3,4-Dihydroxyhydrocinnamic acid conjugated methoxy-poly(ethylene glycol)-poly(lactic acid) polymeric micelles for Bortezomib delivery and efficacy enhancement in doxorubicin-resistant breast cancer

Abstract

Breast cancer (BC) is one of the significant malignant cancers diagnosed in women and is the second cause of mortality in women worldwide. Bortezomib (BTZ) treatment via conventional therapy causes off-targeting and premature drug release. Conjugation of 3,4-dihydroxyhydrocinnamic acid (DC), a phenolic compound with methoxy-poly (ethylene glycol)-poly (D, L-lactide) [mPP] to form a self-assembled amphiphilic polymer, mPP-DC to load BTZ will enhance the drug loading efficiency and provides the synergetic anti-cancerous effect. ¹H NMR and FTIR confirmed the synthesis of the product. Several physicochemical characterization studies were performed, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic light scattering (DLS), X-ray diffraction (XRD) techniques, critical micelles concentration (CMC) determination, encapsulation efficiency (EE), % drug loading (DL), cumulative drug release, and hemolysis studies for the BTZ-mPP and BTZ-mPP-DC micelles. In vitro cell studies were performed using MCF-7 sensitive (S) and MCF-7 resistant (R) cells. Cytotoxicity study showed a reduced IC₅₀ value of the BTZ-mPP-DC compared to free drug and BTZ-mPP. Other in vitro studies such as cellular uptake, mitochondrial membrane potential (MMP) assay, reactive oxygen species (ROS), cell cycle analysis, colony formation assay, anti-proliferation assay, and western blot analysis were performed in both the cells. In vivo pharmacokinetics study was done to analyze the bioavailability of the formulation in the body for a long time. The developed biodegradable, biocompatible nanoformulation showed excellent penetration and cytotoxicity to the cancer cells; hence, BTZ-mPP-DC proves its novel efficacy in cancer treatment, especially in breast cancer.