In situ Co-Delivery of Doxorubicin and Cisplatin by Injectable Thermosensitive Hydrogels for Enhanced Osteosarcoma Treatment

Abstract

Purpose Osteosarcoma 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. Methods A 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. Results The 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. Conclusion The 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.

Research progress on albumin-based hydrogels: Properties, preparation methods, types and its application for antitumor-drug delivery and tissue engineering

“…Hydrogel injections in situ at the site of prostate cancer can protect the rectum from damage by reducing exposure to chemotherapy drugs ( Pinkawa et al, 2016 ; Yu et al, 2023 ). For the treatment of osteosarcoma, in situ injections of hydrogels loaded with DOX and cisplatin are also better at preventing tumor reoccur or metastasis, while also reducing the systemic toxic effects of the drug ( Si et al, 2022 ). Compared to the four types of cancer (breast cancer, rectal cancer, prostate cancer and osteosarcoma) described above, there are currently fewer cases of injectable hydrogels being used in liver or lung cancer.…”

PLGA-based drug delivery systems in treating bone tumors

“…In vitro cell viability assays showed that the hydrogels co-loaded with DOX and CDDP exhibited synergistic anti-proliferative effects as well as high tumor growth inhibition efficiency. The in vivo experimental results indicated that the PLGA-PEG-PLGA hydrogel for local combination chemotherapy promoted increased tumor necrosis and enhanced the modulation of the expression of apoptosis-related genes ( Si et al, 2022 ), indicating synergistic anti-tumor effectiveness in vivo with low systemic toxicity. These results indicated that persistent local co-delivery of DOX and CDDP via PLGA-PEG-PLGA hydrogels could be a promising approach to effectively treating osteosarcoma in the clinic.…”

Doxorubicin-Loaded Microalgal Delivery System for Combined Chemotherapy and Enhanced Photodynamic Therapy of Osteosarcoma

“…4−6 However, chemotherapy is generally accompanied by severe side-effects, poor prognosis, and poor survival. 7,8 Moreover, tumor hypoxia, as one of the characteristics of the tumor microenvironment (TME), severely limited the therapeutic efficiency oxygen-related tumor therapies, such as radiotherapy and photodynamic therapy. 9−13 Tumor hypoxia also often associated with tumor invasion, metastasis, and recurrence.…”

“…Osteosarcoma (OS) is the most common primary malignant bone tumor affecting children and adolescents. − The traditional therapy for OS is surgical resection combined with chemotherapy or radiotherapy. − However, chemotherapy is generally accompanied by severe side-effects, poor prognosis, and poor survival. , Moreover, tumor hypoxia, as one of the characteristics of the tumor microenvironment (TME), severely limited the therapeutic efficiency oxygen-related tumor therapies, such as radiotherapy and photodynamic therapy. − Tumor hypoxia also often associated with tumor invasion, metastasis, and recurrence. , Currently, nanomaterial-based drug delivery systems have been developed to solve these problems. − Such nanodrug delivery systems are able to integrate various functions of targeting, therapeutics, and imaging within a single platform. − Furthermore, oxygen-carrying nanoplatforms were employed as oxygen shuttles to deliver oxygen and relieve tumor hypoxia. , Despite these advantages, these materials are intensively stuck with complex synthetic procedures, high cost, and unexpected toxicity, limiting their use in biological applications. Therefore, there is an urgent need for new strategies for OS treatment with fewer side-effects, higher efficacy, lower cost, and multifunctionality.…”