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Engineering Bifunctional Calcium Alendronate Gene-Delivery Nanoneedle for Synergistic Chemo/Immuno-Therapy Against HER2 Positive Ovarian Cancer.

ABSTRACT: Ovarian cancer is the most lethal gynecological malignancy. Most patients are diagnosed at an advanced stage with widespread peritoneal dissemination and ascites. Bispecific T-cell engagers (BiTEs) have demonstrated impressive antitumor efficacy in hematological malignancies, but the clinical potency is limited by their short half-life, inconvenient continuous intravenous infusion, and severe toxicity at relevant therapeutic levels in solid tumors. To address these critical issues, the design and engineering of alendronate calcium (CaALN) based gene-delivery system is reported to express therapeutic level of BiTE (HER2×CD3) for efficient ovarian cancer immunotherapy. Controllable construction of CaALN nanosphere and nanoneedle is achieved by the simple and green coordination reactions that the distinct nanoneedle-like alendronate calcium (CaALN-N) with a high aspect ratio enabled efficient gene delivery to the peritoneum without system in vivo toxicity. Especially, CaALN-N induced apoptosis of SKOV3-luc cell via down-regulation of HER2 signaling pathway and synergized with HER2×CD3 to generate high antitumor response. In vivo administration of CaALN-N/minicircle DNA encoding HER2×CD3 (MC-HER2×CD3) produces sustained therapeutic levels of BiTE and suppresses tumor growth in a human ovarian cancer xenograft model. Collectively, the engineered alendronate calcium nanoneedle represents a bifunctional gene delivery platform for the efficient and synergistic treatment of ovarian cancer.

SUBMITTER: Chen G

PROVIDER: S-EPMC10190658 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Engineering Bifunctional Calcium Alendronate Gene-Delivery Nanoneedle for Synergistic Chemo/Immuno-Therapy Against HER2 Positive Ovarian Cancer.

Chen Guochuang G Zeng Leli L Bi Bo B Huang Xiuyu X Qiu Miaojuan M Chen Ping P Chen Zhi-Ying ZY He Yulong Y Pan Yihang Y Chen Yu Y Zhao Jing J

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230318 14

Ovarian cancer is the most lethal gynecological malignancy. Most patients are diagnosed at an advanced stage with widespread peritoneal dissemination and ascites. Bispecific T-cell engagers (BiTEs) have demonstrated impressive antitumor efficacy in hematological malignancies, but the clinical potency is limited by their short half-life, inconvenient continuous intravenous infusion, and severe toxicity at relevant therapeutic levels in solid tumors. To address these critical issues, the design an ...[more]

PMID: 36932888

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Project description:Chemo-mild photothermal synergistic therapy can effectively inhibit tumor growth under mild hyperthermia, minimizing damage to nearby healthy tissues and skin while ensuring therapeutic efficacy. In this paper, we develop a multifunctional study based on polyhedral oligomeric sesquisiloxane (POSS) that exhibits a synergistic therapeutic effect through mild photothermal and chemotherapy treatments (POSS-SQ-DOX). The nanoplatform utilizes SQ-N as a photothermal agent (PTA) for mild photothermal, while doxorubicin (DOX) serves as the chemotherapeutic drug for chemotherapy. By incorporating POSS into the nanoplatform, we successfully prevent the aggregation of SQ-N in aqueous solutions, thus maintaining its excellent photothermal properties both in vitro and in vivo. Furthermore, the introduction of polyethylene glycol (PEG) significantly enhances cell permeability, which contributes to the remarkable therapeutic effect of POSS-SQ-DOX NPs. Our studies on the photothermal properties of POSS-SQ-DOX NPs demonstrate their high photothermal conversion efficiency (62.3%) and stability, confirming their suitability for use in mild photothermal therapy. A combination index value (CI = 0.72) verified the presence of a synergistic effect between these two treatments, indicating that POSS-SQ-DOX NPs exhibited significantly higher cell mortality (74.7%) and tumor inhibition rate (72.7%) compared to single chemotherapy and mild photothermal therapy. This observation highlights the synergistic therapeutic potential of POSS-SQ-DOX NPs. Furthermore, in vitro and in vivo toxicity tests suggest that the absence of cytotoxicity and excellent biocompatibility of POSS-SQ-DOX NPs provide a guarantee for clinical applications. Therefore, utilizing near-infrared light-triggering POSS-SQ-DOX NPs can serve as chemo-mild photothermal PTA, while functionalized POSS-SQ-DOX NPs hold great promise as a novel nanoplatform that may drive significant advancements in the field of chemo-mild photothermal therapy.

Dataset Information

Engineering Bifunctional Calcium Alendronate Gene-Delivery Nanoneedle for Synergistic Chemo/Immuno-Therapy Against HER2 Positive Ovarian Cancer.

Publications

Engineering Bifunctional Calcium Alendronate Gene-Delivery Nanoneedle for Synergistic Chemo/Immuno-Therapy Against HER2 Positive Ovarian Cancer.

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