Ciencias Exactas y Ciencias de la Salud
Permanent URI for this collectionhttps://hdl.handle.net/11285/551014
Pertenecen a esta colección Tesis y Trabajos de grado de los Doctorados correspondientes a las Escuelas de Ingeniería y Ciencias así como a Medicina y Ciencias de la Salud.
Browse
Search Results
- Sustained release of antiretroviral therapy from nanochannel delivery implant for HIV pre-exposure prophylaxis and treatment(Instituto Tecnológico y de Estudios Superiores de Monterrey, 2021-04-08) Pons Faudoa, Fernanda Paola; PONS FAUDOA, FERNANDA PAOLA; 781417; Rito Palomares, Marco Antonio; emipsanchez; Anderson, Peter L.; Castorena Torres, Fabiola; González González, Mirna Alejandra; School of Engineering and Sciences; Campus Monterrey; Grattoni, AlessandroHIV-1 pre-exposure prophylaxis (PrEP) adherence and implementation challenges, including pill fatigue and limited medical access, have motivated research into long-acting (LA) strategies such as formulations or controlled release implants to obviate user-dependent dosing. Focusing on a single-drug regimen permits maximal drug loading and prolongs treatment periods. The nanofluidic implant consists of a drug reservoir and a drug-releasing nanochannel membrane. The pharmacokinetics of two different antiretrovirals (ARV), cabotegravir (CAB) and tenofovir alafenamide fumarate (TAF) released from nanofluidic implants were assessed in separate studies. In the first study, 2-hydroxypropyl-β-cyclodextrin enhanced cabotegravir release in vitro and in vivo in Sprague Dawley rats. Nanofluidic implants loaded with 2-hydroxypropyl-β-cyclodextrin (βCAB) maintained clinically relevant plasma CAB concentrations 2 times above the preventive clinical threshold for 3 months. Additionally, sustained CAB release achieved drug penetration into tissues relevant to HIV-1 transmission. In the second study, the first-ever preventive assessment of LA ARV implant and foremost of TAF was conducted. Nonhuman primates (NHP) were subcutaneously implanted with a nanofluidic device loaded with TAF. Pharmacokinetics in HIV-1 target cells, peripheral blood mononuclear cells (PBMC) were monitored for 4 months, achieving median tenofovir diphosphate (TFV-DP) concentrations of 390 fmol/106 PBMC. Importantly, NHP were exposed to rectal simian HIV (SHIV) challenges after TFV-DP concentrations were above clinically protective levels. Constant and sustained administration of TAF from the nanofluidic implant demonstrated partial protection, with a protective efficacy of 67%. Furthermore, the nanofluidic implant exhibited a foreign-body inflammatory response categorized as slight reaction. In addition, the nanofluidic implant was assessed as an HIV-1 treatment platform. Upon SHIV infection, the control NHP cohort from this study was transferred to a TAF treatment study. The viral load reduction from subcutaneous TAF monotherapy was assessed for a month in treatment naïve NHP. Continuous TAF release exhibited a first-phase viral load decay of -1.14 ± 0.81 log10 copies/mL. Notably, TAF delivered at a lower dose from the nanofluidic implant had similar effects to oral TAF. Thus, demonstrating potential as a platform for LA ARV therapy. In conclusion, the nanofluidic device shows promise as an HIV PrEP and treatment delivery platform that addresses poor patient adherence.