Drug-Polymer Nanodroplet Formation and Morphology Drive Solubility Enhancement of GDC-0810.

Nanodroplet formation is important to achieve supersaturation of active pharmaceutical ingredients (APIs) in an amorphous solid dispersion. The aim of the current study was to explore how polymer composition, architecture, molar mass, and surfactant concentration affect polymer-drug nanodroplet morphology with the breast cancer API, GDC-0810. The impact of nanodroplet size and morphology on dissolution efficacy and drug loading capacity was explored using polarized light microscopy, dynamic light scattering, and cryogenic transmission electron microscopy. Poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) (PND) was synthesized as two linear derivatives and two bottlebrush derivatives with carboxylated or PEGylated end-groups. Hydroxypropyl methylcellulose acetate succinate grade MF (HPMCAS-MF) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) were included as commercial polymer controls. We report the first copolymerization synthesis of a PVPVA bottlebrush copolymer, which was the highest performing excipient in this study, maintaining 688 µg/mL GDC-0810 concentration at 60 wt % drug loading. This is likely due to strong polymer-drug noncovalent interactions and the compaction of GDC-0810 along the PVPVA bottlebrush backbone. Overall, it was observed that the most effective formulations had a hydrodynamic radius less than 25 nm with tightly compacted nanodroplet morphologies.

Polycation Architecture Affects Complexation and Delivery of Short Antisense Oligonucleotides: Micelleplexes Outperform Polyplexes.

Herein, we examine the complexation and biological delivery of a short single-stranded antisense oligonucleotide (ASO) payload with four polymer derivatives that form two architectural variants (polyplexes and micelleplexes): a homopolymer poly(2-dimethylaminoethyl methacrylate) (D), a diblock polymer poly(ethylene glycol)methylether methacrylate-block-poly(2-dimethylaminoethyl methacrylate) (ObD), and two micelle-forming variants, poly(2-dimethylaminoethyl methacrylate)-block-poly(n-butyl methacrylate) (DB) and poly(ethylene glycol)methylether methacrylate-block-poly(2-dimethylaminoethyl methacrylate)-block-poly(n-butyl methacrylate) (ObDB). Both polyplexes and micelleplexes complexed ASOs, and the incorporation of an Ob brush enhances colloidal stability. Micellplexes are templated by the size and shape of the unloaded micelle and that micelle-ASO complexation is not sensitive to formulation/mixing order, allowing ease, versatility, and reproducibility in packaging short oligonucleotides. The DB micelleplexes promoted the largest gene silencing, internalization, and tolerable toxicity while the ObDB micelleplexes displayed enhanced colloidal stability and highly efficient payload trafficking despite having lower cellular uptake. Overall, this work demonstrates that cationic micelles are superior delivery vehicles for ASOs denoting the importance of vehicle architecture in biological performance.

Using Microemulsion Phase Behavior as a Predictive Model for Lecithin-Tween 80 Marine Oil Dispersant Effectiveness.

Marine oil dispersants typically contain blends of surfactants dissolved in solvents. When introduced to the crude oil-seawater interface, dispersants facilitate the breakup of crude oil into droplets that can disperse in the water column. Recently, questions about the environmental persistence and toxicity of commercial dispersants have led to the development of "greener" dispersants consisting solely of food-grade surfactants such as l-α-phosphatidylcholine (lecithin, L) and polyoxyethylenated sorbitan monooleate (Tween 80, T). Individually, neither L nor T is effective at dispersing crude oil, but mixtures of the two (LT blends) work synergistically to ensure effective dispersion. The reasons for this synergy remain unexplained. More broadly, an unresolved challenge is to be able to predict whether a given surfactant (or a blend) can serve as an effective dispersant. Herein, we investigate whether the LT dispersant effectiveness can be correlated with thermodynamic phase behavior in model systems. Specifically, we study ternary "DOW" systems comprising LT dispersant (D) + a model oil (hexadecane, O) + synthetic seawater (W), with the D formulation being systematically varied (across 0:100, 20:80, 40:60, 60:40, 80:20, and 100:0 L:T weight ratios). We find that the most effective LT dispersants (60:40 and 80:20 L:T) induce broad Winsor III microemulsion regions in the DOW phase diagrams (Winsor III implies that the microemulsion coexists with aqueous and oil phases). This correlation is generally consistent with expectations from hydrophilic-lipophilic deviation (HLD) calculations, but specific exceptions are seen. This study then outlines a protocol that allows the phase behavior to be observed on short time scales (ca. hours) and provides a set of guidelines to interpret the results. The complementary use of HLD calculations and the outlined fast protocol are expected to be used as a predictive model for effective dispersant blends, providing a tool to guide the efficient formulation of future marine oil dispersants.