Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 12, Issue 1, Pages 1707-1720Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.9b20178
Keywords
drug combination; cytotoxic drug; apatinib; metastasis inhibition; cancer nanomedicine
Funding
- National Natural Science Foundation of China [81773193, 81571799, 81972745]
- Zhejiang Province Preeminence Youth Fund [LR19H160002]
- National Science and Technology Major Project [2017ZX10203205]
- Ten Thousand Plan Youth Talent Support Program of Zhejiang Province [ZJWR0108009]
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Combinatorial regimens that rationally pair molecular inhibitors with standard cytotoxic chemotherapeutics are used to improve therapeutic outcomes. Simultaneously engineering these therapies within a single nanocarrier that spans cytotoxic, antiangiogenic, and anti-invasive mechanisms and that enables the delivery of unique drug combinations remains a technical challenge. In this study, we developed a simple and broadly applicable strategy in which ultrastable cytotoxic nanoparticles with an established excellent antitumor efficacy and pi-rich inner core structure supramolecularly stabilized the antiangiogenic molecular inhibitor apatinib to create a synergistic drug delivery system (termed sTKI-pSN38). This small-sized nanoparticle accomplished the sequential release of both encapsulated drugs to exert antimetastatic, antivascular, and cytotoxic activities simultaneously. In xenograft models of hepatocellular carcinoma, a single intravenous administration of sTKI-pSN38 elicited robust and durable tumor reduction and suppressed metastasis to lymph nodes. Interestingly, sTKI-pSN38 treatment alleviated intratumoral hypoxia, which could contribute to impaired tumor metastasis and reduced drug resistance. Collectively, this nanotherapeutic platform offers a new strategy for cancer therapy by simply engineering a drug cocktail in conventional nanoparticles and by enabling the spatiotemporal modulation of drug release to enhance the synergy of the combined drugs.
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