Breast cancer is the most prevalent and aggressive type of cancer, causing high mortality rates in women globally. Many drawbacks and side effects of the current chemotherapy force us to develop a robust chemotherapeutic system that can deal with off-target hazards and selectively combat cancer growth, invasiveness, and cancer-initiating cells. Here, a pH-responsive cross-linked nanocarrier (140-160 nm) endowed with poly-β-thioester functionality (CBAPTL) has been sketched and fabricated for noncovalent firm encapsulation of anticancer drug, parthenolide (PTL) at physiological pH (7.4), which enables sustain release of PTL at relevant endosomal pH (∼5.0-5.3). For this, a bolaamphiphilic molecule integrated with β-thioester and acrylate functionality was synthesized to fabricate the pH-responsive poly-β-thioester-based cross-linked nanocarrier via Michael addition click reactions in water. The poly-β-thioester functionality of CBAPTL hydrolyzes at endosomal acidic conditions, thus leading to the selective release of PTL inside the cancer cell. Cross-linked nanocarriers exhibit high serum stability, dilution insensitivity, and targeted cellular uptake at tumor microenvironment (TME), contrasting normal cells. In vitro study using human MCF-7 breast cancer cells demonstrated that CBAPTL exhibited selective cytotoxicity, reduced clonogenic potential, increased reactive oxygen species (ROS) generation, and arrested the progression of the cell cycle at the G0/G1 phase efficiently. CBAPTL induced apoptosis via downregulating pro-proliferative protein Bcl-2 and upregulating proapoptotic proteins p53, BAD, p21, and cleaved PARP-1. CBAPTL inhibited proliferating signaling by suppressing AKT phosphorylation and p38 expression. CBAPTL also blocked the invasion and migration of MCF-7 cells. CBAPTL effectively inhibits primary and secondary mammosphere formation, thereby preventing cancer-initiating cells' growth. Conversely, CBAPTL has negligible effect on human red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs). These findings highlight the superior efficacy of CBAPTL compared to PTL alone in suppressing cancer cell growth, inducing apoptosis, and preventing invasiveness of MCF-7 cells. Thus, CBAPTL could be considered a possible selective chemotherapeutic cargo against breast cancer without affecting normal cells.
Keywords: breast cancer cell; cross-linked nanocarrier; dual pH sensitivity; parthenolide encapsulation; poly-β-thioester; targeted drug delivery.