Synthesis and characterization of variable conformation pH responsive block co-polymers for nucleic acid delivery and targeted cell entry

Teresa Matini,Stefano Salmaso,Cameron Alexander,Joaquin Sanchis,Paolo Caliceti,Nora Francini,Maria J Vicent,Anna Battocchio,Sebastian G Spain,Francesca Mastrotto,Elena Gallon,Giuseppe Mantovani

doi:10.1039/c3py00744h

Teresa Matini, Stefano Salmaso + Show 10 more

Open Access

https://doi.org/10.1039/c3py00744h

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Journal: Polym. Chem.	Publication Date: Jan 1, 2014
Citations: 36	License type: cc-by

Affiliation: University of Padua, University of Nottingham

Abstract

Responsive materials that change conformation with varying pH have been prepared from a range of amphiphilic block co-polymers. The individual blocks are composed of (a) permanently hydrophilic chains with neutral functionality and (b) acrylate polymers with weakly basic side-chains. Variation in co-monomer content, molar mass and block ratios/compositions leads to a range of pH-responses, manifest through reversible self-assembly into micelles and/or polymersomes. These transitions can be tuned to achieve environmental responses in a pH range from 5–7, as shown by turbidimetric analysis, NMR and dynamic light scattering measurements (DLS). Further characterization by transmission electron microscopy (TEM) indicates that polymersomes with diameters of 100–200 nm can be formed under certain pH-ranges where the weakly basic side-chains are deprotonated. The ability of the systems assembled with these polymers to act as pH-responsive containers is shown by DNA encapsulation and release studies, and their potential for application as vehicle for drug delivery is proved by cell metabolic activity and cell uptake measurements.

Highlights

Polymeric carriers offer many advantages for controlled release applications, drug delivery and nanomedicine.1–4 A number of macromolecular carrier systems are currently under investigation in order to improve the delivery of potent but delicate drugs such as proteins and nucleic acids.5,6 These systems need to be water-soluble, non-toxic and non-immunogenic, as well as compatible with serum components
Tetrahydrofuran anhydrous (THF), azobisisobutyronitrile (AIBN), imidazole, sodium hydride (NaH), sodium hydroxide (NaOH), methacryloyl chloride, 6-chloro-1-hexanol, 4-chloro-1butanol, acetic anhydride, magnesium sulfate, potassium carbonate (K2CO3), glycerol methacrylate (GMA), N,N0-dimethylamino pyridine (DMAP) dimethylsulfoxide anhydrous (DMSO), N,N0dimethylacetamide (DMAC), dichloromethane (DCM), ethyl acetate (EtOAc), methanol (MeOH), diethylether (Et2O), petroleum ether (b.p. 40–60 C), N,N0-dicyclohexylcarbodiimide (DCC), 4-cyano-4(phenylcarbonothioylthio)pentanoic acid (CPADB), triethylamine (Et3N), tri uoroacetic acid (TFA), N-hydroxysuccinimide (NHS) and t-Boc–NH–PEG3500Da were obtained from Sigma-Aldrich, Alfa Aesar, JenKem and Fisher Scienti c companies and used without further puri cation
In this work a novel family of N-alkyl imidazole monomers was designed to produce the pH-responsive domains of the intended drug nanocarriers

Summary

Introduction

Polymeric carriers offer many advantages for controlled release applications, drug delivery and nanomedicine. A number of macromolecular carrier systems are currently under investigation in order to improve the delivery of potent but delicate drugs such as proteins and nucleic acids. These systems need to be water-soluble, non-toxic and non-immunogenic, as well as compatible with serum components. A number of macromolecular carrier systems are currently under investigation in order to improve the delivery of potent but delicate drugs such as proteins and nucleic acids.. A number of macromolecular carrier systems are currently under investigation in order to improve the delivery of potent but delicate drugs such as proteins and nucleic acids.5,6 These systems need to be water-soluble, non-toxic and non-immunogenic, as well as compatible with serum components. Polymer based delivery systems must be capable of being either degraded to harmless breakdown products or eliminated entirely from the body These carriers need functional groups that allow them to interact with or encapsulate a drug of interest, and preferably should contain recognition motifs, which target disease-related antigens or receptors. The combination of these factors is hard to achieve with existing materials, leading to an urgent need for new highly functional and active biomedical polymers.

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