Synthesis and modification of functional polymer nanogels using pulsed-electron beam ionising irradiation

Abstract

Nanogels made of bio-compatible hydrophilic polymers can be used in various medical applications such as targeted nano-medicine delivery and imaging agents. Intravenously introduced nanogel-drug conjugates may accumulate in tumors through the enhanced permeability and retention effect. We present our latest results on the synthesis and kinetic analysis of two nanogel systems (1) poly)vinyl pyrrolidone) (PVP) and (2) gelation/polyethylene glycol (GEL/PEG) using ionizing irradiation (g-ray, electron beams). The characteristics of nanogels depend on the radiation synthesis parameters (e.g. total dose, pulse repetition rate, etc.). Specifically, one may tune the parameters to promote the crosslinking reaction within the same polymer chain (intra-crosslinking) and to suppress the crosslinking between two different chains (inter-crosslinking). At higher temperatures (>60°C), there is a disruption of polymer-water hydrogel bonds resulting in a collapsed form. Smaller nanogels can be produced with high repetition rates of the pulsed electron beam irradiation while low dose rate pulses favour inter-molecular crosslinking. The nanogels were analysed using asymmetric flow field-flow fractionation coupled to multi-angle static light scattering and dynamic light scattering detectors. The measured hydrodynamic radius (Rh) of the PVP hydrogels were concentration dependent with a range from 15 to 80 nm with a polydispersity index of 0.2-0.3 and molecular weight of 0.4-13 MDa. On the other hand, the RH of the GEL/PEG mixed nanogels decrease from 350 to 20 nm as function of the dose. Additionally, atomic force images confirm the synthetic approach results in globular shapes. X-rays photoelectron spectroscopy (XPS) measurements confirm that the chemical structure of these nanomaterials closely resemble that of the un-irradiated polymers. Moreover, XPS also provides data on the level of oxidation and enables confirmation of chemical grafting. In addition, pulse radiolysis elucidates the mechanism that leads to nanogel generation. The second order reaction rates constants (k2) of PVP radical recombination are determined to be ca. 1.1-2.8 E9 Lmol-1s-1. The activation energy (Ea) of this reaction is calculated from the Arrhenius plot of PVP radical decay rate constants at the series of temperatures and show 1.0 kcal mol-1 below 60°C. These two measured Ea constants can be explained by the different rate determining mechanisms of PVP radical recombination reaction at two temperature regions. Below 60°C, the low Ea reflects the diffusion controlled polymer radical reaction in a good solvent. But at higher temperatures, above 60°C, polymer chains are segregated from the aqueous solution by micro-phase separation and collapse.