RESUMO
Gene therapy is pivotal in nanomedicine, offering a versatile approach to disease treatment. This study aims to achieve an optimal balance between biocompatibility and efficacy, which is a common challenge in the field. A copolymer library is synthesized, incorporating niacin-derived monomers 2-acrylamidoethyl nicotinate (AAEN) or 2-(acryloyloxy)ethyl nicotinate (AEN) with N,N-(dimethylamino)ethyl acrylamide (DMAEAm) or hydrolysis-labile N,N-(dimethylamino)ethyl acrylate (DMAEA). Evaluation of the polymers' cytotoxicity profiles reveals that an increase in AAEN or DMAEA molar ratios correlates with improved biocompatibility. Remarkably, an increase in AAEN in both DMAEA and DMAEAm copolymers demonstrated enhanced transfection efficiencies of plasmid DNA in HEK293T cells. Additionally, the top-performing polymers demonstrate promising gene expression in challenging-to-transfect cells (THP-1 and Jurkat cells) and show no significant effect on modulating immune response induction in ex vivo treated murine monocytes. Overall, the best performing candidates exhibit an optimal balance between biocompatibility and efficacy, showcasing potential advancements in gene therapy.
Assuntos
Niacina , Polímeros , Humanos , Células HEK293 , Niacina/química , Niacina/farmacologia , Animais , Camundongos , Polímeros/química , Polímeros/farmacologia , Técnicas de Transferência de Genes , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Células Jurkat , Terapia Genética/métodos , Transfecção/métodos , Plasmídeos/genética , Células THP-1 , DNA/químicaRESUMO
Polymeric nanoparticles (NPs) with an integrated dual delivery system enable the controlled release of bioactive molecules and drugs, providing therapeutic advantages. Key design targets include high biocompatibility, cellular uptake, and encapsulating efficiency. In this study, a polymer library derived from niacin, also known as vitamin B3 is synthesized. The library comprises poly(2-(acryloyloxy)ethyl nicotinate) (PAEN), poly(2-acrylamidoethyl nicotinate) (PAAEN), and poly(N-(2-acrylamidoethyl)nicotinamide) (PAAENA), with varying hydrophilicity in the backbone and pendant group linker. All polymers are formulated, and those with increased hydrophobicity yield NPs with homogeneous spherical distribution and diameters below 150 nm, as confirmed by scanning electron microscopy and dynamic light scattering. Encapsulation studies utilizing a model drug, neutral lipid orange (NLO), reveal the influence of polymer backbone on encapsulation efficiency. Specifically, efficiencies of 46% and 96% are observed with acrylate and acrylamide backbones, respectively. Biological investigations showed that P(AEN) and P(AAEN) NPs are non-toxic up to 300 µg mL-1, exhibit superior cellular uptake, and boost cell metabolic activity. The latter is attributed to the cellular release of niacin, a precursor to nicotinamide adenine dinucleotide (NAD), a central coenzyme in metabolism. The results underline the potential of nutrient-derived polymers as pro-nutrient and drug-delivery materials.