Amphiphilic and biodegradable methoxy polyethylene glycol-block-(polycaprolactone-graft-poly(2-(dimethylamino)ethyl methacrylate)) as an effective gene carrier (2023)

Poly(ε-caprolactone) (PCL) has been one of the most important biomaterials, but its instinct hydrophobicity and slow biodegradation limit its broad applications. Herein, copolymerization of CL and a hydrophilic macrolactone, 2-oxo-15-crown-5 ether (O15C), was achieved through ring opening polymerization catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) using benzyl alcohol as the initiator at room temperature. A series of poly(CL-co-O15C) copolymers with different O15C contents were prepared by simply tuning the feeding ratio of [CL]/[O15C]. They showed molecular weights ranging from 11.0 to 20.6kgmol⁻¹, and polydispersity index between 1.4 and 1.6, characterized by SEC (Size Exclusion Chromatography). Analysis of ¹H NMR indicated that the copolymers belong to a random copolymer structure. The introduction of O15C had a significant influence on thermal stability, hydrophilicity and degradability of the copolymers. With increasing the O15C content, the crystalline ability of PCL segment among the copolymers reduced, while the hydrophilic property was improved obviously. Through hydrolysis experiment, the poly(CL-co-O15C) with O15C content of 38mol% exhibited a much faster degradable rate than that of the copolymer with O15C content of 10mol%. Therefore, copolymerization of CL with a crown ether monomer via organic catalyst mediated ROP will be a feasible strategy for modification of polyester materials.

The request of new materials, matching strict requirements to be applied in precision and patient-specific medicine, is pushing for the synthesis of more and more complex block copolymers. Amphiphilic block copolymers are emerging in the biomedical field due to their great potential in terms of stimuli responsiveness, drug loading capabilities and reversible thermal gelation. Amphiphilicity guarantees self-assembly and thermoreversibility, while grafting polymers offers the possibility of combining blocks with various properties in one single material. These features make amphiphilic block copolymers excellent candidates for fine tuning drug delivery, gene therapy and for designing injectable hydrogels for tissue engineering. This manuscript revises the main techniques developed in the last decade for the synthesis of amphiphilic block copolymers for biomedical application. Strategies for fine tuning the properties of these novel materials during synthesis are discussed. A deep knowledge of the synthesis techniques and their effect on the performance and the biocompatibility of these polymers is the first step to move them from the lab to the bench. Current results predict a bright future for these materials in paving the way towards a smarter, less invasive, while more effective, medicine.

Disruption of DNA carriers triggered by intracellular bio-stimulants has been broadly considered as most convenient strategy for efficient DNA delivery. In this direction, we have designed and synthesized pH, redox and ATP responsive cationic cross-linked polymers (CLPs) having disulfide and reversible boronic ester linkages. These CLPs also contain folate groups that are known for their targeting capability towards cancer cells. Biophysical studies showed that these cationic CLPs exhibited more effective DNA condensation in comparison to cationic linear polymers resulting in the formation of nano-sized polyplexes with sufficient positive zeta potentials and good colloidal stability at neutral pH (∼7.4). More interestingly, the polyplexes prepared from these CLPs have the ability to selectively release complexed DNA under conditions similar to those prevalent in cancer cells such as acidic pH, ATP rich surroundings or presence of glutathione, as revealed by ethidium bromide exclusion assay, agarose gel electrophoresis, AFM measurements, etc. Therefore, these cross-linked polymers have high potential of being effective non-viral gene delivery vehicles.

Gene therapy is an auspicious alternative to treat diseases. However, the design of efficient vectors remains as a challenge due to the innumerous intracellular and extracellular barriers that should be faced during the gene delivery process. Among some types of carries, polymeric gene vectors have gained increasingly attention. Aiming to improve the polymeric vectors' performance, several strategies have been applied such as diversification of the monomers, synthesis routes, polymers architecture, addition of specific targeting units, shielding domains, and inorganic nanoparticles. Besides, the use of controlled polymerization in the synthesis of these carries have led to improvements, especially ATRP, a very robust and versatile technique. Therefore, the aims of this review are summarizing the recent advances in gene vectors produced through ATRP; propose a division according to the main gene carries characteristics and strategies used to improve their performance; and also provide a critical analysis of the current and future perspectives on the use of ATRP in the synthesis of gene vectors.

Within the field of gene therapy, there is a considerable need for the development of non-viral vectors that are able to compete with the efficiency obtained by viral vectors, while maintaining a good toxicity profile and not inducing an immune response within the body. While there have been many reports of possible polymeric delivery systems, few of these systems have been successful in the clinical setting due to toxicity, systemic instability or gene regulation inefficiency, predominantly due to poor endosomal escape and cytoplasmic release. The objective of this review is to provide an overview of previously published polymeric non-coding RNA and, to a lesser degree, oligo-DNA delivery systems with emphasis on their positive and negative attributes, in order to provide insight in the numerous hurdles that still limit the success of gene therapy.

