TY - JOUR
T1 - A long-acting 3TC ProTide nanoformulation suppresses HBV replication in humanized mice
AU - Wang, Weimin
AU - Smith, Nathan
AU - Makarov, Edward
AU - Sun, Yimin
AU - Gebhart, Catherine L.
AU - Ganesan, Murali
AU - Osna, Natalia A.
AU - Gendelman, Howard E.
AU - Edagwa, Benson J.
AU - Poluektova, Larisa Y.
N1 - Publisher Copyright:
© 2020 The Authors
PY - 2020/8
Y1 - 2020/8
N2 - Nowadays, there is a strong request for the treatment of chronic HBV-infection with direct acting antivirals. Furthermore, prevalent human immunodeficiency virus (HIV-1) and hepatitis B (HBV) co-infections highlight an immediate need for dual long-acting and easily administered antivirals. To this end, we modified lamivudine (3TC), a nucleoside analog inhibitor of both viruses, into a lipophilic monophosphorylated prodrug (M23TC). Prior work demonstrated that nanoformulation of M23TC (NM23TC) enhanced drug stability, controlled dissolution and improved access to sites of viral replication. The present study evaluated the efficacy of a NM23TC in HBV-infected chimeric liver humanized mice. Levels of HBV DNA and HBsAg in plasma were monitored up to 8 weeks posttreatment. A single intramuscular dose of 75 mg/kg 3TC equivalents of nanoformulated NM23TC provided sustained drug levels and suppressed HBV replication in humanized mice for 4 weeks. The results support further development of this long-acting 3TC nanoformulation for HBV treatment and prevention.
AB - Nowadays, there is a strong request for the treatment of chronic HBV-infection with direct acting antivirals. Furthermore, prevalent human immunodeficiency virus (HIV-1) and hepatitis B (HBV) co-infections highlight an immediate need for dual long-acting and easily administered antivirals. To this end, we modified lamivudine (3TC), a nucleoside analog inhibitor of both viruses, into a lipophilic monophosphorylated prodrug (M23TC). Prior work demonstrated that nanoformulation of M23TC (NM23TC) enhanced drug stability, controlled dissolution and improved access to sites of viral replication. The present study evaluated the efficacy of a NM23TC in HBV-infected chimeric liver humanized mice. Levels of HBV DNA and HBsAg in plasma were monitored up to 8 weeks posttreatment. A single intramuscular dose of 75 mg/kg 3TC equivalents of nanoformulated NM23TC provided sustained drug levels and suppressed HBV replication in humanized mice for 4 weeks. The results support further development of this long-acting 3TC nanoformulation for HBV treatment and prevention.
KW - Hepatitis B virus (HBV)
KW - Humanized liver mice
KW - Lamivudine (3TC)
KW - Long-acting nanoformulation
KW - TK-NOG mice
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U2 - 10.1016/j.nano.2020.102185
DO - 10.1016/j.nano.2020.102185
M3 - Article
C2 - 32217146
AN - SCOPUS:85085933481
SN - 1549-9634
VL - 28
JO - Nanomedicine: Nanotechnology, Biology, and Medicine
JF - Nanomedicine: Nanotechnology, Biology, and Medicine
M1 - 102185
ER -