György Kasza

The poor solubility, stability issues, and restricted bioavailability of numerous drugs and potential pharmaceutical compounds highlight the critical need for the development of polymeric nanoparticles as effective drug delivery systems. Ideal polymers for such applications must be biocompatible, provide controlled drug loading and release, and maintain the high colloidal stability of the nanoformulation. In this study, LCST-type thermoresponsive poly­(N-isopropylacrylamide)-g-(hyperbranched polyglycerol) (PNiPAAm-g-HbPG) graft copolymers, composed of two biocompatible components, were synthesized by grafting amino-monofunctional HbPG, prepared by multibranching anionic ring-opening polymerization, onto PNiPAAm chains containing succinimide active ester groups. In both aqueous solutions and phosphate-buffered saline, these graft copolymers undergo reversible aggregation and disaggregation in response to temperature changes, with linear increase of the critical solution temperature (CST) as a function of grafting density. The architecture of the copolymers enables efficient encapsulation of curcumin, a natural anticancer agent, by a simple mixing process at elevated temperatures, and the hydrophilic HbPG side chains provide excellent colloidal stability for the polymer–drug nanoformulations. Sustained release of curcumin from the PNiPAAm-g-HbPG aggregates was found, which depends on the grafting density, and the release rate can be externally triggered by decreasing the temperature. The potential biocompatibility of the PNiPAAm-g-HbPG graft copolymers was demonstrated in vitro, with no evidence of cytotoxicity or hemolytic activity against human cells. The nanoformulations of curcumin with these new graft copolymers enhanced its internalization into HT-29 human colorectal adenocarcinoma cells and significantly improved its cytostatic effect against colon cancer cells. These properties of the novel PNiPAAm-g-HbPG graft copolymers make them superior candidates for advanced drug encapsulation and delivery systems.

Delivering of hydrophobic drugs by polymeric nanoparticles is an intensively investigated research and development field worldwide due to the insufficient solubility of many existing and potential new drugs in aqueous media. Among polymeric nanoparticles, micelles of biocompatible amphiphilic block copolymers are among the most promising candidates for solubilization, encapsulation, and delivery of hydrophobic drugs to improve the water solubility and thus the bioavailability of such drugs. In this study, amphiphilic ABA triblock copolymers containing biocompatible hydrophilic hyperbranched (dendritic) polyglycerol (HbPG) outer and hydrophobic poly(tetrahydrofuran) (PTHF) inner segments were synthesized using amine-telechelic PTHF as a macroinitiator for glycidol polymerization. These hyperbranched–linear–hyperbranched block copolymers form nanosized micelles with 15–20 nm diameter above the critical micelle concentration. Coagulation experiments proved high colloidal stability of the aqueous micellar solutions of these block copolymers against temperature changes. The applicability of block copolymers as drug delivery systems was investigated using curcumin, a highly hydrophobic, water-insoluble, natural anti-cancer agent. High and efficient drug solubilization up to more than 3 orders of magnitude to that of the water solubility of curcumin (>1500-fold) is achieved with the HbPG-PTHF-HbPG block copolymer nanomicelles, locating the drug in amorphous form in the inner PTHF core. Outstanding stability of and sustained curcumin release from the drug-loaded block copolymer micelles were observed. The in vitro bioactivity of the curcumin-loaded nanomicelles was investigated on U-87 glioblastoma cell line, and an optimal triblock copolymer composition was found, which showed highly effective cellular uptake and no toxicity. These findings indicate that the HbPG-PTHF-HbPG triblock copolymers are promising candidates for advanced drug solubilization and delivery systems.

