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Pharmacological and genetic studies over the past decade have established the follicle-stimulating hormone (FSH) as an actionable target for diseases affecting millions, namely osteoporosis, obesity, and Alzheimer’s disease. Blocking FSH action prevents bone loss, fat gain, and neurodegeneration in mice. We recently developed a first-in-class, humanized, epitope-specific FSH-blocking antibody, MS-Hu6, with a KD of 7.52 nM. Using a Good Laboratory Practice (GLP)-compliant platform, we now report the efficacy of MS-Hu6 in preventing and treating osteoporosis in mice and parameters of acute safety in monkeys. Biodistribution studies using 89Zr-labeled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. The MS-Hu6 displayed a β phase t½ of 7.5 days (180 hr) in humanized Tg32 mice. We tested 217 variations of excipients using the protein thermal shift assay to generate a final formulation that rendered MS-Hu6 stable in solution upon freeze-thaw and at different temperatures, with minimal aggregation, and without self-, cross-, or hydrophobic interactions or appreciable binding to relevant human antigens. The MS-Hu6 showed the same level of “humanness” as human IgG1 in silico and was non-immunogenic in ELISpot assays for IL-2 and IFN-γ in human peripheral blood mononuclear cell cultures. We conclude that MS-Hu6 is efficacious, durable, and manufacturable, and is therefore poised for future human testing.

Temperature-induced, rapid changes in the viscosity and reproducible 3-D structure formation makes thermos-sensitive hydrogels an ideal delivery system to act as a cell scaffold or a drug reservoir. Moreover, the hydrogels’ minimum invasiveness, high biocompatibility, and facile elimination from the body have gathered a lot of attention from researchers. This review article attempts to present a complete picture of the exhaustive arena, including the synthesis, mechanism, and biomedical applications of thermosensitive hydrogels. A special section on intellectual property and marketed products tries to shed some light on the commercial potential of thermosensitive hydrogels.

The present investigation aims to develop and explore mannosylated lipid-based carriers to deliver an anti-HIV drug, Etravirine (TMC) and Selenium nanoparticles (SeNPs), to the HIV reservoirs via the mannose receptor. The successful mannosylation was evaluated by the change in zeta potential and lectin binding assay using fluorescence microscopy. Electron microscopy and scattering studies were employed to study the structure and surface of the nanocarrier system. The presence of selenium at the core-shell of the nanocarrier system was confirmed by X-ray photoelectron spectroscopy and energy dispersive X-ray analysis. Further, the in vitro anti-HIV1 efficacy was assessed using HIV1 infected TZM-bl cells followed by in vivo biodistribution studies to evaluate distribution to various reservoirs of HIV. The results exhibited higher effectiveness and a significant increase in the therapeutic index as against the plain drug. The confocal microscopy and flow cytometry studies exhibited the efficient uptake of the coumarin-6 tagged respective formulations. The protective effect of nano selenium toward oxidative stress was evaluated in rats, demonstrating the potential of the lipidic nanoparticle-containing selenium in mitigating oxidative stress in all the major organs. The in vivo biodistribution assessment in rats showed a 12.44, 8.05 and 9.83-fold improvement in the brain, ovary, and lymph node biodistribution, respectively as compared with plain TMC. Delivery of such a combination via mannosylated nanostructured lipid carriers could be an efficient approach for delivering drugs to reservoirs of HIV while simultaneously reducing the oxidative stress induced by such long-term therapies by co-loading Nano-Selenium.

