Targeted Drug Delivery To Leukocytes with ICAM-1 Derived Peptides

Abstract

Intercellular adhesion molecule-1 (ICAM-1) derived cyclic peptide cIBR [cyclo(1,12)PenPRGGSVLVTGC] showed high affinity for leukocyte function associated antigen-1 (LFA-1) receptor and was internalized into the MOLT-3 T-cells. Therefore, the objective of the dissertation was to explore the possibility of selectively delivering drugs to leukocytes using ICAM-1 derived peptides. Fluorescein isothiocyanate conjugated cIBR (FITC-cIBR) and doxorubicin conjugated cIBR (DOX-cIBR) entered the HL-60 cells by receptor mediated endocytosis and passive diffusion, respectively. High hydrophobicity of DOX-cIBR was proposed to be responsible for its energy-independent entry (chapter 2). To check the effect of hydrophobicity on internalization, two relatively more hydrophilic cIBR-derived peptides were conjugated to DOX. However, both the DOX-peptide conjugates were internalized passively (chapter 3). Degradation mechanism of methotrexate conjugate of cIBR (MTX-cIBR) was studied and suitable formulation conditions were developed. Stability of MTX-cIBR was assessed with in vitro biological matrices to determine optimum dosing regimen for in vivo studies (chapter 4).