Thermoresponsive block copolymer micelles with tunable pyrrolidone-based polymer cores: structure/property correlations and application as drug carriers

Abstract

A-B block copolymer micelles comprised of thermoresponsive hydrophilic PNIPAAm (poly(Nisopropylacrylamide)) coronae and hydrophobic PNP (poly(N-acryloyl-2-pyrrolidone)), PMNP (poly(Nacryloyl-5-methoxy-2-pyrrolidone)), or PBNP (poly(N-acryloyl-5-butoxy-2-pyrrolidone)) cores were examined to identify how systematic adjustments to core-segment structure affect micellar physicochemical properties, drug loading efficiency (DLE), and thermoresponsive drug release among these novel systems. Critical micelle concentrations (CMCs) were found to decrease by two orders of magnitude in the order of PNIPAAm-PNP, PNIPAAm-PMNP, and PNIPAAm-PBNP indicating that minor modifications to the pyrrolidone scaffold significantly affect its hydrophobic character. Moreover, the structural modifications were also found to influence micelle size and intermicellar aggregation that occurs above the lower critical solution temperature (LCST). In line with the CMC data, DLE values of doxorubicin-loaded (i.e., DOX-loaded) micelles increase in the order of PNIPAAm-PNP, PNIPAAm-PMNP, and PNIPAAm-PBNP, a trend attributed to enhanced cohesive forces (i.e. London dispersion forces) between DOX and core as the latter becomes more hydrophobic. When heated above the LCST, DOX release decreases in the order of PNIPAAm-PNP, PNIPAAm-PMNP, and PNIPAAm-PBNP suggesting that release processes are impeded by the cohesive forces responsible for efficient encapsulation. Finally, cytotoxicity assays performed above the LCST reveal that DOX-loaded micelles are as cytotoxic as the free drug in formulations where DOX concentrations are equivalent.

Effect of residue structure on the thermal and thermoresponsive properties of γ-substituted poly(N-acryloyl-2-pyrrolidones)

“…4 As a result, modified pyrrolidone-based polymers have been used as nanoparticle stabilizers, 5 and complexing agents, 6 and are of considerable interest for use in catalysis 7 and nanoscale drug delivery applications. 8 Taken together, the results of these investigations indicate that the physicochemical properties of these polymers correlate strongly to the molecular architecture of the constituent repeat units. Recently, we communicated a facile route to γ-substituted poly(N-acryloyl-2-pyrrolidone)s from pyroglutamic acid (PGA), a bio-derived resource.…”

Smart Stimuli-Responsive Nano-sized Hosts for Drug Delivery

“…This is associated with the relationship between the core's increasing desire to be hydrophobic and the enhanced cohesive forces displayed between it and the drug [ 30 ]. When temperatures are greater than the LCST, the release of the drug is as follows, which implies that the cohesive forces that allow for excellent encapsulation also hinder release: "PNIPAAm-PNP > PNIPAAm-PMNP > PNIPAAm-PBNP" [ 30 ]. pH-responsive micelles are copolymers containing pH-sensitive segments which are capable of varying their dimensions when responding to pH variations of their surrounding medium [ 31 , 32 ].…”

“…Micelles loaded with DOX displayed the following DLE trend: "PNIPAAm-PNP < PNIPAAm-PMNP < PNIPAAm-PBNP." This is associated with the relationship between the core's increasing desire to be hydrophobic and the enhanced cohesive forces displayed between it and the drug [ 30 ]. When temperatures are greater than the LCST, the release of the drug is as follows, which implies that the cohesive forces that allow for excellent encapsulation also hinder release: "PNIPAAm-PNP > PNIPAAm-PMNP > PNIPAAm-PBNP" [ 30 ].…”

“…The evaluation of micelle cores consisting of thermally sensitive "PNIPAAm, PMNP [poly(N-acryloyl-5-methoxy-2-pyrrolidone)]", or "PBNP [poly(N-acryloyl-5-butoxy-2-pyrrolidone)]" were performed in order to determine their DOX-loading effi ciency (DLE) [ 30 ]. Micelles loaded with DOX displayed the following DLE trend: "PNIPAAm-PNP < PNIPAAm-PMNP < PNIPAAm-PBNP."…”

Intelligent micellar polymeric nanocarriers for therapeutics and diagnosis

“…The micelles obtained featured a core–shell–corona structure with a hydrophobic PA inner core, a thermoresponsive PNIPAAm shell, and a hydrophilic PEG corona; these provided the system with the biocompatibility of PEG and the thermosensitive behavior of PNIPAAm. DOX encapsulation and release was also evaluated for a series of BCMs made from PNIPAAm and hydrophobic poly( N ‐acryloyl‐2‐pyrrolidone) blocks of different lengths . Although the drug release was almost negligible at 20°C, a clear enhancement was observed when the temperature rose to 37°C, with slower diffusion rates noted for micelles with the most hydrophobic cores.…”