Background: The clinical outcome of anti-HIV therapy is poor due to the inherent fallouts of anti-HIV therapy. It is further worsened due to the presence of viral reservoirs in immune cells like the macrophages. An ideal anti-HIV therapy must reach, deliver the drug and exert its action inside macrophages. To address this, we developed novel cationic nanostructured lipid carriers of efavirenz (cationic EFV-NLC). Methods: The developed cationic EFV NLCs were evaluated for particle size, zeta potential, encapsulation efficiency, in-vitro drug release, DSC, XRD, TEM, cytotoxicity, cellular uptake studies and anti-HIV efficacy in a monocyte-derived macrophage cell line (THP-1). ANOVA was used for statistical analysis. Results: Cationic EFV-NLCs showed high encapsulation efficiency (90.54 ± 1.7%), uniform particle size distribution (PDI 0.3-0.5 range) and high colloidal stability with positive zeta potential (+23.86 ± 0.49 mV). DSC and XRD studies confirmed the encapsulation of EFV within NLCs. Cytotoxicity studies (MTT assay) revealed excellent cytocompatibility (CC50 13.23 ± 0.54 µg/mL). Fluorescence microscopy confirmed the efficient uptake of cationic EFV-NLCs, while flow cytometry revealed time and concentration dependant uptake within THP-1 cells. Cationic EFV-NLCs showed higher retention and sustained release with 2.32-fold higher percent inhibition of HIV-1 in HIV-1 infected macrophages as compared to EFV solution at equimolar concentrations. Interestingly, they demonstrated 1.23-fold superior anti-HIV efficacy over plain NLCs at equimolar concentrations. Conclusion: Cationic NLCs were capable of inhibiting the viral replication at higher limits consistently for 6 days suggesting successful prevention of HIV-1 replication in infected macrophages and thus can prove to be an attractive tool for promising anti-HIV therapy.

Polymeric nanocomposites have been outstanding functional materials and have garnered immense attention as sustainable materials to address multi-disciplinary problems. MXenes have emerged as a newer class of 2D materials that produce metallic conductivity upon interaction with hydrophilic species, and their delamination affords monolayer nanoplatelets of a thickness of about one nm and a side size in the micrometer range. Delaminated MXene has a high aspect ratio, making it an alluring nanofiller for multifunctional polymer nanocomposites. Herein, we have classified and discussed the structure, properties and application of major polysaccharide-based electroactive hydrogels (hyaluronic acid (HA), alginate sodium (SA), chitosan (CS) and cellulose) in biomedical applications, starting with the brief historical account of MXene's development followed by successive discussions on the synthesis methods, structures and properties of nanocomposites encompassing polysaccharides and MXenes, including their biomedical applications, cytotoxicity and biocompatibility aspects. Finally, the MXenes and their utility in the biomedical arena is deliberated with an eye on potential opportunities and challenges anticipated for them in the future, thus promoting their multifaceted applications.

There is a dire need for dual-long-acting therapy that could simultaneously target different stages of the HIV life cycle and providing a dual-prolonged strategy for improved anti-HIV therapy while reducing oxidative stress associated with the prolonged treatment. Thus, in the present work, nanostructured lipid carriers of Etravirine were developed and modified with nano-selenium. The dual-loaded nanocarrier system was fabricated using the double emulsion solvent evaporation method, further screened and optimized using the design of experiments methodology. The spherical core-shell type of a system was confirmed with an electron microscope and small-angle neutron scattering, while XPS confirmed the presence of selenium at the core-shell of the nanocarrier. In vitro assessment against HIV1 (R5 and X4 strains) infected TZM-bl cells exhibited higher efficacy for the dual-loaded nanocarrier system than the plain drug, which could be attributed to the synergistic effect of the nano-selenium. Confocal microscopy and flow cytometry results exhibited enhanced uptake in TZM-bl cells compared to plain drug. A significant increase of GSH, SOD, CAT was observed in animals administered with the dual-loaded nanocarrier system containing nano-selenium, suggesting the protective potential of the lipidic nanoparticle containing the nano-selenium. Improvement in the in vivo pharmacokinetic parameters was also observed, along with a higher accumulation of the dual-loaded nanocarrier in remote HIV reservoir organs like the brain, ovary, and lymph node. The results suggest the potential of a dual-loaded formulation for synergistically targeting the HIV1 infection while simultaneously improving the intracellular anti-oxidant balance for improving a prolonged anti-HIV therapy.

Macrophages act as a cellular reservoir in HIV infection. Elimination of HIV from macrophages has been an unfulfilled dream due to the failure of drugs to reach them. To address this, we developed CD44 receptor-targeted, novel hyaluronic acid (HA)-coated nanostructured lipid carriers (NLCs) of efavirenz via washless layer-by-layer (LbL) assembly of HA and polyallylamine hydrochloride (PAH). NLCs were subjected to TEM analysis, size and zeta potential, in vitro release and encapsulation efficiency studies. The uptake of NLCs in THP-1 cells was studied using fluorescence microscopy and flow cytometry. The anti-HIV efficacy was evaluated using p24 antigen inhibition assay. NLCs were found to be spherical in shape with anionic zeta potential (-23.66 ± 0.87 mV) and 241.83 ± 5.38 nm particle size. NLCs exhibited prolonged release of efavirenz during in vitro drug release studies. Flow cytometry revealed 1.73-fold higher uptake of HA-coated NLCs in THP-1 cells. Cytotoxicity studies showed no significant change in cell viability in presence of NLCs as compared with the control. HA-coated NLCs distributed throughout the cell including cytoplasm, plasma membrane and nucleus, as observed during fluorescence microscopy. HA-coated NLCs demonstrated consistent and significantly higher inhibition (81.26 ± 1.70%) of p24 antigen which was 2.08-fold higher than plain NLCs. The obtained results suggested preferential uptake of HA-coated NLCs via CD44-mediated uptake. The present finding demonstrates that HA-based CD44 receptor targeting in HIV infection is an attractive strategy for maximising the drug delivery to macrophages and achieve effective viral inhibition.

The inadequate bioavailability and toxicity potential of antiretroviral therapy limit their effectiveness in the complete eradication of HIV from viral reservoirs. The penetration of these drugs into the brain is challenging because of the unfavorable physicochemical properties required to cross the membranes, limiting the transport of the drugs. Thus, in the current study, the authors report a nanocarrier-based drug delivery of a highly hydrophobic drug to overcome the existing limitations of the conventional therapies. An explicitly simple approach was used to overcome the limitations of existing anti-HIV therapies. The monophasic hot homogenized solution of lipid, drug, and solubilizer was diluted with the predetermined hot surfactant solution followed by the ultrasonication to generate the polydisperse nanoparticles with the size range of 50-1000 nm. The anti-HIV1 potential of nanostructured lipid carriers of Etravirine on HIV-infected cell lines showed efficacy with an appreciable increase in the therapeutic index as compared with the plain drug. Further, the results obtained from confocal microscopy along with flow cytometry exhibited efficient uptake of the nanocarrier loaded with coumarin-6 in cells. The pharmacokinetics of Etravirine nanostructured carriers was significantly better in all aspects compared to the plain drug solution, which could be attributed to molecular dispersion in the lipid matrix of the nanocarrier. A significant enhancement of Etravirine concentration of several-fold was also observed in the liver, ovary, lymph node, and brain, respectively, as compared to plain drug solution when assessed by biodistribution studies in rats. In conclusion, ETR-NLC systems could serve as a promising approach for simultaneous multi-site targeting and could provide therapeutic benefits for the efficient eradication of HIV/AIDS infections.

A key challenge of HIV treatment with multiple antiretroviral drugs is patient adherence. Thus, there is an urgent need for long-acting depot systems for delivering drugs over an extended duration. Although the parenteral route is preferred for depot systems, it is associated with obvious drawbacks, such as painful injections, potentially-contaminated sharps waste, and the necessity of trained healthcare personnel for administration. Amongst a small number of alternatives in development microneedles are versatile delivery systems enabling systemic drug delivery and potentially improving patient adherence due to their capacity for self-administration. We have developed dissolving microneedle (DMNs) embedded with etravirine nanosuspension (ETR NS) as a long-acting HIV therapy to improve patient adherence. The ETR NS prepared by sonoprecipitation yielded particle sizes of 764 ± 96.2 nm, polydispersity indices of of 0.23 ± 0.02, and zeta potentials of -19.75 ± 0.55 mV. The DMNs loaded with ETR NS demonstrated 12.84 ± 1.33% ETR deposition in ex-vivo neonatal porcine skin after 6 h application. In in vivo rat pharmacokinetic studies, the Cmax exhibited by DMNs loaded with ETR powder and ETR NS were 158 ± 10 ng/mL and 177 ± 30 ng/mL, respectively. DMN groups revealed a higher t , Tmax, and mean residence time compared to intravenous ETR solutions, suggesting the long-acting potential of etravirine delivered intradermally using DMNs. [Abstract copyright: Copyright © 2021. Published by Elsevier B.V.]

