NanoART Synthesis, Characterization, Uptake, Release and Toxicology for Human Monocyte–Macrophage Drug Delivery

Abstract

Background Factors limiting the efficacy of conventional antiretroviral therapy for HIV-1 infection include treatment adherence, pharmacokinetics and penetration into viral sanctuaries. These affect the rate of viral mutation and drug resistance. In attempts to bypass such limitations, nanoparticles containing ritonavir, indinavir and efavirenz (described as nanoART) were manufactured to assess macrophage-based drug delivery. Methods NanoART were made by high-pressure homogenization of crystalline drug with various surfactants. Size, charge and shape of the nanoparticles were assessed. Monocyte-derived macrophage nanoART uptake, drug release, migration and cytotoxicity were determined. Drug levels were measured by reverse-phase high-performance liquid chromatography. Results Efficient monocyte-derived macrophage cytoplasmic vesicle uptake in less than 30 min based on size, charge and coating was observed. Antiretroviral drugs were released over 14 days and showed dose-dependent reduction in progeny virion production and HIV-1 p24 antigen. Cytotoxicities resulting from nanoART carriage were limited. Conclusion These results support the continued development of macrophage-mediated nanoART carriage for HIV-1 disease.

Endosomal Trafficking of Nanoformulated Antiretroviral Therapy Facilitates Drug Particle Carriage and HIV Clearance

“…The zeta potential was Ϫ28.9 mV, and the negative charge was contributed by P407. Scanning electron microscopy revealed smooth rod-like morphologies for the nano-ATV particles (data not shown) and confirmed the size measurements and distribution, which were consistent with our previous studies (9,10).…”

“…Drug retention in MDM was determined 24 h after treatment. In MDM treated with nanoATV, drug levels of 28.5 g/10 6 cells and 14.0 g/10 6 cells in the 70-and 30-g/ml treatment groups, respectively, were sustained over 24 h. Sustained release was expected for up to 15 days with nanoparticle treatment based on previous studies (6,10). Much less ATV was detected 24 h following treatment with native ATV.…”

“…With this in mind, our laboratories pioneered the use of monocytes and monocyte-derived macrophages (MDM) as nanoART carriers and drug depots. Macrophages can increase drug stability by preventing drug metabolic degradation, and because of their highly mobile nature, they may also be used for delivery of ART to and from lymphocytes and other viral reservoirs (9)(10)(11). How drug nanoparticles remain sequestered in macrophages for extended periods is incompletely understood.…”

Comparative manufacture and cell-based delivery of antiretroviral nanoformulations

“…4,11,12 Prior works demonstrated that such nanoART could be carried in monocyte-macrophages and reach viral sanctuaries. [11][12][13][14][15] These studies also showed that size, shape, and charge of crystalline indinavir (IDV), ritonavir (RTV), atazanavir (ATV), and efavirenz (EFV) affect uptake, release, cytotoxicities, and antiretroviral responses.…”

Anti-HIV-1 nanotherapeutics: promises and challenges for the future

“…26 Nano-ART can be taken up within minutes by circulating monocytes and released in tissues over a period of 2 weeks. [56][57][58][59][60] Theoretically, cell-based nano-ART would travel to sites of inflammation and release drug(s) slowly with limited tissue toxicities. Such a drug-delivery system can revolutionize HIV-1 therapeutics and can particularly target virus sequestration.…”