Dual thermoresponsive and pH-responsive self-assembled micellar nanogel for anticancer drug delivery

Abstract

In this article, we prepared a dual thermoresponsive and pH-responsive self-assembled micellar nanogel for anticancer drug delivery by using a degradable pH-responsive ketal derivative, mPEG2000-Isopropylideneglycerol (mPEG-IS, PI) polymer. The purpose of this study is to develop an injectable dual-responsive micellar nanogel system which has a sol-gel phase transition by the stimulation of body temperature with improved stability and biocompatibility as a controlled drug delivery carrier for cancer therapy. The pH-responsive PI was designed with pH-responsive ketal group as hydrophobic moieties and PEG group as hydrophilic moieties. The PI micelles encapsulated paclitaxel (PTX) was fabricated. Then, the PI micelles were formed in a thermo-nanogel. The micellar nanogel could improve the solubility and stability of PTX. The physiochemical properties of PI micelles and micellar nanogel were characterized. The results showed that dual-responsive micellar nanogel could carry out sol-gel transition at 37 C. The PI polymer can spontaneously self-assemble into micellar structure with size of 100-200 nm. The dual-responsive micellar nanogel could be degraded under lower pH condition. The test in vitro PTX release showed that dual-responsive micellar nanogel could release about 70% for 70 h under pH 5.0 while about 10% release at pH 7.4 and pH 9.0. The dual-responsive micellar nanogel was of lower cytotoxicity and suppressed tumor growth most efficiently. The micellar nanogel will be a new potential dual-responsive drug delivery system for cancer therapy.

Layer-by-layer pH-sensitive nanoparticles for drug delivery and controlled release with improved therapeutic efficacy in vivo

“…A series of chemical anticancer drugs have been well developed and clinically used in these decades, such as doxorubicin (DOX) (Zhang et al, 2012;Fabbri et al, 2016), paclitaxel (PTX) (Markman & Mekhail, 2002;Yang et al, 2018), and camptothecin (CPT) (Venditto & Simanek, 2010;Llin as et al, 2018); however, these drugs are limited in the further clinical applications due to the serious side-effects caused by offtargeting and low therapeutic efficacy (Jungk et al, 2016;Yoshizawa et al, 2016). To overcome these obstacles, nanoscale drug delivery systems (DDSs) have attracted more and more attention and been extensively investigated (Chen et al, 2014), such as polymeric micelles (PMs), nanoparticles (NPs), prodrug, and liposome (Zhang et al, 2016;Zylberberg & Matosevic, 2016;Huang et al, 2018;Li et al, 2018;Dong et al, 2019). These effective DDSs are used to deliver hydrophobic or hydrophilic therapeutics which exhibit poor pharmacokinetics and high cytotoxicity to the site of tumor (Wang et al, 2016;Qin et al, 2017;Li et al, 2019).…”

An l-proline based thermoresponsive and pH-switchable nanogel as a drug delivery vehicle

“…14 More recently, research has focused on materials with dual functionality, where two stimuli are combined. 15 In particular, materials showing dual temperature and pH response characteristics have been developed for drug delivery applications, 16 demonstrating efficient tailored release. 17,18 The area of stimuli-triggered drug delivery has witnessed significant advances, with systems such as polymersomes, 19 dendrimers 20 and nanocomposite hydrogels 21 all showing promising results.…”

Nanogels for Pharmaceutical and Biomedical Applications and Their Fabrication Using 3D Printing Technologies

“…In vitro, this nanogel system demonstrated pH-sensitive release of its payload, doxorubicin, demonstrating that doxorubicin release was significantly accelerated when placed in the acidic medium (pH 6.8) [ 22 ]. Chen et al prepared dual thermo- and pH-sensitive micellar nanogels composed of mPEG-isopropylideneglycerol [ 23 ]. First, pH-responsive micelles carrying paclitaxel were formed and then incorporated into the thermosensitive nanogel matrix.…”

“…This drug delivery system was structured to primarily develop injectable nanogels which stay in a sol-state at room temperature, but forms a gel at body temperature. Paclitaxel incorporated in the micelles with a particle size of 100–200 nm was released at an elevated rate in an acidic medium which mimics the extracellular environment of tumor [ 23 ]. Chen et al used the glutathione gradient (four times greater in concentration in tumors) to reduce disulfide bonds and activate the destabilization of the nanogel [ 24 ].…”