TY - JOUR
T1 - Changes in local tissue microenvironment in response to subcutaneous long-acting delivery of tenofovir alafenamide in rats and non-human primates
AU - Pons-Faudoa, Fernanda P.
AU - Di Trani, Nicola
AU - Capuani, Simone
AU - Hernandez, Nathanael
AU - Wood, Anthony M.
AU - Nehete, Bharti
AU - Niles, Jean
AU - Shelton, Kathryn A.
AU - Kezar, Sarah
AU - Bushman, Lane R.
AU - Chua, Corrine Ying Xuan
AU - Ittmann, Michael M.
AU - Anderson, Peter L.
AU - Nehete, Pramod N.
AU - Arduino, Roberto C.
AU - Nichols, Joan E.
AU - Grattoni, Alessandro
N1 - Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2023/6
Y1 - 2023/6
N2 - Several implantable long-acting (LA) delivery systems have been developed for sustained subcutaneous administration of tenofovir alafenamide (TAF), a potent and effective nucleotide reverse transcriptase inhibitor used for HIV pre-exposure prophylaxis (PrEP). LA platforms aim to address the lack of adherence to oral regimens, which has impaired PrEP efficacy. Despite extensive investigations in this field, tissue response to sustained subcutaneous TAF delivery remains to be elucidated as contrasting preclinical results have been reported in the literature. To this end, here we studied the local foreign body response (FBR) to sustained subdermal delivery of three forms of TAF, namely TAF free base (TAFfb), TAF fumarate salt (TAFfs), and TAFfb with urocanic acid (TAF-UA). Sustained constant drug release was achieved via titanium–silicon carbide nanofluidic implants previously shown to be bioinert. The analysis was conducted in both Sprague-Dawley (SD) rats and rhesus macaques over 1.5 and 3 months, respectively. While visual observation did not reveal abnormal adverse tissue reaction at the implantation site, histopathology and Imaging Mass Cytometry (IMC) analyses exposed a local chronic inflammatory response to TAF. In rats, UA mitigated foreign body response to TAF in a concentration-dependent manner. This was not observed in macaques where TAFfb was better tolerated than TAFfs and TAF-UA. Notably, the level of FBR was tightly correlated with local TAF tissue concentration. Further, regardless of the degree of FBR, the fibrotic capsule (FC) surrounding the implants did not interfere with drug diffusion and systemic delivery, as evidenced by TAF PK results and fluorescence recovery after photobleaching (FRAP).
AB - Several implantable long-acting (LA) delivery systems have been developed for sustained subcutaneous administration of tenofovir alafenamide (TAF), a potent and effective nucleotide reverse transcriptase inhibitor used for HIV pre-exposure prophylaxis (PrEP). LA platforms aim to address the lack of adherence to oral regimens, which has impaired PrEP efficacy. Despite extensive investigations in this field, tissue response to sustained subcutaneous TAF delivery remains to be elucidated as contrasting preclinical results have been reported in the literature. To this end, here we studied the local foreign body response (FBR) to sustained subdermal delivery of three forms of TAF, namely TAF free base (TAFfb), TAF fumarate salt (TAFfs), and TAFfb with urocanic acid (TAF-UA). Sustained constant drug release was achieved via titanium–silicon carbide nanofluidic implants previously shown to be bioinert. The analysis was conducted in both Sprague-Dawley (SD) rats and rhesus macaques over 1.5 and 3 months, respectively. While visual observation did not reveal abnormal adverse tissue reaction at the implantation site, histopathology and Imaging Mass Cytometry (IMC) analyses exposed a local chronic inflammatory response to TAF. In rats, UA mitigated foreign body response to TAF in a concentration-dependent manner. This was not observed in macaques where TAFfb was better tolerated than TAFfs and TAF-UA. Notably, the level of FBR was tightly correlated with local TAF tissue concentration. Further, regardless of the degree of FBR, the fibrotic capsule (FC) surrounding the implants did not interfere with drug diffusion and systemic delivery, as evidenced by TAF PK results and fluorescence recovery after photobleaching (FRAP).
KW - Foreign body response
KW - Immune microenvironment
KW - Long acting drug delivery
KW - Subcutaneous implants
KW - Tenofovir alafenamide
KW - Alanine/therapeutic use
KW - Rats
KW - Adenine
KW - Macaca mulatta
KW - Anti-HIV Agents
KW - Rats, Sprague-Dawley
KW - Tenofovir
KW - HIV Infections/prevention & control
KW - Animals
UR - http://www.scopus.com/inward/record.url?scp=85153863363&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85153863363&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2023.04.037
DO - 10.1016/j.jconrel.2023.04.037
M3 - Article
C2 - 37120032
AN - SCOPUS:85153863363
SN - 0168-3659
VL - 358
SP - 116
EP - 127
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -