Engineering alginate microparticles for optimized accumulation in fetal rat myelomeningocele.

INTRODUCTION: Intraamniotic microparticle injection is a novel technique for the treatment of myelomeningocele (MMC) in which microparticles are delivered in-utero in a minimally invasive fashion to bind to and protect the exposed spinal cord. This technique could offer earlier intervention and greater access to prenatal treatment of MMC. Here we demonstrate progress on the engineering of the microparticles to promote binding to the MMC defect. We hypothesized that when the particle's surface charge was decreased and delivery concentration increased, particles would bind to the MMC defect more frequently and more specifically. METHODS: Alginate microparticles underwent surface modification to alter the particle charge. Dye-loaded alginate, alginate- dextran sulfate, and alginate- chitosan were injected on e17 into the amnion of a rat model of MMC and the incidence of successful binding and specificity of particle binding to the MMC defect were calculated. Specificity of binding was described using a defect-to-skin brightness ratio based on specimen imaging. Comparisons were made with chi-square, p< 0.05 marked significance. RESULTS: There was no difference in the incidence of successful binding at e17 with 0.6 mg/fetal kg between the three tested alginate particles. However, alginate- dextran sulfate bound most specifically to the defect (p< 0.05). Alginate-dextran sulfate also demonstrated more frequent binding at higher doses than lower doses (79% at 1.2 mg/kg vs 38% at 0.6 mg/kg and 24% at 0.8 mg/kg, p< 0.01 for both). Specificity was not sacrificed at higher dose injections: defect-to-skin brightness ratio of 5.4 at 1.2 mg/kg vs 1.8 at 0.6 mg/kg (p< 0.05) CONCLUSION: We demonstrate that the intraamniotic injection of alginate-dextran sulfate microparticles at high concentration bind more frequently and more specifically to MMC defects than the previously tested unmodified alginate microparticles.

Long-acting and extended-release implant and nanoformulations with a synergistic antiretroviral two-drug combination controls HIV-1 infection in a humanized mouse model.

The HIV pandemic has affected over 38 million people worldwide with close to 26 million currently accessing antiretroviral therapy (ART). A major challenge in the long-term treatment of HIV-1 infection is nonadherence to ART. Long-acting antiretroviral (LA-ARV) formulations, that reduce dosing frequency to less than once a day, are an urgent need that could tackle the adherence issue. Here, we have developed two LA-ART interventions, one an injectable nanoformulation, and the other, a removable implant, for the delivery of a synergistic two-drug ARV combination comprising a pre-clinical nonnucleoside reverse transcriptase inhibitor (NNRTI), Compound I, and the nucleoside reverse transcriptase inhibitor (NRTI), 4'-ethynyl-2-fluoro-2'-deoxyadenosine. The nanoformulation is poly(lactide-co-glycolide)-based and the implant is a copolymer of ω-pentadecalactone and p-dioxanone, poly(PDL-co-DO), a novel class of biocompatible, biodegradable materials. Both the interventions, packaged independently with each ARV, released sustained levels of the drugs, maintaining plasma therapeutic indices for over a month, and suppressed viremia in HIV-1-infected humanized mice for up to 42 days with maintenance of CD4+ T cells. These data suggest promise in the use of these new drugs as LA-ART formulations in subdermal implant and injectable mode.

Alginate microparticles loaded with basic fibroblast growth factor induce tissue coverage in a rat model of myelomeningocele.

BACKGROUND/PURPOSE: We sought to develop a minimally invasive intra-amniotic therapy for prenatal treatment of myelomeningocele (MMC) in an established rat model. METHODS: Time-dated pregnant rats were gavage-fed retinoic acid to induce MMC. Groups received intraamniotic injections at E17.5 with alginate particles loaded with fluorescent dye, basic fibroblast growth factor (Alg-HSA-bFGF), fluorescently tagged albumin (Alginate-BSA-TR), free bFGF, blank alginate particles (Alg-Blank), or PBS. Groups were analyzed at 3 h for specific particle binding or at term (E21) to determine MMC coverage. RESULTS: Alginate microparticles demonstrated robust binding to the MMC defect 3 h after injection. Of those specimens analyzed at E21, 150 of 239 fetuses (62.8%) were viable. Moreover, 18 of 61 (30%) treated with Alg-HSA-bFGF showed evidence of soft tissue coverage compared to 0 of 24 noninjected (P = 0.0021), 0 of 13 PBS (P = 0.0297), and 0 of 42 free bFGF (P = P < 0.0001). Scaffolds of aggregated particles associated with disordered keratinized tissue were observed covering the defect in 2 of 18 (11%) Alg-BSA-TR and 3 of 19 (16%) Alg-Blank specimens. CONCLUSIONS: Injection of microparticles loaded with bFGF resulted in significant soft tissue coverage of the MMC defect compared to controls. Alginate microparticles without growth factors might result in scaffold development over the fetal MMC. TYPE OF STUDY: Basic science. LEVEL OF EVIDENCE: N/A.