A Co-delivery System Based on a Dimeric Prodrug and Star-Shaped Polymeric Prodrug Micelles for Drug Delivery.

Man Zhou,Man Zhou,Xiaoqing Yi,Xiuguang Yi,Tingting Chen,Weijia Zeng,Yongxiu Li,Xiaoqing Yang,Lulu Zhang,Yan Luo,Yan Luo,Xiaoyan He

doi:10.3389/fchem.2021.765021

Abstract

Chemotherapy is one of the commonly used therapies for the treatment of malignant tumors. Insufficient drug-loading capacity is the major challenge for polymeric micelle–based drug delivery systems of chemotherapy. Here, the redox-responsive star-shaped polymeric prodrug (PSSP) and the dimeric prodrug of paclitaxel (PTX) were prepared. Then the dimeric prodrug of PTX (diPTX, diP) was loaded into the core of the star-shaped polymeric prodrug micelles of PSSP by hydrophobic interaction forming the redox-responsive prodrug micelles of diPTX@PSSP for intracellular drug release in tumor cells. The hydrodynamic diameter of diPTX@PSSP nanoparticles was 114.3 nm ± 2.1 (PDI = 0.219 ± 0.016), and the micelles had long-term colloidal stability and the drug-loading content (DLC) of diPTX and PTX is 16.7 and 46.9%, respectively. The prepared micelles could broke under the reductive microenvironment within tumor cells, as a result, the dimeric prodrug of diP and polymeric prodrug micelles of PSSP were rapidly disassembled, leading to the rapid release of intracellular drugs. In vitro release studies showed that under the condition of reduced glutathione (GSH) (10 mM), the release of PTX was significantly accelerated with approximately 86.6% released within 21 h, and the released PTX in cytoplasm could promote the disintegration of microtubules and induce cell apoptosis. These results indicated that the new type of this reduction-sensitive nanodrug delivery system based on dimeric prodrug@polymeric prodrug micelles would be a promising technology in chemotherapy.

Highlights

Polymeric micelles with a well-defined core-shell structure, which can improve the solubility, bioavailability, and circulation half-life of hydrophobic drugs became a promising nanocarrier for cancer treatment (Feng et al, 2020; Gauger et al, 2020; Yi et al, 2021a)
SCHEME 1 | A reduction-sensitive nanodrug delivery system based on dimeric prodrug@polymeric prodrug micelles for drug delivery. (A) The structure of the starshaped polymeric prodrug (4-arm PEG-SS-PTX, PSSP) and reduction-sensitive dimer-PTX (PTX-SS-PTX, diP) with disulfide linker. (B) diP was encapsulated into the core of PSSP micelles to obtain diP@PSSP micelles by hydrophobic effect. (C) PTX release mechanism of diP@PSSP micelles in tumor cells
Nano-sized polymeric micelles can efficiently accumulate in tumor tissues, insufficient drug loading is still one of the main challenges for polymeric micelles in the drug delivery system

Summary

INTRODUCTION

Polymeric micelles with a well-defined core-shell structure, which can improve the solubility, bioavailability, and circulation half-life of hydrophobic drugs became a promising nanocarrier for cancer treatment (Feng et al, 2020; Gauger et al, 2020; Yi et al, 2021a). In order to obtain the nanodrug delivery system with a high drug-loading content (DLC), in this study, a prodrug micelle with DLC composed of a redox-responsive star-shaped polymeric prodrug of paclitaxel (PTX) and a redox-responsive dimeric prodrug of PTX was established to inhibit the growth of FIGURE 3 | 1H NMR spectrum (400 MHz, d-DMSO) of PSSP. The diP@PSSP micelle has good stability, the size of the diP@PSSP micelle is 114.3 nm ± 2.1 (PDI 0.219 ± 0.016), and the DLC of diPTX and PTX is 16.7 and 46.9%, respectively This diP@PSSP micelle is internalized into tumor cells by EPR effect and the disulfide. The released drug would disrupt the balance of microtubule polymerization and depolymerization to inhibit the growth of tumor cells

RESULTS AND DISCUSSION

CONCLUSION

DATA AVAILABILITY STATEMENT