PEGylated Amine-Functionalized Poly(ε-caprolactone) for the Delivery of Plasmid DNA

Abstract

As a promising strategy for the treatment of various diseases, gene therapy has attracted increasing attention over the past decade. Among various gene delivery approaches, non-viral vectors made of synthetic biomaterials have shown significant potential. Due to their synthetic nature, non-viral vectors can have tunable structures and properties by using various building units. In particular, they can offer advantages over viral vectors with respect to biosafety and cytotoxicity. In this study, a well-defined poly(ethylene glycol)-block-poly(α-(propylthio-N,N-diethylethanamine hydrochloride)-ε-caprolactone) diblock polymer (PEG-b-CPCL) with one poly(ethylene glycol) (PEG) block and one tertiary amine-functionalized cationic poly(ε-caprolactone) (CPCL) block, as a novel non-viral vector in the delivery of plasmid DNA (pDNA), was synthesized and studied. Despite having a degradable polymeric structure, the polymer showed remarkable hydrolytic stability over multiple weeks. The optimal ratio of the polymer to pDNA for nanocomplex formation, pDNA release from the nanocomplex with the presence of heparin, and serum stability of the nanocomplex were probed through gel electrophoresis. Nanostructure of the nanocomplexes was characterized by DLS and TEM imaging. Relative to CPCL homopolymers, PEG-b-CPCL led to better solubility over a wide range of pH. Overall, this work demonstrates that PEG-b-CPCL possesses a range of valuable properties as a promising synthetic vector for pDNA delivery.

Well-Defined Diblock Poly(ethylene glycol)-b-Poly(ε-caprolactone)-Based Polymer-Drug Conjugate Micelles for pH-Responsive Delivery of Doxorubicin

“…Alkyne-functionalized CL (1) was synthesized according to Scheme 1, based on a previously reported procedure but with allyl bromide replaced by propargyl bromide [22]. The structure of 1 was confirmed using 500 MHz 1 H NMR analysis in CDCl 3 (Figure 2a).…”

“…The structure of 1 was confirmed using 500 MHz 1 H NMR analysis in CDCl3 (Figure 2a). Alkyne-functionalized CL (1) monomer was polymerized using the ROP technique with TBD as the organocatalyst [17,22,23,28,33]. Due to the water-sensitive nature of this reaction, all the reagents must be adequately dried.…”

“…PCL is composed of hexanoate repeat units. As an FDA-approved polymer for clinic use, PCL has been utilized in a broad range of biomedical applications, such as drug and gene delivery, implants, stents, and prosthetics [19][20][21][22][23]. Some of the properties of polymeric micelles are associated with the type of the hydrophobic block of the PDC.…”

“…As an FDA-approved polymer for clinic use, PCL has been utilized in a broad range of biomedical applications, such as drug and gene delivery, implants, stents, and prosthetics [19][20][21][22][23]. All of these notable applications rely on the biodegradable feature of PCL [22]. In vivo degradation of PCL leads to nontoxic 6-hydroxyhexanoic acid, which is a natural human body metabolite [24].…”

Well-Defined pH-Responsive Self-Assembled Block Copolymers for the Effective Codelivery of Doxorubicin and Antisense Oligonucleotide to Breast Cancer Cells

“…Significant advancements in cancer treatment have been achieved by gene therapy, in which nucleic acids such as DNA, antisense oligonucleotides, miRNA, and siRNA are delivered to tumor cells to result in therapeutic effects via various mechanisms. − This has motivated the development of cationic nanocarriers which can condense with the therapeutic genes and help overcome the preclinical limitations associated with this mode of therapy, such as low stability and poor transfection efficiency of naked genes . Substantial progresses have been achieved using positively charged chitosan, polylysine, polyamidoamine dendrimer, poly­(2-(dimethylamino)­ethyl methacrylate) (PDMAEMA), − poly­(β-amino ester), polyethyleneimine, cationic polylactide, and cationic polypeptide with tunable charge density, providing good protection and enhanced cellular uptake of the loaded genes. − Owing to the complex nature of cancer tissues, the integration of gene therapy with chemotherapy has gained remarkable attention because it can result in higher therapeutic potency due to its synergistic effects. − Therefore, there has been substantial effort in developing nanocarriers to enable the co-delivery of chemotherapeutic drugs and antitumor genes, meanwhile allowing site-specific release of the loaded cargos.…”