constructed a tumor extracellular pH (pHe) sensitive methotrexate-chitosan conjugate (MTX-GC-DEAP) and co-assembled it with quercetin (QUE) to achieve co-delivered nanodrugs (MTX-GC-DEAP/QUE). The pHe sensitive protonation and disassembly enabled MTX-GC-DEAP/QUE for stroma-specific delivery of QUE and positive-charged MTX-GC-DEAP molecular conjugates, thereby achieving deep tumor penetration via the combination of QUE-mediated CAF inactivation and adsorption-mediated transcytosis. On the basis of significantly promoted drug availability, a strengthened "omnidirectional" inhibition of pre-metastatic initiation was generated both in vitro and in vivo from the CAF inactivation-mediated reversion of metastasis-promoting environments as well as the inhibition of epithelial-mesenchymal transition, local and blood vessel invasion via QUE-mediated direct regulation on tumor cells. Our tailor-designed versatile nanodrug provides a deep insight into potentiating multi-faceted penetration of multi-mechanism-based regulating agents for intensive metastasis inhibition.

The programmed site-specific delivery of LY3200882 and PD-L1 siRNA boosts immunotherapy for triple-negative breast cancer by remodeling tumor microenvironment.

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-ß) 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-ß 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.

Dual Targeting of Cancer Cells and MMPs with Self-Assembly Hybrid Nanoparticles for Combination Therapy in Combating Cancer.

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.

Development and validation of a predictive score for venous thromboembolism in newly diagnosed non-small cell lung cancer.

INTRODUCTION: The risk of venous thromboembolism (VTE) varies among tumour types, and different cancer type-specific risks for VTE prediction remain undefined. We aimed to establish a prediction model for non-small lung cancer (NSCLC)-associated VTE. MATERIALS AND METHODS: We analysed data from a prospective cohort of patients with newly diagnosed NSCLC. We then developed a VTE risk prediction model using data of patients who were recruited from 2013 to 2017 (n = 602, development cohort) and validated this model using date of patients recruited from 2018 to 2019 (n = 412, validation cohort). The cumulative 6 months VTE incidence observed in both cohorts was calculated. RESULTS: The parameters in this new model included Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (1 point), EGFR mutation (-1 point), neutrophil count ≥7.5 × 109/L (2 points), hemoglobin <115 g/L (1 point), CEA ≥5.0 ng/mL (2 points), and D-dimer level ≥1400 ng/mL (4 points). The cross-validated concordance indices of the model in the development and validation cohorts were 0.779 and 0.853, respectively. Furthermore, the areas under the curve in the two cohorts were 0.7563 (95% confidence interval [CI]: 0.6856-0.8129, P < 0.001) and 0.8211 (95% CI: 0.7451-0.8765, P < 0.001) for development and validation cohorts, respectively. CONCLUSIONS: The new VTE risk prediction model incorporated patient characteristics, laboratory values, and oncogenic status, and was able to stratify patients at high risk of VTE in newly diagnosed NSCLC within 6 months of diagnosis.

Redox-sensitive hyaluronic acid-cholesterol nanovehicles potentiate efficient transmembrane internalization and controlled release for penetrated "full-line" inhibition of pre-metastatic initiation.

Metastatic breast cancer is a major cause of cancer-related mortality worldwide. The tumor-specific penetration and triggered drug release for "full-line" inhibition of pre-metastatic initiation are of essential importance in improving mortality rates. Here, a crosslinked, redox-sensitive amphiphilic conjugate (cHLC) was constructed with a combination of features, including hyaluronic acid (HA)-mediated tumor active targeting, lipoic acid (LA) core-crosslinking based bio-stability and reducibility, and lipid raft anchoring-promoted HA-mediated endocytosis through cholesterol (CHO) modification for the penetrated co-delivery of paclitaxel (PTX) and the multi-targeted anti-metastatic agent, silibinin (SB). Resultantly, the nanodrug (cHLC/(PTX + SB)) demonstrated enhanced tumor cytoplasm-selective rapid drug delivery in a 4T1 model both in vitro and in vivo. The released SB efficiently sensitized cells to PTX treatment and inhibited the whole process of pre-metastatic initiation including epithelial-to-mesenchymal transition (EMT), local and blood vessel invasion. The exquisite design of this delivery system provides a deep insight into enhancing focus accessibility of multi-targeted drugs for an efficient inhibition of tumor metastasis.