Amphiphilic dual graft copolymer composed of starch (St) as main chain, poly caprolactone (PCL) and poly (2-ethyl 2-oxazoline) (POX) as hydrophobic and hydrophilic side chains were synthesized and characterized successfully. Firstly, polycaprolactone with propargyl end group prepared and attached to the surface of azido starch (St-N₃) which was prepared through incomplete azidation of starch tosylate, by click chemistry reaction. Thereafter, the polymerization of 2-ethyl-2-oxazoline initiated from the remaining tosyl groups of PCL-starch. Finally, polymerization of POX quenched by doxorubicin (DOX) as anticancer drug as well as terminator and curcumin (Cur) physically loaded in to the obtained copolymer. Dual graft copolymer (PCL-St-POX) as the co-delivery system containing covalently conjugated doxorubicin and non-covalently loaded curcumin could be promising biocompatible system to achieve combination therapy. The SEM images showed that resulting copolymer exhibited sphere-shaped particles ranging from 50 to 100 nm which is completely different from ungrafted starch. The release studies also revealed that obtained copolymer is pH-sensitive and the release rate was more favorable at acidic pH (tumor cells) than neutral pH (normal cells) for both drugs.

Carbohydrate Polymers, Volume 155, 2017, pp. 303-312

The aim of this study was to synthesize chitosan hydrogels, in macro- and nano-size, grafted with N-vinylcaprolactam (NVCL) using gamma radiation, and evaluate their potential application as a drug delivery system, using 5-fluorouracil (5-FU) as a model drug. The effect of dose and monomer concentration in the grafting process was studied, and the materials were characterized by FTIR, TGA, DLS, SEM and AFM. Higher grafting percentages were observed for the nanogels system. Although both the grafted macro- and nanogels, (net-CS)-g-NVCL, showed a response to pH (4.75) and temperature (31–33°C), the nanogels showed a better swelling response to both stimuli because of their higher surface area. Both systems were able to load 5-FU in small amounts (2–3.5mgg⁻¹) and the release was sustained for more than 12h, showing that the modified macro and nanogels can be a potential alternative for the administration of drugs.

World Neurosurgery, Volume 102, 2017, pp. 583-592

Radiation Physics and Chemistry, Volume 119, 2016, pp. 228-235

N-vinylcaprolactam (NVCL) and N,N-dimethylacrylamide (DMAAm) were grafted onto crosslinked chitosan by gamma radiation, using direct and indirect (pre-irradiation oxidative) methods. The binary graft systems were synthesized in one and two steps to evaluate the influences of architecture on the properties of the polymeric material. Maximum grafting percentages were obtained by the direct method. The different systems obtained were characterized by FTIR and TGA. The equilibrium swelling time of the (net-CS)-g-NVCL/DMAAm and [(net-CS)-g-NVCL]-g-DMAAm systems was 75 and 25min, respectively, while crosslinked CS required about 24h. Thermal and pH sensitivity were conserved in all systems; the pH response in [(net-CS)-g-NVCL]-g-DMAAm (LCST: 37°, pH: 5.2) is more defined than (net-CS)-g-NVCL/DMAAm (LCST: 37°C, pH: 3.8). Grafting radiation showed to be an effective technique to modify CS hydrogels.

World Neurosurgery, Volume 120, 2018, pp. e63-e67

Tetrahedron Letters, Volume 58, Issue 30, 2017, pp. 2915-2918

We describe a total synthesis of a polyunsaturated fatty acid (PUFA)-containing glucuronosyldiacylglycerol (GlcADG), which is a surrogate glycolipid whose synthesis is remarkably upregulated in plant membranes under phosphorus-depleted conditions. Glycosylation between the glucuronide donor bearing 3,4-dimethoxybenzyl (DMPM) protecting groups and di-acylglycerol acceptor proceeded smoothly in the presence of gold(I) catalyst to provide the protected α-isomer of GlcADG as the major product.

Materials Letters, Volume 196, 2017, pp. 26-29

Mesoporous silica MCM-41 was grafted with a thermoresponsive terpolymer composed of triethoxyvinylsilane, N-isopropylacrylamide, and β-cyclodextrin (TEVS/NIPAAm/βCD). The terpolymer was grafted to the surface of MCM-41 (MCM-T) by coupling TEVS via silane chemistry. Grafting was a function of the NIPAAm/βCD molar ratio. MCM-T samples showed sensitivity to temperature (lower critical solution temperature, LCST) close to that of NIPAAm. The new material was capable of easily adsorbing ibuprofen and released it above its LCST.