Dataset Information

Vascular Disruptive Hydrogel Platform for Enhanced Chemotherapy and Anti-Angiogenesis through Alleviation of Immune Surveillance.

ABSTRACT: Patients undergoing immunotherapy always exhibit a low-response rate due to tumor heterogeneity and immune surveillance in the tumor. Angiogenesis plays an important role in affecting the status of tumor-infiltrated lymphocytes by inducing hypoxia and acidosis microenvironment, suggesting its synergistic potential in immunotherapy. However, the antitumor efficacy of singular anti-angiogenesis therapy often suffers from failure in the clinic due to the compensatory pro-angiogenesis signaling pathway. In this work, classic injectable thermosensitive PLGA-PEG-PLGA copolymer was used to construct a platform to co-deliver CA4P (vascular disruptive agent) and EPI for inducing immunogenic cell death of cancer cells by targeting the tumor immune microenvironment. Investigation of 4T1 tumor-bearing mouse models suggests that local administration of injectable V+E@Gel could significantly inhibit the proliferation of cancer cells and prolong the survival rate of 4T1 tumor-bearing mouse models. Histological analysis further indicates that V+E@Gel could effectively inhibit tumor angiogenesis and metastasis by down-regulating the expression of CD34, CD31, MTA1 and TGF-β. Moreover, due to the sustained release kinetics of V+E@Gel, its local administration relieves the immune surveillance in tumor tissues and thus induces a robust and long-lasting specific antitumor immune response. Overall, this work provides a new treatment strategy through the mediation of the tumor immune microenvironment by vascular disruption to fulfill enhanced chemotherapy and immunotherapy.

SUBMITTER: Li F

PROVIDER: S-EPMC9505154 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Vascular Disruptive Hydrogel Platform for Enhanced Chemotherapy and Anti-Angiogenesis through Alleviation of Immune Surveillance.

Li Fasheng F Shao Xinmei X Liu Dehui D Jiao Xiaogang X Yang Xinqi X Yang Wencai W Liu Xiaoyan X

Pharmaceutics 20220828 9

Patients undergoing immunotherapy always exhibit a low-response rate due to tumor heterogeneity and immune surveillance in the tumor. Angiogenesis plays an important role in affecting the status of tumor-infiltrated lymphocytes by inducing hypoxia and acidosis microenvironment, suggesting its synergistic potential in immunotherapy. However, the antitumor efficacy of singular anti-angiogenesis therapy often suffers from failure in the clinic due to the compensatory pro-angiogenesis signaling path ...[more]

PMID: 36145556

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Project description:Cardiovascular diseases (CVDs) are the leading cause of death among all non-communicable diseases globally. Although expanded polytetrafluoroethylene (ePTFE) has been widely used for larger-diameter vascular graft transplantation, the persistent thrombus formation and intimal hyperplasia of small-diameter vascular grafts (SDVGs) made of ePTFE to treat severe CVDs remain the biggest challenges due to lack of biocompatibility and endothelium. In this study, bi-layered poly(acrylamide-co-2-Acrylamido-2-methyl-1-propanesulfonic acid sodium)-xanthan hydrogel-ePTFE (poly(AAm-co-NaAMPS)-xanthan hydrogel-ePTFE) vascular grafts capable of promoting endothelialization and prohibiting thrombosis were synthesized and fabricated. While the external ePTFE layer of the vascular grafts provided the mechanical stability, the inner hydrogel layer offered much-needed cytocompatibility, hemocompatibility, and endothelialization functions. The interface morphology between the inner hydrogel layer and the outer ePTFE layer was observed by scanning electron microscope (SEM), which revealed that the hydrogel was well attached to the porous ePTFE through mechanical interlocking. Among all the hydrogel compositions tested with cell culture using human umbilical vein endothelial cells (HUVECs), the hydrogel with the molar ratio of 40:60 (NaAMPS/AAm) composition (i.e., Hydrogel 40:60) exhibited the best endothelialization function, as it produced the largest endothelialization area that was three times more than of that of plain ePTFE on day 14, maintained the highest average cell viability, and had the best cell morphology. Hydrogel 40:60 also showed excellent hemocompatibility, prolonged activated partial thromboplastin time (aPTT), and good mechanical properties. Overall, bi-layered poly(AAm-co-NaAMPS)-xanthan hydrogel-ePTFE vascular grafts with the Hydrogel 40:60 composition could potentially solve the critical challenge of thrombus formation in vascular graft transplantation applications.

Project description:Injectable, self-healing hydrogels with enhanced solubilization of hydrophobic drugs are urgently needed for antimicrobial intravaginal therapies. Here, we report the first hydrogel systems constructed of dynamic boronic esters cross-linking unimolecular micelles, which are a reservoir of antifungal hydrophobic drug molecules. The selective hydrophobization of hyperbranched polyglycidol with phenyl units in the core via ester or urethane bonds enabled the solubilization of clotrimazole, a water-insoluble drug of broad antifungal properties. The encapsulation efficiency of clotrimazole increases with the degree of the HbPGL core modification; however, the encapsulation is more favorable in the case of urethane derivatives. In addition, the rate of clotrimazole release was lower from HbPGL hydrophobized via urethane bonds than with ester linkages. In this work, we also revealed that the hydrophobization degree of HbPGL significantly influences the rheological properties of its hydrogels with poly(acrylamide-ran-2-acrylamidephenylboronic acid). The elastic strength of networks (GN) and the thermal stability of hydrogels increased along with the degree of HbPGL core hydrophobization. The degradation of the hydrogel constructed of the neat HbPGL was observed at approx. 40 °C, whereas the hydrogels constructed on HbPGL, where the monohydroxyl units were modified above 30 mol %, were stable above 50 °C. Moreover, the flow and self-healing ability of hydrogels were gradually decreased due to the reduced dynamics of macromolecules in the network as an effect of increased hydrophobicity. The changes in the rheological properties of hydrogels resulted from the engagement of phenyl units into the intermolecular hydrophobic interactions, which besides boronic esters constituted additional cross-links. This study demonstrates that the HbPGL core hydrophobized with phenyl units at 30 mol % degrees via urethane linkages is optimal in respect of the drug encapsulation efficiency and rheological properties including both self-healable and injectable behavior. This work is important because of a proper selection of a building component for the construction of a therapeutic hydrogel platform dedicated to the intravaginal delivery of hydrophobic drugs.

Dataset Information

Vascular Disruptive Hydrogel Platform for Enhanced Chemotherapy and Anti-Angiogenesis through Alleviation of Immune Surveillance.

Publications

Vascular Disruptive Hydrogel Platform for Enhanced Chemotherapy and Anti-Angiogenesis through Alleviation of Immune Surveillance.

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