Here we report an ultra-long-acting tunable, biodegradable, and removable polymer-based delivery system that offers sustained drug delivery for up to one year for HIV treatment or prophylaxis. This robust formulation offers the ability to integrate multiple drugs in a single injection, which is particularly important to address the potential for drug resistance with monotherapy. Six antiretroviral drugs were selected based on their solubility in N-methyl-2-pyrrolidone and relevance as a combination therapy for HIV treatment or prevention. All drugs released with concentrations above their protein-adjusted inhibitory concentration and retained their physical and chemical properties within the formulation and upon release. The versatility of this formulation to integrate multiple drugs and provide sustained plasma concentrations from several weeks to up to one year, combined with its ability to be removed to terminate the treatment if necessary, makes it attractive as a drug delivery platform technology for a wide range of applications.

A series of aliphatic polyester dendrons, generations 1 through 8, were prepared with a core p-toluenesulfonyl ethyl (TSe) ester as an easily removable protecting group that can be efficiently replaced with a variety of nucleophiles. Using amidation chemistry, a tridentate bis(pyridyl)amine ligand which is known to form stable complexes with both Tc(I) and Re(I) was introduced at the dendrimer core. Metalation of the core ligand with (99m)Tc was accomplished for generations 5 through 7, and resulted in regioselective radiolabeling of the dendrimers. The distribution of the radiolabeled dendrimers was evaluated in healthy adult Copenhagen rats using dynamic small-animal single photon emission computed tomography (SPECT). The labeled dendrimers were cleanly and rapidly eliminated from the bloodstream via the kidneys with negligible nonspecific binding to organs or tissues being observed. These data were corroborated by a quantitative biodistribution study on the generation 7 dendrimer following necropsy. The quantitative biodistribution results were in excellent agreement with the data obtained from the dynamic SPECT images.

Dendronized surfaces were prepared by chemisorption of poly(ethylene glycol) monothiol (HS-PEG 650 -OH) onto gold-coated silicon wafers followed by functionalization of the PEG terminal OH group with aliphatic polyester dendrons, generation 1-4, using divergent dendron growth. PEG monomethyl ether (PEG-OMe) chains of various molecular weight (MW) were covalently attached to the peripheral hydroxyl groups of the dendronized surfaces via EDC coupling and investigated for protein adsorption. Protein adsorption studies were carried out using fibrinogen (Fg) and lysozyme (Lys) as model proteins from phosphate buffered saline (PBS) (Fg, Lys) and plasma (Fg). In the first part of this study, the effect of functionalization of the peripheral hydroxyl groups with PEG-OMe oligomers (M n ) 350 Da) on protein adsorption was investigated. Results showed that adsorption of both Fg and Lys was reduced when dendronized surfaces were grafted with PEG-OMe oligomers. To investigate the effect of molecular weight on protein adsorption, PEG-OMe chains of greater length (750, 2000, and 5000 Da) were coupled to first generation dendronized surfaces (Au-G1(OH)). Results showed that protein adsorption decreased with increasing PEG-OMe MW up to 2000 Da. To further investigate the effect of dendron generation on protein resistance, dendronized surfaces of generation 1-4 were coupled with PEG 2000acid. Subsequent protein studies showed a decrease in Fg and Lys adsorption with increasing dendron generation.

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Non-adherence to medication is an important health care problem, especially in the treatment of chronic conditions. Injectable long-acting (LA) formulations of antiretrovirals (ARVs) represent a viable alternative to improve adherence to HIV/AIDS treatment and prevention. However, the LA-ARV formulations currently in clinical trials cannot be removed after administration even if adverse events occur. Here we show an ultra-LA removable system that delivers drug for up to 9 months and can be safely removed to stop drug delivery. We use two pre-clinical models for HIV transmission and treatment, non-human primates (NHP) and humanized BLT (bone marrow/liver/thymus) mice and show a single dose of subcutaneously administered ultra-LA dolutegravir effectively delivers the drug in both models and show suppression of viremia and protection from multiple high-dose vaginal HIV challenges in BLT mice. This approach represents a potentially effective strategy for the ultra-LA drug delivery with multiple possible therapeutic applications.

3D bioprinting has recently emerged as a very useful tool in tissue engineering and regenerative medicine. However, developing suitable bioinks to fabricate specific tissue constructs remains a challenging task. Herein, we report on a nanocellulose/chitosan-based bioink, which is compatible with a 3D extrusion-based bioprinting technology, to design and engineer constructs for bone tissue engineering and regeneration applications. Bioinks were prepared using thermogelling chitosan, glycerophosphate, hydroxyethyl cellulose, and cellulose nanocrystals (CNCs). Formulations were optimized by varying the concentrations of glycerophosphate (80−300 mM), hydroxyethyl cellulose (0−0.5 mg/mL), and CNCs (0−2% w/v) to promote fast gelation kinetics (<7 s) at 37 °C and retain the shape integrity of constructs post 3D bioprinting. We investigated the effect of CNCs and pre-osteoblast cells (MC3T3-E1) on the rheological properties of bioinks, bioink printability, and mechanical properties of bioprinted scaffolds. We demonstrate that the addition of CNCs and cells (5 million cells/mL) significantly improved the viscosity of bioinks and the mechanical properties of chitosan scaffolds post-fabrication. The bioinks were biocompatible and printable at an optimized range of printing pressures (12−20 kPa) that did not compromise cell viability. The presence of CNCs promoted greater osteogenesis of MC3T3-E1 cells in chitosan scaffolds as shown by the upregulation of alkaline phosphatase activity, higher calcium mineralization, and extracellular matrix formation. The versatility of this CNCs-incorporated chitosan hydrogel makes it attractive as a bioink for 3D bioprinting to engineer scaffolds for bone tissue engineering and other therapeutic applications.

The application of solid-state NMR methods to characterize the structure and dynamics of imidazolebased proton-conducting polymeric materials provides insight into the mechanism (Grotthus vs vehicle) of proton-mobility. The presented materials are built on a siloxane backbone, and are of interest as potential new proton-conducting membranes for fuel cells able to function at temperatures above 130°C. This is expected to improve the CO tolerance of the catalyst in the fuel cell, as compared to water-based systems. High-resolution solid-state 1 H NMR is achieved under fast magic-angle spinning (MAS) conditions (30 kHz), and provides resolution of resonances in the hydrogen-bonding region. Homonuclear double quantum filtered (DQF) NMR spectra, acquired using the back-to-back sequence, provided identification of mobile protons. It was found that proton conductivity, observed macroscopically using impedance spectroscopy, is correlated with local proton mobility, observed via 1 H NMR line width trends observed for the hydrogenbonded protons. 1 H MAS and DQF NMR experiments show no crystal packing of these materials in contrast to model oligo-ethyleneoxide-tethered imidazole materials (Imi-nEO) studied previously. Comparisons of macroscopic and microscopic measures of proton mobility are also presented in the activation energies of pure and acid-doped siloxane oligomers and polymers functionalized with imidazole. The acid-doped materials show enhanced proton mobility, and hence higher conductivity, relative to the pure material.