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Doxorubicin and CD?CUR inclusion complex co?loaded in thermosensitive hydrogel PLGA?PEG?PLGA localized administration for osteosarcoma.

ABSTRACT: Combination therapy is a promising and prevalent strategy for osteosarcoma treatment. Curcumin (CUR), as a chemosensitizer, improves the antitumor effect of first?line chemotherapy drugs. However, due to its poor solubility and instability in physiological conditions, the bioavailability of CUR is limited. In order to improve the physicochemical properties of natural CUR, ??cyclodextrin was adopted to generate a ??cyclodextrin curcumin (CD?CUR) inclusion complex. A thermosensitive hydrogel, poly(D,L?lactide?co?glycolide)-poly(ethylene?glycol)?poly(D,L?lactide?co?glycolide), was selected and synthesized to co?deliver doxorubicin (DOX) and CD?CUR to tumor sites. The dual?drug delivery system (gel+DOX+CD?CUR) was prepared by mixing drugs with hydrogels and had a perfect sol?gel phase transition temperature (18.3?C for 20% concentration). Both DOX and CUR were released from hydrogels in a sustained manner in PBS (pH 7.4) medium. The combination therapy based on DOX+CD?CUR exhibited higher antitumor activity than monotherapies in vitro. Combined CD?CUR therapy significantly downregulated Bcl?2 expression and upregulated caspase?3 expression, suggesting that DOX combined with CD?CUR treatment has a higher apoptosis?inducing efficiency. The antitumor efficiency of the gel+DOX+CD?CUR strategy was evaluated in K?7 tumor?bearing mice, and this localized combination therapy demonstrated a higher antitumor efficiency compared with free DOX+CD?CUR or single?drug strategies. There were no significant differences in body weight and histological changes of major organs in each group. Therefore, the present combination treatment based on hydrogel may be a feasible approach to co?deliver DOX and CD?CUR to osteosarcoma tumor sites in clinical practice.

SUBMITTER: Yang Z

PROVIDER: S-EPMC7307595 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Doxorubicin and CD‑CUR inclusion complex co‑loaded in thermosensitive hydrogel PLGA‑PEG‑PLGA localized administration for osteosarcoma.

Yang Zhiming Z Liu Jianguo J Lu Yichen Y

International journal of oncology 20200519 2

Combination therapy is a promising and prevalent strategy for osteosarcoma treatment. Curcumin (CUR), as a chemosensitizer, improves the antitumor effect of first‑line chemotherapy drugs. However, due to its poor solubility and instability in physiological conditions, the bioavailability of CUR is limited. In order to improve the physicochemical properties of natural CUR, β‑cyclodextrin was adopted to generate a β‑cyclodextrin curcumin (CD‑CUR) inclusion complex. A thermosensitive hydrogel, poly ...[more]

PMID: 32468050

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Project description:PurposeOsteosarcoma is considered as the most common primary malignant bone tumor in children and adolescents, and the treatments including chemotherapy and surgery were far from satisfactory. Localized tumor treatments by hydrogels incorporating combined chemotherapeutic drugs have recently emerged as superior approaches for enhanced anti-tumor effects and reduced systemic toxicity.MethodsA novel injectable thermosensitive poly (lactide-co- glycolide)-poly (ethylene glycol)-poly(lactide-co-glycolide) triblock copolymer hydrogel containing doxorubicin and cisplatin for the localized chemotherapy of osteosarcoma were synthesized and characterized. The in vitro drug release properties of the drugs-loaded hydrogels were investigated. To study the anti-tumor efficacy of hydrogels depots in vitro, the cytotoxicity and apoptosis rate against Saos-2 and MG-63 cells were evaluated by MTT, Annexin V and PCR methods. The in vivo synergistic anti-tumor efficacy of the multi-drugs co-loaded hydrogels was investigated by human osteosarcoma xenografts. Additionally, the systemic toxic side effects were evaluated by ex vivo histological analysis of the major organs of the mice.ResultsThe PLGA-PEG-PLGA copolymer solution underwent a sol-gel transition at appropriate temperature and degraded in the PBS, presenting a friendly biocompatibility in vitro. The in vitro cell viability tests demonstrated that DOX and CDDP co-loaded hydrogels exhibited synergistic anti-proliferation effect, due to the sustained release of drugs from the drugs-loaded hydrogel. The treatment with DOX and CDDP co-loaded hydrogel led to the highest efficiency in inhibiting the tumor growth, enhanced tumor necrosis rate and increased regulation of the apoptosis-related gene expressions, indicating a synergistic anti-tumor efficacy in vivo. Additionally, ex vivo histological analysis of the nude mice exhibited low systemic toxicity.ConclusionThe combination treatment of osteosarcoma by localized, sustained co-delivery of DOX and CDDP by PLGA-PEG-PLGA hydrogel may serve as a promising strategy for efficient clinical treatment of osteosarcoma.

Dataset Information

Doxorubicin and CD?CUR inclusion complex co?loaded in thermosensitive hydrogel PLGA?PEG?PLGA localized administration for osteosarcoma.

Publications

Doxorubicin and CD‑CUR inclusion complex co‑loaded in thermosensitive hydrogel PLGA‑PEG‑PLGA localized administration for osteosarcoma.

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