Abstract
In this paper, we report the polymersome-mediated intracellular delivery of pro-apoptotic BikDDA gene using two different peptide–copolymer covalent conjugation strategies specific for prostate cancer targeting. The BikDDA gene was used as a therapeutic agent on prostate cancer cells. The transfection efficiency of BikDDA-loaded poly[oligo(ethyleneglycol) methacrylate]-co-poly[2-(diisopropylamino) ethyl methacrylate] (P(OEG10MA)20-PDPA100) polymersomes revealed that they could serve as a suitable non-viral gene transfection tool. The targeted delivery of BikDDA into prostate cancer cells (LNCaP) using polymersomes was successfully carried out by conjugating the PSMA-targeting moiety (peptide 563) to P(OEG10MA)20-PDPA100 copolymer using either succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) as a bifunctional linker between the thiol-bearing targeting peptide and amino-bearing P(OEG10MA)20-PDPA100 copolymer or attaching a maleimide-modified targeting peptide onto a thiol-terminated P(OEG10MA)20-PDPA100 copolymer. The pH-responsive and biocompatible polymersomes, conjugated with peptide 563, exhibited an enhanced cellular uptake by LNCaP cells in comparison to the healthy prostate epithelial cell line PNT1A, thus indicating the cell-specific delivery. The increased Bik mRNA expression and cell death in these LNCaP cells indicates high effectiveness of the targeting polymersomes. According to these results, we believe more efficient gene delivery systems via specifically targeted pH-sensitive polymersomes can be a promising approach and promote the development of novel therapies against prostate cancer.
Highlights
Prostate cancer is the second most common type of cancer amongst men, with 1.1 million cases recorded worldwide (International Agency for Research on Cancer 2012)
As the second conjugation strategy, the NH2-P(OEG10MA)20PDPA100 copolymer was primarily reacted with the succinimide group of succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) by the using NHS ester amidification reaction in DMF to functionalize the copolymer with the maleimide group, purified by dialysis to remove unreacted SMCC
Peptide-copolymer conjugation was achieved by the reaction between maleimide-thiol groups and using SMCC as a linker between the peptide cysteine residual and a primary amine expressed in the copolymer
Summary
Prostate cancer is the second most common type of cancer amongst men, with 1.1 million cases recorded worldwide (International Agency for Research on Cancer 2012). In order to eliminate the shortcomings of conventional therapies and to replace the standard treatment protocols, employment of the novel nanomaterials ranging from polymer / lipid based particles (e.g. polymersomes, dendrimers, micelles, mesoporous silica particles, and liposomes) to metallic particles (e.g. gold / silver particles), resulting in major improveme nts. These nanoscale tools can be utilized to offer controlled drug release, enhance drugs’ pharmacokinetic profiles, reduce dosage amounts and frequency, augment cell permeability, enable targeted molecule delivery and improve therapeutic efficacy/safety (Banik et al 2016). From this point of view, the targeted delivery of pro-apoptotic genes and/or drugs to specific cancer cells using nanomaterials represents a promising approach
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