药物输送
白蛋白
下调和上调
体内
癌症研究
肿瘤微环境
化学
药理学
药品
紫杉醇
体外
毒品携带者
血清白蛋白
癌细胞
癌症
医学
内科学
生物化学
生物
肿瘤细胞
生物技术
有机化学
基因
作者
Binbin Zheng-Lin,Yanping Chen,Liman Niu,Mengjie Zhang,Y.B. Yang,Shanzhao Wang,Wei Chen,Zhiming Cai,Wei Huang,Weiren Huang
标识
DOI:10.1016/j.jconrel.2023.12.057
摘要
Insufficient delivery of therapeutic agents into solid tumors by systemic administration remains a major challenge in cancer treatment. Secreted protein acidic and rich in cysteine (SPARC) has high binding affinity to albumin and has been shown to enhance the penetration and uptake of albumin-based drug carriers in tumors. Here, we developed a strategy to alter the tumor microenvironment (TME) by upregulating SPARC to enhance the delivery efficiency of albumin-based drug carriers into tumors. We prepared albumin nanoparticles encapsulating an NF-κB controllable CRISPR activation system (SP-NPs). SP-NPs achieved tumor-selective SPARC upregulation by responding to the highly activated NF-κB in tumor cells. Whereas a single dose of SP-NPs only modestly upregulated SPARC expression, serial administration of SP-NPs created a positive feedback loop that induced progressive increases in SPARC expression as well as tumor cell uptake and tumor penetration of the nanoparticles in vitro, in organoids, and in subcutaneous tumors in vivo. Additionally, pre-treatment with SP-NPs significantly enhanced the anti-tumor efficacy of Abraxane, a commercialized albumin-bound paclitaxel nanoformulation. Our data provide evidence that modulating SPARC in the TME can enhance the efficiency of albumin-based drug delivery to solid tumors, which may result in new strategies to increase the efficacy of nanoparticle-based cancer drugs.
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