Association of Venous Thromboembolism and Early Mortality in Patients with Newly Diagnosed Metastatic Non-Small Cell Lung Cancer.

PURPOSE: To explore the relationship between venous thromboembolism (VTE) and early mortality (within six months) in Chinese patients with newly diagnosed metastatic non-small cell lung cancer (NSCLC) after entering the era of precision treatment. METHODS: A cohort of 706 consecutive subjects with newly diagnosed metastatic NSCLC were prospectively observed. Clinical and survival data were recorded over a six-month follow-up period. The predictive factors for the occurrence of VTE and the relationship with early mortality were evaluated through univariate and multivariate analyses. RESULTS: During the six-month follow-up period, VTE events occurred in 12.2% (86/706) of the enrolled patients. In the multivariate analyses for VTE, an age older than 70 years (vs < 70: sub-distribution hazard radio [SHR], 1.678; 95% confidence interval (CI), 1.073-2.600; P=0.022), an Eastern Cooperative Oncology Group performance status ≥2 (vs 0/1: SHR, 1.946; 95% CI, 1.277-2.970; P=0.002), and having an ALK rearrangement (vs non-rearrangement: SHR, 2.377; 95% CI, 1.186-4.760; P=0.015) were significantly associated with the occurrence of VTE. Within six months, 116 subjects (16.4%) died, and the occurrence of VTE (vs no VTE: adjusted HR: 1.863; 95% CI: 1.178-2.947, P=0.008) was remarkably associated with early mortality. Further analysis showed 98 patients (13.9%) with early mortality had EGFR/ALK wild-type genes, with a risk of early mortality 5.935-fold higher than that of patients with an EGFR mutation/ALK rearrangement. Finally, subgroup analyses showed that VTE occurrence was a significant factor for predicting early mortality in patients with EGFR/ALK wild-type genes (adjusted HR: 1.682; 95% CI: 1.023-2.768, P=0.041). CONCLUSION: Patients with an EGFR mutation/ALK rearrangement had a significantly decreased risk of early mortality in the era of targeted therapy; however, VTE occurrence remained an important predictor for early mortality in metastatic NSCLC patients, especially in patients with EGFR/ALK wild-type genes.

Hypoxia-Sensitive Zwitterionic Vehicle for Tumor-Specific Drug Delivery through Antifouling-Based Stable Biotransport Alongside PDT-Sensitized Controlled Release.

A hypoxia-sensitive zwitterionic vehicle, DHigh-PEI-(A+P), with the ability for antifouling-mediated, stable biotransport and a photodynamic therapy (PDT)-sensitized hypoxic response for spatiotemporal controlled drug release, was developed for the tumor-specific delivery of chemotherapeutics and biomacromolecules. The amphiphilic DHigh-PEI-(A+P) was constructed from a betaine monomer (DMAAPS), a photosensitizer (PpIX), and an azobenzene-4,4'-dicarboxylic acid-modified polyethylenimine. Herein paclitaxel (PTX) was selected as a common model drug to verify the functions of the designed polymer. First, DHigh-PEI-(A+P) was demonstrated to spontaneously coassemble with PTX in aqueous solution with high drug loading (>35%). The desirable antifouling ability of DHigh-PEI-(A+P) was independently verified by efficient 4T1 endocytosis in serum alongside systemic tumor targeting. Furthermore, PpIX-mediated PDT was verified to aggravate and homogenize a hypoxic microenvironment at the cell and tissue levels for a sharp responsive disassembly of DHigh-PEI-(A+P) and thus a robust drug release in a well-controlled manner. As a result, DHigh-PEI-(A+P) amplified the therapeutic outcome of PTX on orthotopic 4T1 mouse models with minimal collateral damage. We proposed that DHigh-PEI-(A+P) may serve as a tailor-designed universal vehicle for the tumor-specific delivery of drugs with distinct physicochemical properties.

Biomineralization-inspired dasatinib nanodrug with sequential infiltration for effective solid tumor treatment.

