Cellular Uptake and Cytotoxic Effect of Epidermal Growth Factor Receptor Targeted and Plitidepsin Loaded Co-Polymeric Polymersomes on Colorectal Cancer Cell Lines

Abstract

Encapsulating chemotherapy drugs in targeted nanodelivery systems is one of the most promising approaches to tackle cancer disease, avoiding side effects of common treatment. In the last decade, several nanocarriers with different nature have been tested, but polypeptide-based copolymers have attracted considerable attention for their biocompatibility, controlled and slow biodegradability as well as their low toxicity. In this work, we synthesized, characterized and evaluated poly(trimethylene carbonate)-bock-poly(L-glutamic acid) derived polymersomes, targeted to epidermal growth factor receptor (EGFR), loaded with plitidepsin and ultimately tested in HT29 and LS174T colorectal cancer cell lines for specificity and efficacy. Furthermore, morphology, physico-chemical properties and plitidepsin loading were carefully investigated. A thorough in vitro cytotoxicity analysis of the unloaded polymersomes was carried out for biocompatibility check, studying viability, cell membrane asymmetry and reactive oxygen species levels. Those cytotoxicity assays showed good biocompatibility for plitidepsin-unloaded polymersomes. Cellular uptake and cytotoxic effect of EGFR targeted and plitidepsin loaded polymersome indicated that colorectal cancer cell lines were.more sensitive to anti-EGFR-drug-loaded than untargeted drug-loaded polymersomes. Also, in both cell lines, the use of untargeted polymersomes greatly reduced plitidepsin cytotoxicity as well as the cellular uptake, indicating that the use of this targeted nanocarrier is a promising approach to tackle colorectal cancer disease and avoid the undesired effects of the usual treatment. Furthermore, in vivo assays support the in vitro conclusions that EGFR targeted polymersomes could be a good drug delivery system. This work provides a proof of concept for the use of encapsulated targeted drugs as future therapeutic treatments for cancer.

Plitidepsin: design, development, and potential place in therapy

“…In search of alternatives, two nanoparticle-based formulations of plitidepsin have been tested in a renal xenograft tumor model,22 showing equivalent anticancer activity, compared to the Cremophor ® formulation, but improved biodistribution profiles, presenting novel tools for future plitidepsin-based therapies. Also, in colorectal cancer cell lines, the use of epidermal growth factor receptor (EGFR) targeted polymersomes greatly reduced plitidepsin cytotoxicity as well as the cellular uptake, indicating that the use of this targeted nanocarrier is a promising approach to tackle colorectal cancer disease and avoid the undesired effects of the usual treatment 23…”

Epidermal growth factor receptor based active targeting: a paradigm shift towards advance tumor therapy

“…Goñi-de-Cerio et al [19] synthesized polypeptide-based copolymers such as poly (trimethylene carbonate)-bockpoly(L-glutamic acid) and encapsulated plitidepsin for targeting potential to EGFR with regard to HT29 and LS174T colorectal cancer cell lines. The cytotoxicity profile indicated excellent biocompatibility and cellular uptake of EGFR targeted and plitidepsin loaded polymersome indicated that colorectal cancer cell lines were more sensitive to anti-EGFRdrug-loaded than non-targeted drug-loaded polymersomes [19].…”

Recent Progress of Marine Polypeptides as Anticancer Agents

“…A recent investigation demonstrated that plitidepsin exerts its antitumor activity by targeting eEF1A2 [49]. Nanoparticles with poly (trimethylene carbonate)-bockpoly(L-glutamic acid) derived polymersomes and plitidepsin were designed to target epidermal growth factor receptor (EGFR) and results have showed that the new designed composite exhibited significant antitumor activity against cancer cells overexpressing EGFR both in vitro and in vivo [50].…”