TY - JOUR
T1 - Application of a scavenger receptor a1-targeted polymeric prodrug platform for lymphatic drug delivery in HIV
AU - Stern, Stephan T.
AU - Stevens, David M.
AU - Adiseshaiah, Pavan
AU - Dasa, Siva S.K.
AU - Potter, Tim M.
AU - Skoczen, Sarah L.
AU - Snapp, Kelsie S.
AU - Cedrone, Edward
AU - Patel, Nimit
AU - Busman-Sahay, Kathleen
AU - Rosen, Elias P.
AU - Sykes, Craig
AU - Cottrell, MacKenzie
AU - Dobrovolskaia, Marina A.
AU - Estes, Jacob D.
AU - Kashuba, Angela D.M.
N1 - Funding Information:
The study was supported in whole or in part by federal funds from the National Cancer Institute, the National Institutes of Health, under contract HHSN261200800001E, and by the University of North Carolina at Chapel Hill Center for AIDS Research (CFAR), an NIH funded program P30 AI50410. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does the mention of trade names, commercial products, or organizations implies endorsement by the U.S. Government. The authors would like to acknowledge Drs. Yingwen Hu and Jeffrey Clogston (Nanotechnology Characterization Lab, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, Maryland) for their assistance in performing SEC/MALS analysis.
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/10/5
Y1 - 2020/10/5
N2 - We have developed a macromolecular prodrug platform based on poly(L-lysine succinylated) (PLS) that targets scavenger receptor A1 (SR-A1), a receptor expressed by myeloid and endothelial cells. We demonstrate the selective uptake of PLS by murine macrophage, RAW 264.7 cells, which was eliminated upon cotreatment with the SR-A inhibitor polyinosinic acid (poly I). Further, we observed no uptake of PLS in an SR-A1-deficient RAW 264.7 cell line, even after 24 h incubation. In mice, PLS distributed to lymphatic organs following i.v. injection, as observed by ex vivo fluorescent imaging, and accumulated in lymph nodes following both i.v. and i.d. administrations, based on immunohistochemical analysis with high-resolution microscopy. As a proof-ofconcept, the HIV antiviral emtricitabine (FTC) was conjugated to the polymer's succinyl groups via ester bonds, with a drug loading of 14.2% (wt/wt). The prodrug (PLS-FTC) demonstrated controlled release properties in vitro with a release half-life of 15 h in human plasma and 29 h in esterase-inhibited plasma, indicating that drug release occurs through both enzymatic and nonenzymatic mechanisms. Upon incubation of PLS-FTC with human peripheral blood mononuclear cells (PBMCs), the released drug was converted to the active metabolite FTC triphosphate. In a pharmacokinetic study in rats, the prodrug achieved ∼7-19-fold higher concentrations in lymphatic tissues compared to those in FTC control, supporting lymphatic-targeted drug delivery. We believe that the SR-A1-targeted macromolecular PLS prodrug platform has extraordinary potential for the treatment of infectious diseases.
AB - We have developed a macromolecular prodrug platform based on poly(L-lysine succinylated) (PLS) that targets scavenger receptor A1 (SR-A1), a receptor expressed by myeloid and endothelial cells. We demonstrate the selective uptake of PLS by murine macrophage, RAW 264.7 cells, which was eliminated upon cotreatment with the SR-A inhibitor polyinosinic acid (poly I). Further, we observed no uptake of PLS in an SR-A1-deficient RAW 264.7 cell line, even after 24 h incubation. In mice, PLS distributed to lymphatic organs following i.v. injection, as observed by ex vivo fluorescent imaging, and accumulated in lymph nodes following both i.v. and i.d. administrations, based on immunohistochemical analysis with high-resolution microscopy. As a proof-ofconcept, the HIV antiviral emtricitabine (FTC) was conjugated to the polymer's succinyl groups via ester bonds, with a drug loading of 14.2% (wt/wt). The prodrug (PLS-FTC) demonstrated controlled release properties in vitro with a release half-life of 15 h in human plasma and 29 h in esterase-inhibited plasma, indicating that drug release occurs through both enzymatic and nonenzymatic mechanisms. Upon incubation of PLS-FTC with human peripheral blood mononuclear cells (PBMCs), the released drug was converted to the active metabolite FTC triphosphate. In a pharmacokinetic study in rats, the prodrug achieved ∼7-19-fold higher concentrations in lymphatic tissues compared to those in FTC control, supporting lymphatic-targeted drug delivery. We believe that the SR-A1-targeted macromolecular PLS prodrug platform has extraordinary potential for the treatment of infectious diseases.
KW - Emtricitabine
KW - FTC
KW - HIV
KW - Lymphatic distribution
KW - Macromolecular prodrug
KW - Polymeric prodrug
KW - Prodrug
KW - Scavenger receptor A1 (SR-A1)
UR - http://www.scopus.com/inward/record.url?scp=85092682007&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85092682007&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.0c00562
DO - 10.1021/acs.molpharmaceut.0c00562
M3 - Article
C2 - 32841040
AN - SCOPUS:85092682007
SN - 1543-8384
VL - 17
SP - 3794
EP - 3812
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 10
ER -