The complex blood environment, heterogenic enhanced permeability and retention (EPR) effect, and dense matrix comprise the primary "leakage obstacles" impeding specific accumulation and penetration of nanodrugs against solid tumors, thus forming a key bottleneck for their clinical application. Herein, we present a biomineralization-inspired dasatinib (DAS) nanodrug (CIPHD/DAS) that sequentially permeates all of the abovementioned hindrances for efficient treatment of solid tumors. CIPHD/DAS exhibited a robust hybrid structure constructed from an iRGD-modified hyaluronic acid-deoxycholic acid organic core and a calcium phosphate mineral shell. In vitro and in vivo data demonstrated the mechanism of sequential tumoral infiltration was based on mineral-stiffened blood circulation with decreased premature drug leakage, iRGD-endowed tumor-specific transendothelial transport for "first-order promotion of accumulation" and DAS-mediated restoration of fibrotic stromal homeostasis for "second-order promotion of penetration". Resultantly, CIPHD/DAS showed remarkable distal drug availability in desmoplastic 4T1/CAFs orthotropic mouse models and significantly suppressed tumor growth and metastasis. This optimized strategy with sequential permeabilization of the capital "leakage obstacles" validates a promising paradigm to conquer the "impaired delivery and penetration" associated bottleneck of nanodrugs in the clinical treatment of solid tumors.

Novel Chitosan Derivatives with Reversible Cationization and Hydrophobicization for Tumor Cytoplasm-Specific Burst Co-delivery of siRNA and Chemotherapeutics.

Despite the great potential of combination therapy based on siRNA and chemotherapeutics, an efficient vehicle with abilities of well drug co-loading, synchronizing in vivo trafficking, and target-specific co-burst release remains elusive, which results in a suboptimal synergistic potency. Herein, a novel chitosan amphiphile (PEI-ss-HECS-ss-OA, HSPO) with glutathione (GSH)-reversible cationization and hydrophobicization by polyethylenimine (PEI) and octylamine (OA), respectively, was developed for this purpose. HSPO spontaneously assembled in aqueous solution to be a micellar system and effectively co-encapsulated the two drugs with an adjustable dosage ratio. With a surface charge inversion strategy by hyaluronic acid (HA) coating, the HA(HSPO) co-delivery micelles with a negative surface charge (-21.45 ± 1.44 mV) and suitable size (192.52 ± 7.41 nm) selectively accumulated into CD44 overexpressed A549 tumors through a combination of passive and active targeting mechanism. Then, tumor cytoplasm-selective co-burst release was obtained through GSH triggered collapse of the amphiphilic assembly alongside a decrease of positive charge condensation, finally leading to an enhanced synergistic antitumor effect with a superior inhibition ratio of 86.63%. Overall, this study validated the great promise of HSPO as an efficient site-specific rapid co-trafficking vehicle of siRNA and chemotherapeutics for a remarkable synergistic tumor inhibition.

Co-delivery of silybin and paclitaxel by dextran-based nanoparticles for effective anti-tumor treatment through chemotherapy sensitization and microenvironment modulation.

Modulation of tumor microenvironment (TME) has been indicated as an approach to improve efficacy of cancer therapy. Here, we proposed a nano co-delivery based combination therapy of paclitaxel (PTX) and silybin (SB) which can employ the synergistic effects through chemotherapy sensitization and microenvironment modulation. A dextran-based amphiphilic polymer (Dex-DOCA) was successfully developed for in vivo co-delivery and thus "synchronizing" the biodistribution, transport and release of PTX and SB. Resultantly, Dex-DOCA exhibited an excellent encapsulating efficiency for both PTX and SB with adjustable loading ratio for an optimal synergistic antitumor activity. Moreover, the co-loaded nanoparticles efficiently discharged the two drugs at the prospective dosage ratio specifically in acid endo/lysosome mimic environments. The results of in vitro cytotoxicity and cell apoptosis assays further confirmed the SB sensitized PTX potency. Finally, in vivo investigation demonstrated that the co-loaded nanoparticles could effectively accumulate in tumor sites by passive targeting, and inhibit tumor growth through an enhanced intratumoral penetration (resulted from stromal components eradication and tumor vessels normalization associated TME modulation), as well as a sensitization effect of SB on PTX cytotoxic chemotherapy.

Remodeling the fibrotic tumor microenvironment of desmoplastic melanoma to facilitate vaccine immunotherapy.