Polymeric nanocomposites have been outstanding functional materials and have garnered immense attention as sustainable materials to address multi-disciplinary problems. MXenes have emerged as a newer class of 2D materials that produce metallic conductivity upon interaction with hydrophilic species, and their delamination affords monolayer nanoplatelets of a thickness of about one nm and a side size in the micrometer range. Delaminated MXene has a high aspect ratio, making it an alluring nanofiller for multifunctional polymer nanocomposites. Herein, we have classified and discussed the structure, properties and application of major polysaccharide-based electroactive hydrogels (hyaluronic acid (HA), alginate sodium (SA), chitosan (CS) and cellulose) in biomedical applications, starting with the brief historical account of MXene’s development followed by successive discussions on the synthesis methods, structures and properties of nanocomposites encompassing polysaccharides and MXenes, including their biomedical applications, cytotoxicity and biocompatibility aspects. Finally, the MXenes and their utility in the biomedical arena is deliberated with an eye on potential opportunities and challenges anticipated for them in the future, thus promoting their multifaceted applications.

In the present work, pulsed radio frequency (RF) plasma (PRFP) was used to functionalize omeprazole (OME) microparticles using precursor monomers methacrylic acid (MAA) and methyl methacrylate (MMA). This method had two significant factors involved – 1) ratio of monomer flow rate and 2) graded deposition by systematically varying the duty cycle of pulsed plasma. The MAA flow was set to 100 cc/min and MMA to 200 cc/min to rationalize the ratio (1:2) of monomers. Systematic variation in duty cycle (keeping ON time constant and increasing OFF time of the pulse) ensured graded deposition and functionalization of OME. The plasma functionalized OME microparticles were evaluated in-vitro via dissolution studies in pH 1.2 buffer showed a cumulative release of 3.6–9.1% within 120 min compared to complete release under 60 min in pH 6.8. Raman analysis exhibited the absence of peaks from 1800 to 1000 cm−1 and XPS studies showed an increase in oxygen-containing moieties on plasma functionalized OME surface. Thermal, NMR and HR-MS analysis confirmed successful deposition without alteration in original OME molecular structure. The decreased contact angle of post plasma treated OME resulted from hydrophilization of the OME surface. XRD data of plasma treated OME showed an improved degree of crystallinity with an increase in average crystallite size. Post plasma treated OME microparticles size through DLS corroborated well with SEM. Thus, the use of graded PRFP functionalization has proved it's potent to deliver a new, safe, and cheaper alternative to contemporary drug surface modification methods.

The pulsed oxygen plasma treatment (POPT) of the ritonavir (RTV) powder/compacts was investigated as a novel possible physical technique for improving wettability, intrinsic dissolution rate (IDR), and, consequently, solubility of the poorly water-soluble RTV drug. Induction of POPT for 30 min enhanced 5.87-folds apparent solubility and 1.95-folds IDR at 24 h, attributed to RTV's surface hydrophilization. The POPT RTV exhibited zero contact angle compared to RTV suggesting improved wettability (untreated RTV = 74° and 30 min after POPT = 0°). The ATR-FTIR showed a broad peak of –OH group around 3300 cm -1, and XPS showed an increase in surface oxygen concentration from 9 % to 12 % aided through POPT lead to improved wettability of RTV. Moreover, the increased negative zeta potential was observed due to surface hydroxylation on the POPT RTV, resulting in increased surface polarity and RTV's solubility. It was found that there was no substantial thermal or physical alteration after POPT, as evident from DSC, SEM, and XRD studies. This study successfully demonstrated the impact of POPT on improvement in the wettability, solubility, and IDR of hydrophobic drugs RTV.