Abstract
Earlier we introduced the concept of ‘nanochemoprevention’ i.e. the use of nanotechnology to improve the outcome of cancer chemoprevention. Here, we extended our work and developed polymeric EGCG-encapsulated nanoparticles (NPs) targeted with small molecular entities, able to bind to prostate specific membrane antigen (PSMA), a transmembrane protein that is overexpressed in prostate cancer (PCa), and evaluated their efficacy in preclinical studies. First, we performed a molecular recognition of DCL- and AG-PEGylation on ligand binding on PSMA active site. Next, the biocompatible polymers PLGA-PEG-A were synthesized and used as base to conjugate DCL or AG to obtain the respective copolymers, needed for the preparation of targeted NPs. The resulting EGCG encapsulating NPs led to an enhanced anti-proliferative activity in PCa cell lines compared to the free EGCG. The behavior of EGCG encapsulated in NPs in modulating apoptosis and cell-cycle, was also determined. Then, in vivo experiments, in mouse xenograft model of prostatic tumor, using EGCG-loaded NPs, with a model of targeted nanosystems, were conducted. The obtained data supported our hypothesis of target-specific enhanced bioavailability and limited unwanted toxicity, thus leading to a significant potential for probable clinical outcome.
Highlights
In this study we developed novel nanosystems encapsulating EGCG, which demonstrated effective antiproliferative activity under in vitro conditions and significant increase of tumor growth inhibition in mouse xenograft model experiments, with respect to native compound
We obtained NPs with optimal combination of physicochemical characteristics, which are needed for preclinical evaluation
NPs composed of a blend of two polymers, PLGA-PEG-A or PLGA-PEG-DCL, or PLGA-PEG-AG, with PCL, resulted precisely controllable in terms of EGCG loading content, encapsulation efficiency and yields of production, peculiar issues for scale-up production
Summary
We and others have repeatedly verified the efficacy of green tea polyphenol, epigallocathechin-3-gallate (EGCG), in various preclinical models of human cancer(s) including that of the prostate gland, the applicability of its use to human has met with only limited success, largely due to inefficient systemic delivery and bioavailability[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. For PCa treatment, prostate-specific membrane antigen (PSMA), a well-known transmembrane protein that is overexpressed on PCa epithelial cells, has demonstrated a promising potential for the management of PCa29–31 To this end, functionalization of NPs with ligands that bind the extracellular domain of these receptors can be suited for selective delivery of bioactive molecules to diseased cells[32,33,34,35,36]. We planned to develop novel targeted polymeric EGCG-loaded biocompatible NPs, coated on their shell surface by small organic molecules as targeting ligands with specificity for PSMA. The goal of this study were to (i) develop novel targeted EGCG-loaded NPs to achieve active cellular targeting, (ii) investigate their anti-proliferative and mechanistic activity as compared to the non-targeted NPs and native EGCG, and, (iii) evaluate the in vivo preclinical efficacy of EGCG-encapsulated nanosystems. Tumor growth inhibition was monitored by quantitative determination of prostate specific antigen (PSA) levels in serum
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