Design and evaluation of polymeric nanogels with tailorable degradation and controlled drug release

Abstract

Chemotherapy constitutes a cornerstone in the treatment of cancer. Degradable polymeric nanogels are promising nanomedicines carriers for tumor-targeted chemotherapeutic drug delivery because they have a number of properties that can be fine-tuned to increase the therapeutic efficacy and safety of clinically used drugs. The aim of the research described in this thesis is to explore the potential of biodegradable nanogels for chemotherapeutic drug delivery and to assess how degradation behavior can be optimized under physiological conditions. Different hydrophilic polymers with biodegradable and cross-linkable side units (i.e. hydroxyethyl methacrylate-oligoglycolates-derivatized poly(hydroxypropyl methacrylamide (pHPMAm-Gly-HEMA) and hydroxyethyl methacrylamide-oligoglycolates-derivatized poly(hydroxyethyl metharcrylamide) (pHEMAm-Gly-HEMAm)) were synthesized and assembled into biodegradable nanogels. The degradation behavior of nanogels is found to be tailored by varying the hydrolysis rate of the crosslinks themselves as well as the crosslink densities of nanogels. To study the in vivo stability and biodegradability of nanocarriers, labeled nanogels with different degrees of PEGylation and degradation rates were prepared and evaluated by three in vitro technologies (i.e. fluorescence single particle tracking (fSPT), tangential flow filtration (TFF) and fluorescence correlation spectroscopy (FCS)). These methods provide extra and valuable information on properties of nanocarriers, and can help to identify and optimize the nanogel formulation. A methacrylamide doxorubicin prodrug (DOX-MA) containing a pH sensitive bond was loaded into the optimized nanogel system. The nanogels were further modified with a folic acid-PEG conjugate as a targeting ligand for reversing multidrug resistance (MDR). Active targeting was confirmed and the ability of overcoming multidrug resistance (MDR) was proved in doxorubicin-resistant cancer cells. An enzyme-activatable prodrug (propGA3-DOX) loaded nanogel system was developed. The induced β-glucuronidase from cancer cells by high intensity focused ultrasound (HIFU) was able to activate the prodrug released from the nanogels to subsequently cause cytotoxicity in vitro. These nanogels with unique properties show clear potential for anticancer treatment.