Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors.
Delivery of small interfering RNAs (siRNAs) into cells is a key obstacle to their therapeutic application. We designed a protamine-antibody fusion protein to deliver siRNA to HIV-infected or envelope-transfected cells. The fusion protein (F105-P) was designed with the protamine coding sequence linked to the C terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody. siRNAs bound to F105-P induced silencing only in cells expressing HIV-1 envelope. Additionally, siRNAs targeted against the HIV-1 capsid gene gag, inhibited HIV replication in hard-to-transfect, HIV-infected primary T cells. Intratumoral or intravenous injection of F105-P-complexed siRNAs into mice targeted HIV envelope-expressing B16 melanoma cells, but not normal tissue or envelope-negative B16 cells; injection of F105-P with siRNAs targeting c-myc, MDM2 and VEGF inhibited envelope-expressing subcutaneous B16 tumors. Furthermore, an ErbB2 single-chain antibody fused with protamine delivered siRNAs specifically into ErbB2-expressing cancer cells. This study demonstrates the potential for systemic, cell-type specific, antibody-mediated siRNA delivery.
Song
Erwei
E
CBR Institute for Biomedical Research and Department of Pediatrics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Zhu
Pengcheng
P
Lee
Sang-Kyung
SK
Chowdhury
Dipanjan
D
Kussman
Steven
S
Dykxhoorn
Derek M
DM
Feng
Yi
Y
Palliser
Deborah
D
Weiner
David B
DB
Shankar
Premlata
P
Marasco
Wayne A
WA
Lieberman
Judy
J
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D019556:COS Cells; D016503:Drug Delivery Systems; D015497:HIV-1; D006801:Humans; D007372:Interferons / Q000378:metabolism; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D011956:Receptors, Cell Surface / Q000502:physiology*; D015728:Receptors, HIV / Q000502:physiology; D011993:Recombinant Fusion Proteins
D000906:Antibodies; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D015728:Receptors, HIV; D011993:Recombinant Fusion Proteins; D007372:Interferons