Block copolymer based targeted nanocarriers for neuroendocrine cancer

Neuroendocrine tumors pose significant challenges in terms of effective treatment due to their heterogeneous nature and limited therapeutic options. The focus of this study is to address these challenges through the development of targeted polymeric micelles for the codelivery of 5-fluorouracil (5-FU) and ribociclib, a CDK4/6 inhibitor, to neuroendocrine tumors. This novel approach involves the synthesis of a 5-FU monomer, two types of amphiphilic block copolymers, and subsequent functionalization of one of the block copolymers with a targeting peptide. In this study, a polymerizable 5-FU monomer was prepared, and two types of block copolymers were synthesized using reversible addition- fragmentation chain transfer (RAFT) polymerization. One type of block copolymer was non- targeted, while the other contained an NHS group, and was functionalized with cRGDfK peptide via activated ester-amine chemistry, providing targeting capability. Micelles loaded with ribociclib were prepared using the synthesized block copolymers, and their size, stability, and drug loading were characterized. In vitro release studies of 5-FU and ribociclib from the micelles were conducted in buffer solutions. Cytotoxicity assays were performed on two neuroendocrine tumor cell lines using targeted and non-targeted ribociclib-loaded micelles, as well as non-targeted micelles. Additionally, the internalization of non-targeted and targeted micelles in these cells was evaluated. The results demonstrate the successful synthesis of a targeted polymeric micellar nanocarrier capable of delivering both 5-FU and ribociclib to neuroendocrine tumors. All micelles showed cytotoxic effect on the cell lines, and targeted micelles were internalized faster compared to the non-targeted micelles, indicating their potential for improved tumor-specific delivery of multiple therapeutic agents to effectively combat these challenging tumors.