RGD-directed 24 nm micellar docetaxel enables elevated tumor-liver ratio, deep tumor penetration and potent suppression of solid tumors

Wencheng Yan; Beibei Guo; Zhe Wang; Jiangtao Yang; Zhiyuan Zhong; Fenghua Meng

doi:10.1016/j.jconrel.2023.06.032

RGD-directed 24 nm micellar docetaxel enables elevated tumor-liver ratio, deep tumor penetration and potent suppression of solid tumors

J Control Release. 2023 Aug:360:304-315. doi: 10.1016/j.jconrel.2023.06.032. Epub 2023 Jul 4.

Authors

Wencheng Yan¹, Beibei Guo², Zhe Wang¹, Jiangtao Yang¹, Zhiyuan Zhong³, Fenghua Meng⁴

Affiliations

¹ Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China.
² Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, PR China.
³ Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, PR China. Electronic address: zyzhong@suda.edu.cn.
⁴ Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China. Electronic address: fhmeng@suda.edu.cn.

PMID: 37356754
DOI: 10.1016/j.jconrel.2023.06.032

Abstract

Nanomedicines while showing a great potential in improving the performance of chemotherapeutics like docetaxel (DTX) are distressed by a high liver deposition and poor tumor penetration, which might not only cause liver toxicity but also moderate therapeutic effect. Herein, we report that cRGD-directed 24 nm disulfide-crosslinked micellar docetaxel (cRGD-MDTX) presents low liver accumulation, high tumor uptake, and deep tumor penetration, leading to the potent suppression of different solid tumors. cRGD-MDTX was optimized with a cRGD density of 4% and DTX loading of 10 wt%. Interestingly, cRGD-MDTX enabled an extraordinary tumor-liver ratio of 2.8/1 with a DTX uptake of 8.3 %ID/g in α_vβ₃ over-expressing PC3 prostate tumor. The therapeutic studies demonstrated striking antitumor effects of cRGD-MDTX toward PC3 prostate tumor, prostate cancer patient-derived xenografts (PDX), orthotopic A549-Luc lung cancer and orthotopic SKOV3-Luc ovarian tumor models, in which tumor growth was effectually inhibited and 6-8 times better improvement of median survival time over free DTX was observed. This small disulfide-crosslinked micellar drug capable of relegating liver deposition opens a new avenue to nanomedicines for targeted therapy.

Keywords: Docetaxel; Liver filtration; Micelles; Targeted delivery; Tumor penetration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Cell Line, Tumor
Disulfides
Docetaxel / therapeutic use
Humans
Liver Neoplasms* / drug therapy
Male
Micelles
Oligopeptides
Prostatic Neoplasms* / drug therapy

Substances

Docetaxel
Micelles
Disulfides
Oligopeptides
Antineoplastic Agents