(264h) High-Throughput Synthesis and Characterization of Rapidly Eroding Polyanhydride Nanoparticle Libraries for Drug Delivery

Oral administration is a preferred route for drug delivery as it is simple, well-tolerated by patients, and doesn’t require a medical professional for needle handling. However, the acidic and enzymatic degrading environment of the gastrointestinal tract can limit the bioavailability of proteins and some small-molecule therapeutics. Oral delivery of hydrophobic drugs, such as estradiol, can be particularly challenging due to low aqueous solubility and a high first pass metabolism, further limiting drug bioavailability [1]. For other drugs, such as chemotherapeutics for cancer, the gut may need protection from toxic drug activity [2]. Controlled drug release nanoparticles could help meet these challenges by protecting their drug payload from the acidic environment of the stomach and releasing their payload in the more pH-neutral environment of the small intestine to allow transport into systemic circulation.

Polyanhydrides are a class of biodegradable, biocompatible polymers that have been used for controlled release of small-molecule drugs and proteinaceous payloads. They display hydrolytic degradation and surface erosion, resulting in a tunable release rate when hydrophobic and hydrophilic monomers are co-polymerized. Sebacic acid (SA) is a hydrophobic polyanhydride monomer that contributes favorable thermal properties for room-temperature synthesis of nanoparticles and a high rate of internalization by phagocytic cells, but its high local acidic microenvironment can negatively impact drug or protein stability. In contrast, 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) is an amphiphilic monomer that has been shown to stabilize protein antigens and also facilitates internalization by immune cells. In this work, we created a new family of CPTEG:SA copolymers with a rapid rate of degradation that could be ideal for oral delivery. Since polyanhydride degradation is base-catalyzed, drug release is expected to be delayed during transport through the stomach, and then progress rapidly in the intestines.

We synthesized CPTEG:SA copolymers of varying compositions via both conventional and high-throughput methods using an automated robot. Number average sequence length analysis indicates that SA-rich chemistries had a high SA sequence length, indicative of weakly segregated block-like microstructure. Chemistries closer to equimolar amounts of CPTEG and SA had similar, moderate sequence lengths, yielding an alternating copolymer. Compositions between 50:50 and 15:85 CPTEG:SA had reactivity ratios close to unity. Thermal characterization of CPTEG:SA polymers indicated semicrystalline behavior in SA-rich chemistries (i.e., at or below 35 mol% CPTEG). All polymers within this range had glass transition temperatures and melting points above room temperature, which facilitates nanoparticle synthesis via flash nanoprecipitation. Film erosion studies showed a faster rate of degradation as SA content increased.

The effect of polymerization time (and thereby molecular weight) on nanoparticle synthesis and morphology was investigated using the high-throughput methodology. A reaction time of five hours, corresponding to number-average molecular weight of approximately 20 kDa, yielded particles with sub-micron diameters. Nanoprecipitation conditions were tested a high-throughput manner, and rhodamine B, a hydrophobic small-molecule model drug, was encapsulated into the particles to investigate release kinetics. CPTEG:SA nanoparticles released rhodamine B rapidly, within three days. Drug release kinetics showed a chemistry-dependent trend, as increasing SA content increased the rate of release, consistent with the erosion kinetics data. Cell internalization assays in human monocyte/macrophage cell line THP-1, murine macrophage cell line J774, and murine bone-marrow derived dendritic cells (BMDCs) revealed chemistry-dependent internalization, with SA-rich 5:95 and 10:90 CPTEG:SA nanoparticles demonstrating the highest internalization by all cell lines. Altogether, the CPTEG:SA copolymers display a high tunability of degradation rates, drug release kinetics, and immune cell internalization at short time scales. This family of biodegradable carriers could facilitate the rational design of controlled release drug delivery and nanovaccine carriers by combining the favorable thermal, protein stabilization, and internalization properties of anhydride monomers.

Selected References

[1] Sahana D K, Mittal G, Bhardwaj V and Kumar M N V R 2008 PLGA Nanoparticles for Oral Delivery of Hydrophobic Drugs: Influence of Organic Solvent on Nanoparticle Formation and Release Behavior In Vitro and In Vivo Using Estradiol as a Model Drug J. Pharm. Sci. 97 1530–42

[2] Sharpe L A, Daily A M, Horava S D and Peppas N A 2014 Therapeutic applications of hydrogels in oral drug delivery. Expert Opin. Drug Deliv. 11 901–15