N-2-Hydroxypropylmethacrylamide–Polycaprolactone Polymeric Micelles in Co-delivery of Proteasome Inhibitor and Polyphenol: Exploration of Synergism or Antagonism

Abstract

Breast cancer leads to the highest mortality among women resulting in a major clinical burden. Multidrug therapy is more efficient in such patients compared to monodrug therapy. Simultaneous combinatorial or co-delivery garnered significant interest in the past years. Caffeic acid (CFA) (a natural polyphenol) has received growing attention because of its anticarcinogenic and antioxidant potential. Bortezomib (BTZ) is a proteasome inhibitor and may be explored for treating breast cancer. Despite its high anticancer activity, the low water solubility and chemical instability restrict its efficacy against solid tumors. In the present study, we designed and investigated a HP-PCL (N-2hydroxypropylmethacrylamide−polycaprolactone) polymeric micellar (PMCs) system for the simultaneous delivery of BTZ and CFA in the treatment of breast cancer. The designed BTZ+CFA−HP-PCL PMCs were fabricated, optimized, and characterized for size, zeta potential, surface morphology, and in vitro drug release. Developed nanosized (174.6 ± 0.24 nm) PMCs showed enhanced cellular internalization and cell cytotoxicity in both MCF-7 and MDA-MB-231 cells. ROS (reactive oxygen species) levels were highest in BTZ−HP-PCL PMCs, while CFA−HP-PCL PMCs significantly (p < 0.001) scavenged the ROS generated in 2′,7′dichlorofluorescein diacetate (DCFH-DA) assay. The mitochondrial membrane potential (MMP) assay revealed intense and significant green fluorescence in both types of cancer cells when treated with BTZ−HP-PCL PMCs (p < 0.001) indicating apoptosis or cell death. The pharmacokinetic studies revealed that BTZ−HP-PCL PMCs and BTZ+CFA−HP-PCL PMCs exhibited the highest bioavailability, enhanced plasma half-life, decreased volume of distribution, and lower clearance rate than the pure combination of drugs. In the organ biodistribution studies, the combination of BTZ+CFA showed higher distribution in the spleen and the heart. Overall findings of in vitro studies surprisingly resulted in better therapeutic efficiency of BTZ−HP-PCL PMCs than BTZ+CFA−HP-PCL PMCs. However, the in vivo tumor growth inhibition study performed in tumor-induced mice concluded that the tumor growth was inhibited by both BTZ−HP-PCL PMCs and BTZ+CFA−HP-PCL PMCs (p < 0.0001) more efficiently than pure BTZ and the combination (BTZ+CFA), which may be due to the conversion of boronate ester into boronic acid. Henceforth, the combination of BTZ and CFA provides further indications to be explored in the future to support the hypothesis that BTZ may work with polyphenol (CFA) in the acidic environment of the tumor.

Molecular Efficacy of Gnetin C as Dual‐Targeted Therapy for Castrate‐Resistant Prostate Cancer

“…These factors may influence sensitivity to therapy and polyphenol's ability to modulate cell response to anticancer therapy. [30,66,70] Our results from 22Rv1-xenograft studies showed somewhat less efficacious effects in terms of reducing the tumor volume. Intriguingly, while tumors under combined treatment appeared to have a higher tumor volume, histopathology of these tumors demonstrated a higher percentage of intratumoral necrosis compared with vehicle-treated groups.…”

“…Notably, other studies have described the antagonism of natural polyphenols with some anticancer drugs. [ 30,70 ] Our in vitro cell viability results with various dose combinations indicated the importance of appropriate doses in co‐treatment approaches to achieve additive or synergistic effects. Moreover, it has been reported that natural products and individual polyphenols at lower doses exert more potent anti‐inflammatory and anticancer effects than at higher doses when used in vivo.…”

“…These factors may influence sensitivity to therapy and polyphenol's ability to modulate cell response to anticancer therapy. [ 30,66,70 ]…”