期刊
SCIENCE ADVANCES
卷 7, 期 6, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aba0776
关键词
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资金
- National Natural Science Foundation of China [51973135]
- National Key Research and Development Program of China [2018YFC1106100, 2018YFC1106103]
- 111 Project [B18035]
- Institute of Biomaterials, Drug Delivery and Regenerative Medicine
By developing cascade-targeting, dual drug-loaded core-shell nanoparticles, precise drug delivery to tumors and overcoming biological barriers were achieved; the degradation of hyaluronic acid shell facilitated drug release and cellular uptake, while the exposure of triphenylphosphonium derivative core allowed for mitochondria-targeted delivery, ultimately inhibiting tumor growth.
Nanoparticle-based drug delivery faces challenges from the imprecise targeted delivery and the low bioavailability of drugs due to complex biological barriers. Here, we designed cascade-targeting, dual drug-loaded, core-shell nanoparticles (DLTPT) consisting of CD44-targeting hyaluronic acid shells decorated with doxorubicin (HA-DOX) and mitochondria-targeting triphenylphosphonium derivative nanoparticle cores loaded with lonidamine (LND) dimers (LTPT). DLTPT displayed prolonged blood circulation time and efficiently accumulated at the tumor site due to the tumor-homing effect and negatively charged hyaluronic acid. Subsequently, the HA-DOX shell was degraded by extracellular hyaluronidase, resulting in decreased particle size and negative-to-positive charge reversal, which would increase tumor penetration and internalization. The degradation of HA-DOX further accelerated the release of DOX and exposed the positively charged LTPT core for rapid endosomal escape and mitochondria-targeted delivery of LND. Notably, when DLTPT was used in combination with anti-PD-L1, the tumor growth was inhibited, which induced immune response against tumor metastasis.
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