Modulation of phase transition of poly(N‐isopropylacrylamide)‐based microgels for pulsatile drug release

Abstract

This work aims to synthesize poly(N-isopropylacrylamide)-based microgels with sharp phase transition by introducing a specific secondary structure to achieve pulsatile drug release near body temperature. To achieve this, N-isopropylacrylamide (NiPAM) based microgels were synthesized by surfactant free-radical polymerization of NiPAM in the presence of polyalanine terminated α-methallyl poly(ethylene glycol) ether (HPEG-Ala x ) as a macro-comonomer and N,N 0 -methylene bisacrylamide (MBA) as a chemical crosslinker. A series of microgels were characterized by TEM, DLS, UV-Vis, 1 H NMR, and other analytical methods. The introduction of hydrophilic HPEG allows the volume phase transition temperature (VPTT) to move towards the body temperature, and α-helix structure confers a high deswelling ratio and response sensitivity to the microgel, overcoming the disadvantage of a broadened phase transition caused by hydrophilic monomers. The presence of HPEG-Ala x significantly improves the stability of the microgel in the electrolyte solution at high temperatures. The drug release of the microgels was investigated with the model drugs, hydrophilic DOX and hydrophobic curcumin, showing that the microgels can release hydrophilic drugs in a pulsatile mechanism.

Microgels and Nanogels for the Delivery of Poorly Water-Soluble Drugs

“…This thermoresponsive behavior can be leveraged to enable hydrophobic drug loading and release by dynamically switching the hydrophobicity of the microgel phase and thus the affinity between the microgel and the drug. 77 A variety of thermoresponsive building blocks has been reported, the most common of which is PNIPAAm given its convenient VPTT value of ∼32 °C. For example, thermosensitive microgels based on HA-g-PNIPAAm were synthesized by cross-linking carboxylic end-capped PNIPAAm to aminated HA through carbodiimide chemistry, enabling the loading of cyclosporine A (CycA, logP = 1.4) 78 through simple coincubation with a drug loading efficiency of 74% and subsequent drug release via convection upon heating above the VPTT.…”

“…77 The Ala x chain segment also transitions from an α-helix to a more hydrophobic β-sheet structure upon heating, leading to aggregation of the hydrophobic β-sheets in the microgel core to create a dense inner domain that allows for more curcumin or DOX binding sites. 77 The microgels were loaded through swelling diffusion at 25 °C which resulted in 85% encapsulation efficiency for DOX-loaded NH-Ala 4 microgels and decreased as the Ala x chain length increased, while curcumin-loaded NH-Ala 4 microgels had 54% encapsulation efficiency which increased as the Ala x chain length increased. 77 At 30 °C, curcumin release of 44% and DOX release of 40% was achieved after 400 min; in contrast, at 38 °C, 67% of curcumin and 95% of DOX were released after 400 min due to the solubilization of hydrophobic curcumin by the now-collapsed Ala x segment (VPTT = 36.2 °C) (Figure 5).…”

“…77 The microgels were loaded through swelling diffusion at 25 °C which resulted in 85% encapsulation efficiency for DOX-loaded NH-Ala 4 microgels and decreased as the Ala x chain length increased, while curcumin-loaded NH-Ala 4 microgels had 54% encapsulation efficiency which increased as the Ala x chain length increased. 77 At 30 °C, curcumin release of 44% and DOX release of 40% was achieved after 400 min; in contrast, at 38 °C, 67% of curcumin and 95% of DOX were released after 400 min due to the solubilization of hydrophobic curcumin by the now-collapsed Ala x segment (VPTT = 36.2 °C) (Figure 5). 77 By cycling the temperature between below and above the VPTT (30 and 38 °C, respectively), the PNIPAAm component drives sequential swelling and deswelling of the microgel, with each cycle also promoting on-demand convective release of both DOX and curcumin (Figure 5) beyond the diffusion/partitioning-regulated release observed at fixed temperatures.…”

“…77 By cycling the temperature between below and above the VPTT (30 and 38 °C, respectively), the PNIPAAm component drives sequential swelling and deswelling of the microgel, with each cycle also promoting on-demand convective release of both DOX and curcumin (Figure 5) beyond the diffusion/partitioning-regulated release observed at fixed temperatures. 77 Copolymers of NIPAAm and N-isopropylmethacrylamide (NIPMAAm) have been used in a similar context, with NIPMAAm added to increase the VPTT slightly above normal body temperature to enable triggered drug release upon induction of hyperthermia. 100 Such microgels with a VPTT of 39 °C were demonstrated to effectively deliver cannabidiol (CBD, logP = 5.9), 100,101 with CBD being loaded into the swollen gel and, upon heating above the VPTT, convectively released out of the microgel network.…”

Microparticle‐hydrogel hybrids for sustained release of dual bioactive compounds

“…[4][5][6] In order to meet this requirement, dual bioactive compounds delivery systems including microparticles (MPs), emulsion, hydrogel/nanoparticles, microgel, electrospun nanofibers, and so forth have been studied. [7][8][9][10][11] Among them, incorporation of polymer-based particles into hydrogels can not only enhance its mechanical properties, but also impart stimuli-responsive functions, thereby further achieving the controlled release. However, in the current study, the drug-loaded polymer particles are usually simply embedded in the hydrogel, making it difficult to achieve individual entrapment and independent release of each drug, and thus it is difficult to distinguish the role of each drug in synergistic efficacy during codelivery.…”