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

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Specialty Biotechnology

Date 2022 Mar 29

PMID 35345787

Authors

Meng Si

Yanni Xia

Menglin Cong

Dandan Wang

Yong Hou

Hecheng Ma

Affiliations

Soon will be listed here.

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.

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References

Ow Y, Green D, Hao Z, Mak T . Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol. 2008; 9(7):532-42. DOI: 10.1038/nrm2434. View

Ritter J, Bielack S . Osteosarcoma. Ann Oncol. 2010; 21 Suppl 7:vii320-5. DOI: 10.1093/annonc/mdq276. View

Park S, Goldstein D, Krishnan A, Lin C, Friedlander M, Cassidy J . Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin. 2014; 63(6):419-37. DOI: 10.3322/caac.21204. View

Anninga J, Gelderblom H, Fiocco M, Kroep J, Taminiau A, Hogendoorn P . Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand?. Eur J Cancer. 2011; 47(16):2431-45. DOI: 10.1016/j.ejca.2011.05.030. View

Li Y, Yang H, Lee D . Advances in biodegradable and injectable hydrogels for biomedical applications. J Control Release. 2020; 330:151-160. DOI: 10.1016/j.jconrel.2020.12.008. View

Qiao M, Chen D, Ma X, Liu Y . Injectable biodegradable temperature-responsive PLGA-PEG-PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels. Int J Pharm. 2005; 294(1-2):103-12. DOI: 10.1016/j.ijpharm.2005.01.017. View

Kempf-Bielack B, Bielack S, Jurgens H, Branscheid D, Berdel W, Exner G . Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol. 2005; 23(3):559-68. DOI: 10.1200/JCO.2005.04.063. View

McTiernan A, Jinks R, Sydes M, Uscinska B, Hook J, Van Glabbeke M . Presence of chemotherapy-induced toxicity predicts improved survival in patients with localised extremity osteosarcoma treated with doxorubicin and cisplatin: a report from the European Osteosarcoma Intergroup. Eur J Cancer. 2011; 48(5):703-12. PMC: 3657154. DOI: 10.1016/j.ejca.2011.09.012. View

Hu J, Chen Y, Li Y, Zhou Z, Cheng Y . A thermo-degradable hydrogel with light-tunable degradation and drug release. Biomaterials. 2016; 112:133-140. DOI: 10.1016/j.biomaterials.2016.10.015. View

10.

Cheng E, Wei M, Weiler S, Flavell R, Mak T, LINDSTEN T . BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell. 2001; 8(3):705-11. DOI: 10.1016/s1097-2765(01)00320-3. View

11.

Widemann B, Adamson P . Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006; 11(6):694-703. DOI: 10.1634/theoncologist.11-6-694. View

12.

Swift L, Rephaeli A, Nudelman A, Phillips D, Cutts S . Doxorubicin-DNA adducts induce a non-topoisomerase II-mediated form of cell death. Cancer Res. 2006; 66(9):4863-71. DOI: 10.1158/0008-5472.CAN-05-3410. View

13.

Ma H, He C, Cheng Y, Li D, Gong Y, Liu J . PLK1shRNA and doxorubicin co-loaded thermosensitive PLGA-PEG-PLGA hydrogels for osteosarcoma treatment. Biomaterials. 2014; 35(30):8723-34. DOI: 10.1016/j.biomaterials.2014.06.045. View

14.

Ma H, He C, Chen X . Injectable Hydrogels as Local Depots at Tumor Sites for Antitumor Immunotherapy and Immune-Based Combination Therapy. Macromol Biosci. 2021; 21(6):e2100039. DOI: 10.1002/mabi.202100039. View

15.

Jeong B, Bae Y, Kim S . Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers. J Control Release. 2000; 63(1-2):155-63. DOI: 10.1016/s0168-3659(99)00194-7. View

16.

Siegel R, Miller K, Jemal A . Cancer statistics, 2020. CA Cancer J Clin. 2020; 70(1):7-30. DOI: 10.3322/caac.21590. View

17.

Oliva N, Conde J, Wang K, Artzi N . Designing Hydrogels for On-Demand Therapy. Acc Chem Res. 2017; 50(4):669-679. PMC: 6527116. DOI: 10.1021/acs.accounts.6b00536. View

18.

Yu L, Zhang Z, Ding J . Influence of LA and GA sequence in the PLGA block on the properties of thermogelling PLGA-PEG-PLGA block copolymers. Biomacromolecules. 2011; 12(4):1290-7. DOI: 10.1021/bm101572j. View

19.

Tanaka K, Kawamoto H, Saito I, Yoshimura K, Fukuda H, Iwamoto Y . Preoperative and postoperative chemotherapy with ifosfamide and adriamycin for adult high-grade soft-tissue sarcomas in the extremities: Japan Clinical Oncology Group Study JCOG0304. Jpn J Clin Oncol. 2009; 39(4):271-3. DOI: 10.1093/jjco/hyn153. View

20.

Loehrer P, Einhorn L . Drugs five years later. Cisplatin. Ann Intern Med. 1984; 100(5):704-13. DOI: 10.7326/0003-4819-100-5-704. View