Gelation Chemistries for the Encapsulation of Nanoparticles in Composite Gel Microparticles for Lung Imaging and Drug Delivery

Abstract

The formation of 10 to 40 μm Composite Gel MicroParticles (CGMPs) comprising ~100 nm drug containing nanoparticles (NPs) in a poly(ethylene glycol)(PEG) gel matrix is described. The CGMP particles enable targeting to the lung by filtration from the venous circulation. UV radical polymerization and Michael addition polymerization reactions are compared as approaches to form the PEG matrix. A fluorescent dye in the solid core of the NP was used to investigate the effect of reaction chemistry on the integrity of encapsulated species. When formed via UV radical polymerization, the fluorescence signal from the NPs indicated degradation of the encapsulated species by radical attack. The degradation decreased fluorescence by 90% over 15 minutes of UV exposure. When formed via Michael addition polymerization, the fluorescence was maintained. Emulsion processing using controlled shear stress enabled control of droplet size with narrow polydispersities. To allow for emulsion processing, the gelation rate was delayed by adjusting the solution pH. At a pH= 5.4 the gelation occurred at 3.5 hours. The modulus of the gels was tuned over the range of 5 to 50 kPa by changing the polymer concentration between 20 and 70 vol %. NPs aggregation during polymerization, driven by depletion forces, was controlled by the reaction kinetics. The ester bonds in the gel network enabled CGMP degradation. The gel modulus decreased by 50% over 27 days, followed by complete gel degradation after 55 days. This permits ultimate clearance of the CGMPs from the lungs. The demonstration of uniform delivery of 15.8 ± 2.6 μm CGMPs to the lungs of mice, with no deposition in other organs, is shown, and indicates the ability to target therapeutics to the lung while avoiding off-target toxic exposure.

Poroelastic properties of hydrogel microparticles

“…With the universal curve presented here for particle compression, it is now possible to quantify the poroelastic properties of biological entities such as cells, which have been shown to behave poroelastically 45 , and hydrogel particles for drug delivery in vivo 9,12 .…”

“…In particular, hydrogel particles hold great promise for use as controlled drug delivery systems due to their biocompatibility, ease of manufacture, and precise control of strength and size [8][9][10] . Control of size and strength is critically important for successful delivery of active ingredients in vivo.…”

“…For example, softer particles are able to circulate longer in the bloodstream in comparison to stiffer particles because they can move through narrow vessels, and are also able to avoid detection and subsequent removal by the immune system 11 . Drug delivery to the lungs is critically dependent on particle size and modulus, where particles larger or stiffer than red blood cells are filtered out of circulation 12 .…”

Single‐Step Assembly of Multimodal Imaging Nanocarriers: MRI and Long‐Wavelength Fluorescence Imaging

“…Of note is the dye photostabilization afforded by trapping the dye in a solid state within the CNC core, which minimizes photoinduced degradation . Previous work has demonstrated that fluorophores in CNC cores undergo only minor photobleaching when exposed to intense UV or blue–green light . This robustness ensures minimal degradation of the CNC fluorescence signal during extended imaging experiments.…”

NCI investment in nanotechnology: achievements and challenges for the future

“…Recent examples of NCI-supported progress for clinical applications span the development of novel diagnostic assays, 50,51 in vivo imaging tools, 52-57 novel drug delivery tools, [58][59][60][61][62][63] new cytotoxic agents 64,65 and so-called theranostic platforms (bearing combined therapeutic and diagnostic capabilities). [66][67][68][69] Furthermore, NCI manages a 36 Cooperative nanoparticles for amplified tumor targeting…”