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

Abstract

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. Passive tumor accumulation and active targeting of MTX-loaded polymeric nanoparticles to folate expressing cells were confirmed by intravenous administration of theseTc-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.

Radiolabelling of nanomaterials for medical imaging and therapy

“…As with other NP types, several studies have reported the radiolabelling of polymeric micelles with 99m Tc using the direct labelling method. [390][391][392][393][394][395][396][397][398] Once again, this was shown to be a robust technique; with reported RCYs generally being 495% under optimised conditions and serum stability ca. 98% after 24 h. [395][396][397] The radioiodination of polymeric micelles has also been reported.…”

Nano-engineered delivery systems for cancer imaging and therapy: Recent advances, future direction and patent evaluation

“…Increasing the survival rates of the treated mice indicate the potent anticancer effect of these polymer NPs. This study proved the availability to use these NPs as a potential theranostic replacement for both chemotherapeutic and diagnostic agent for cervical carcinoma [96].…”

Nanomaterials for Nanotheranostics: Tuning Their Properties According to Disease Needs

“…Encapsulation of methotrexate (MTX), a chemotherapeutic agent, in polymeric NPs is crucial in controlling its toxicity and side effects. 89 Two different block copolymers (poly(ethylene glycol)-b-poly(glutamic acid)-b-poly(ethylene glycol) (GEG) and poly(ethylene glycol)-bpoly(glutamic acid) (EG) conjugated with FA have been designed and used to encapsulate MTX. Both NPs, named M-GEG and M-EGFA NPs, are employed for passive and active targeting of cervical carcinoma, respectively [see Figure 3a (ii)].…”

“…Both NPs, named M-GEG and M-EGFA NPs, are employed for passive and active targeting of cervical carcinoma, respectively [see Figure 3a (ii)]. 89 FA has been used as a homing device to actively target and direct M-EGFA NPs towards the tumor, facilitating targeted drug release at the tumor site. On the other hand, M-GEG NPs passively target and accumulate at the cancer cells, by exploiting the EPR effect.…”