Tuning the critical solution temperature (CST) of thermoresponsive polymers is essential to exploit their immense potential in various applications. In the present study, the effect of PEG-methyl ether methacrylate with a higher molecular weight of 1100 g/mol (mPEGMA₁₁₀₀) as a comonomer was investigated for its suitability for the CST adjustment of LCST-type polymers. Accordingly, a library of mPEGMA₁₁₀₀-based copolymers was established with varying compositions (X_mPEGMA1100) using four main comonomers, namely di(ethylene glycol) ethyl ether acrylate, N-isopropyl acrylamide and methacrylamide, and mPEGMA₃₀₀, with different CST values (cloud points, T_CP, and clearing points, T_CL, by turbidimetry). It was found that less than 20 mol% of the mPEGMA₁₁₀₀ in the copolymers is practically sufficient for tuning the CST in the entire measurable temperature range, i.e., up to 100 °C, regardless of the CST of the homopolymer of the main comonomer (CST₀). Moreover, a predictive asymptotic model was developed based on the measured CST values, which strikingly revealed that the CSTs of mPEGMA₁₁₀₀-containing copolymers depend only on the two main parameters of these copolymers, X_mPEGMA1100 and the CST of the homopolymer of the main comonomer (CST₀), that is, CST = f(CST₀, X_mPEGMA1100). The revealed two-parameter relationship defines a surface in 3D plotting, and it is applicable to determine the CST of copolymers in advance for a given composition or to define the suitable composition for a required CST value. These unprecedented results on the dependence of CSTs on two major well-defined parameters enable to design a variety of novel macromolecular structures with tailored thermoresponsive properties.

Responsive (smart, intelligent, adaptive) polymers have been widely explored for a variety of advanced applications in recent years. The thermoresponsive poly(N,N-diethylacrylamide) (PDEAAm), which has a better biocompatibility than the widely investigated poly(N,N-isopropylacrylamide), has gained increased interest in recent years. In this paper, the successful synthesis, characterization, and bioconjugation of a novel thermoresponsive copolymer, poly(N,N-diethylacrylamide-co-glycidyl methacrylate) (P(DEAAm-co-GMA)), obtained by free radical copolymerization with various comonomer contents and monomer/initiator ratios are reported. It was found that all the investigated copolymers possess LCST-type thermoresponsive behavior with small extent of hysteresis, and the critical solution temperatures (CST), i.e., the cloud and clearing points, decrease linearly with increasing GMA content of these copolymers. The P(DEAAm-co-GMA) copolymer with pendant epoxy groups was found to conjugate efficiently with α-chymotrypsin in a direct, one-step reaction, leading to enzyme–polymer nanoparticle (EPNP) with average size of 56.9 nm. This EPNP also shows reversible thermoresponsive behavior with somewhat higher critical solution temperature than that of the unreacted P(DEAAm-co-GMA). Although the catalytic activity of the enzyme–polymer nanoconjugate is lower than that of the native enzyme, the results of the enzyme activity investigations prove that the pH and thermal stability of the enzyme is significantly enhanced by conjugation the with P(DEAAm-co-GMA) copolymer.

Despite the great interest in nanoconfined materials nowadays, nanocompartmentalized poly(ionic liquid)s (PILs) have been rarely investigated so far. Herein, we report on the successful alkylation of poly(1-vinylimidazole) with methyl iodide in bicontinuous nanophasic poly(1-vinylimidazole)-l-poly(tetrahydrofuran) (PVIm-l-PTHF) amphiphilic conetworks (APCNs) to obtain nanoconfined methylated PVImMe-l-PTHF poly(ionic liquid) conetworks (PIL-CNs). A high extent of alkylation (~95%) was achieved via a simple alkylation process with MeI at room temperature. This does not destroy the bicontinuous nanophasic morphology as proved by SAXS and AFM, and PIL-CNs with 15–20 nm d-spacing and poly(3-methyl-1-vinylimidazolium iodide) PIL nanophases with average domain sizes of 8.2–8.4 nm are formed. Unexpectedly, while the swelling capacity of the PIL-CN dramatically increases in aprotic polar solvents, such as DMF, NMP, and DMSO, reaching higher than 1000% superabsorbent swelling degrees, the equilibrium swelling degrees decrease in even highly polar protic (hydrophilic) solvents, like water and methanol. An unprecedented Gaussian-type relationship was found between the ratios of the swelling degrees versus the polarity index, indicating increased swelling for the nanoconfined PVImMe-l-PTHF PIL-CNs in solvents with a polarity index between ~6 and 9.5. In addition to the nanoconfined structural features, the unique selective superabsorbent swelling behavior of the PIL-CNs can also be utilized in various application fields.

EGFR targeting drug–polymer–peptide conjugates have enhanced solubility wherein in vitro biological activity highly depends on the structure of conjugates due to their amphiphilic character and self-aggregation properties.