Highly fibrotic and collagen-rich properties in desmoplastic melanoma (DM) result in an immune-suppressive fibrotic tumor microenvironment (TME) that resists clinical therapies. The different clinical and pathological properties, as compared to conventional melanoma, lead to delayed diagnosis and it is difficult to deliver drugs effectively due to fibrosis. Herein, we designed a chemo-immuno strategy focused on combining vaccination immunotherapy with multi-targeting sunitinib (SUN) nano-therapy to remodel TME and generate a robust immune response and a stronger synergistic anti-cancer effect. This strategy was evaluated side-by-side with non-desmoplastic melanoma and achieved significant improvement in therapeutic efficacy. The combination treatment was also synergistically assessed with the desmoplastic melanoma model. This strategy can remodel the fibrotic immunosuppressive TME and result in a robust cytotoxic T-cell response by reducing the collagen content, normalizing blood vessels, inhibiting tumor-associated fibroblasts and reducing high levels of suppressor immune cells. The modification of fibrotic immunosuppressive TME may serve as a good approach to further enhance immunotherapy for desmoplastic tumors.

Hyaluronic acid-decorated redox-sensitive chitosan micelles for tumor-specific intracellular delivery of gambogic acid.

Introduction: Herein, a hyaluronic acid (HA)-coated redox-sensitive chitosan-based nanoparticle, HA(HECS-ss-OA)/GA, was successfully developed for tumor-specific intracellular rapid delivery of gambogic acid (GA). Materials and methods: The redox-sensitive polymer, HECS-ss-OA, was prepared through a well-controlled synthesis procedure with a satisfactory reproducibility and stable resulted surface properties of the assembled cationic micelles. GA was solubilized into the inner core of HECS-ss-OA micelles, while HA was employed to coat outside HECS-ss-OA/GA for CD44-mediated active targeting along with protection from cation-associated in vivo defects. The desirable redox-sensitivity of HA(HECS-ss-OA)/GA was demonstrated by morphology and particle size changes alongside in vitro drug release of nanoparticles in different simulated reducing environments. Results: The results of flow cytometry and confocal microscopy confirmed the HA-receptor mediated cellular uptake and burst drug release in highly reducing cytosol of HA(HECS-ss-OA)/GA. Consequently, HA(HECS-ss-OA)/GA showed the highest apoptosis induction and cytotoxicity over the non-sensitive (HA(HECS-cc-OA)/GA) and HA un-coated (HECS-ss-OA/GA) controls against A549 NSCLC model both in vitro and in vivo. Furthermore, a diminished systemic cytotoxicity was observed in HA(HECS-ss-OA)/GA treated mice compared with those treated by HA un-coated cationic ones and GA solution.

Free Adriamycin-Loaded pH/Reduction Dual-Responsive Hyaluronic Acid-Adriamycin Prodrug Micelles for Efficient Cancer Therapy.

Currently, tumor-targeted nanocarriers self-assembled from amphiphilic polymer-drug conjugates are of great demand. The appeal of these carriers arises mainly through their excellent loading efficiency of homologous drug molecules with microenvironment-triggered drug release. Herein, doxorubicin (DOX) was constructed to a hyaluronic acid (HA) backbone through hydrazone and disulfide linkages to construct pH and reduction coresponsive prodrug conjugates (HA-ss-DOX). During formulation, the amphipathic HA-ss-DOX spontaneously assembled into distinct core/shell micelles in aqueous media and showed conspicuous physical DOX loading capabilities (29.1%, DOX/HA-ss-DOX) based on homologous compatibility. DOX/HA-ss-DOX micelles were shown to be stable in normal physiological environments, while accomplishing selective, rapid DOX release at acidic pH and/or highly reducing conditions. The efficacy of DOX/HA-ss-DOX micelles was tested on A549 human lung cancer cells, wherein flow cytometry and confocal microscopy analysis revealed their HA receptor-mediated endocytosis mechanism. In comparison, DOX-loaded redox-insensitive micelles (DOX/HA-DOX) still demonstrated pH-dependent drug release. However, a more rapid intracellular DOX release profile was achieved in DOX/HA-ss-DOX micelles because of their sensitivity to both acidic and reducing environments. Resultantly, DOX/HA-ss-DOX exhibited the strongest cytotoxicity and apoptosis-inducing ability among all tested groups when tested on an A549 cell line and xenograft model.