Abstract
Polymeric prodrugs, synthesized by conjugating chemotherapeutic agents to functional polymers, have been extensively investigated and employed for safer and more efficacious cancer therapy. By rational design, a pH and reduction dual-sensitive dextran-di-drugs conjugate (oDex-g-Pt+DOX) was synthesized by the covalent conjugation of Pt (IV) prodrug and doxorubicin (DOX) to an oxidized dextran (oDex). Pt (IV) prodrug and DOX were linked by the versatile efficient esterification reactions and Schiff base reaction, respectively. oDex-g-Pt+DOX could self-assemble into nanoparticles with an average diameter at around 180 nm. The acidic and reductive (GSH) environment induced degradation and drug release behavior of the resulting nanoparticles (oDex-g-Pt+DOX NPs) were systematically investigated by optical experiment, DLS analysis, TEM measurement, and in vitro drugs release experiment. Effective cellular uptake of the oDex-g-Pt+DOX NPs was identified by the human cervical carcinoma HeLa cells via confocal laser scanning microscopy. Furthermore, oDex-g-Pt+DOX NPs displayed a comparable antiproliferative activity than the simple combination of free cisplatin and DOX (Cis+DOX) as the extension of time. More importantly, oDex-g-Pt+DOX NPs exhibited remarkable reversal ability of tumor resistance compared to the cisplatin in cisplatin-resistant lung carcinoma A549 cells. Take advantage of the acidic and reductive microenvironment of tumors, this smart polymer-dual-drugs conjugate could serve as a promising and effective nanomedicine for combination chemotherapy.
Highlights
Nanosized drug delivery systems with an ability to load multiple chemotherapeutic agents simultaneously have gained considerable interest for precise and efficient cancer therapy [1,2,3,4,5,6]
A novel dual-drugs delivery system composed of nanocrystalline cellulose and L-lysine were developed for efficient co-encapsulation of model chemotherapeutic curcumin and methotrexate [19]
Previous reports demonstrated the application of these polymeric Nanosized drug delivery systems (nDDSs) for combination chemotherapy could conquer the problem of poor water solubility of most hydrophobic chemotherapeutic agents, improve their biodistribution, enhance treatment efficiency, and reduce the systemic toxicity
Summary
Nanosized drug delivery systems (nDDSs) with an ability to load multiple chemotherapeutic agents simultaneously have gained considerable interest for precise and efficient cancer therapy [1,2,3,4,5,6]. Previous reports demonstrated the application of these polymeric nDDSs for combination chemotherapy could conquer the problem of poor water solubility of most hydrophobic chemotherapeutic agents, improve their biodistribution, enhance treatment efficiency, and reduce the systemic toxicity. An effective way to further enhance the chemotherapeutic efficiency is to adopt tumor site-specific responsive linkage for drug conjugation. We prepare a novel pH and reduction dual-sensitive polymeric prodrug oDex-g-Pt+DOX, in which Pt (IV) prodrug was conjugated to the oxidized dextran (oDex) as reduction-sensitive segment, and DOX was conjugated via acid-cleavable hydrazone bond (Scheme 1). Our results revealed that this novel polymeric prodrug oDex-g-Pt+DOX NPs presented pH and reduction dual-triggered drug release behavior, could effectively kill cancer cells after intracellular internalization, and reverse cisplatin resistance in cisplatin-resistant lung carcinoma A549 cells (A549/DDP cells). The light yellow solution was freeze-dried to obtain oDex-g-Pt conjugates
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