Optimizing PNVCL Hydrogels for Drug Delivery—A Molecular Weight Odyssey

The consumption of traditional drugs, usually by oral intake, injections or topical has some limitations that has driven the development of modern drug delivery systems. Among those limitations, the lack of targeted delivery systems leads to active ingredients distributed throughout the body, which can result in adverse effects. Another limiting factor is the difficulty of controlling the drug release profile. Medications need to be delivered at a specific and controlled rate at the target site to achieve best efficacy and safety, however traditional methodologies often struggle to achieve precise release profiles, leading to suboptimal treatment outcomes. Furthermore, some medications are sensitive to environmental factors such as pH, temperature, or enzymatic activity. Without proper protection or targeting, these drugs may degrade prematurely or become inactive before reaching their intended site of action. To overcome these limitations, stimuli-responsive drug delivery systems (DDS) have emerged as a promising solution. These materials are designed to respond to specific stimuli, triggering drug release only at the proper time and location. This approach enhances drug efficacy, minimizes systemic exposure and reduces the risk of adverse effects. In light of that, this study aims to use poly(N-vinylcaprolactam) (PNVCL) hydrogels as controlled drug delivery systems. PNVCL with different molecular weights (MW) were synthesized in order to understand how the MW affect the absorption and release profile of a range of antibiotic drugs. The polymer was synthesized by radical polymerization of NVCL using 2,2'-azobis(2-methylpropionitrile) (AIBN) as initiator at 70 °C for 4 h in DMSO. 18nm SiO₂ nanoparticles were used to catalyze the reaction and obtain polymers of different molar weights. Measurements of DLS and viscosimetry showed that the polymers with molecular weights ranging from 66 to 195 kDa were obtained. Kinetic studies revealed that increasing SiO₂ resulted in a lower conversion rate and higher molecular weights. The solubility temperature was determined by dynamic light scattering, where aqueous solutions of the polymers were analyzed between 25 and 38 °C. The LCST was attributed to the temperature at which a substantial change in the hydrodynamic diameter was observed. This temperature is the point or range below which the polymer is soluble in water and above which it becomes insoluble. Results shown a consistent pattern where the LCST increases with decreasing molecular weight, while the glass transition temperature shows a directly proportional increase. These materials were used as a vehicle for controlled release of target molecules, given that above the LCST they exist in a hydrogel form. Those materials were encapsulated with methylene blue dye in neutral (pH = 7.4) and acidic (pH = 4.0) environments to determine kinetic parameters and release mechanism, as well as with antibiotics (ciprofloxacin and metronidazole) and doxorubicin. Significant differences were observed in the release profiles at different pHs, determining that in a neutral environment, the drug release occurs through matrix diffusion, whereas in an acidic environment, it happens through anomalous transport, involving both diffusion and dissolution. For the other drugs, controlled and prolonged release for 7 days was observed, with release rates varying depending on the type of drug and molecular weight of the matrix. The results suggest that the differences between the materials come from the nature of the target molecules and their own, as well as the way in which they interact with the polymer chains. These assays demonstrate that the material is a strong candidate for use as a vehicle of controlled drug release, especially due to its ability to control molecular weight and thus tune release parameters.<br/><br/>AKNOWLEDGEMENTS<br/>This work was partly funded by FAPESP grants #2013/07296-2 and #2022/10016-0, CNPq 309711/2019-3 and CAPES