Block Copolymer Based Nanoparticles for Theranostic Intervention of Cervical Cancer: Synthesis, Pharmacokinetics, and in Vitro/in Vivo Evaluation in HeLa Xenograft Models

Polymer-based nanoparticles have proven to be viable carriers of therapeutic agents. In this study, we have developed nanoparticles (NPs) from polypeptide-polyethylene glycol based triblock and diblock copolymers. The synthesized block copolymers poly(ethylene glycol)-b-poly(glutamic acid)-b-poly(ethylene glycol) (GEG) and poly(ethylene glycol)-b-poly(glutamic acid) (EG) conjugated with folic acid for targeting specificity (EGFA) have been used to encapsulate methotrexate (MTX) to form M-GEG and M-EGFA NPs aimed at passive and active targeting of cervical carcinoma. In-vitro SRB cytotoxicity and hemolysis assays revealed that these NPs were cytocompatible to healthy human cells and hemocompatible to human RBCs. Cellular uptake by FACS demonstrated their prompt internalization by human cervical carcinoma (HeLa) cells and points toward an apoptotic mechanism of cell kill as confirmed by AO/EB staining as well as histological analysis of explanted HeLa tumors. Pharmacokinetics and biodistribution studies were performed in New Zealand albino rabbits and HeLa xenografted Athymic mice models, respectively, by radiolabeling these NPs with Tc-99m. Passive tumor accumulation and active targeting of MTX-loaded polymeric nanoparticles to folate expressing cells were confirmed by intravenous, administration of these Tc-99m-labeled M-GEG and M-EGFA NPs in HeLa tumor bearing nude mice and clearly visualized by whole-body gamma-SPECT images of these mice. Survival studies of these xenografted mice established the antiproliferative effect of these MTX-loaded NPs while corroborating the targeting effect of folic acid. These studies proved that the M-GEG NPs and M-EGFA NPs could be effective alternatives to conventional chemotherapy along with simultaneous diagnostic abilities and thus potentially viable theranostic options for human cervical carcinoma.