title: Folate receptor-mediated enhanced and specific delivery of far-red light-activatable prodrugs of combretastatin A-4 to FR-positive tumor.
abstract: We examined the concept of a novel prodrug strategy in which anticancer drug can be locally released by visible/near IR light, taking advantage of the photodynamic process and photo-unclick chemistry. Our most recently formulated prodrug of combretastatin A-4, Pc-(L-CA4)2, showed multifunctionality for fluorescence imaging, light-activated drug release, and the combined effects of PDT and local chemotherapy. In this formulation, L is a singlet oxygen cleavable linker. Here, we advanced this multifunctional prodrug by adding a tumor-targeting group, folic acid (FA). We designed and prepared four FA-conjugated prodrugs 1-4 (CA4-L-Pc-PEGn-FA: n = 0, 2, 18, ∼45) and one non-FA-conjugated prodrug 5 (CA4-L-Pc-PEG18-boc). Prodrugs 3 and 4 had a longer PEG spacer and showed higher hydrophilicity, enhanced uptake to colon 26 cells via FR-mediated mechanisms, and more specific localization to SC colon 26 tumors in Balb/c mice than prodrugs 1 and 2. Prodrug 4 also showed higher and more specific uptake to tumors, resulting in selective tumor damage and more effective antitumor efficacy than non-FA-conjugated prodrug 5. FR-mediated targeting seemed to be an effective strategy to spare normal tissues surrounding tumors in the illuminated area during treatment with this prodrug.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma 73117, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Nkepang
authors.forename: Moses
authors.initials: M
authors.lastname: Bio
authors.forename: Pallavi
authors.initials: P
authors.lastname: Rajaputra
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Awuah
authors.forename: Youngjae
authors.initials: Y
authors.lastname: You
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D045744:Cell Line, Tumor / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D015195:Drug Design; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000737:chemistry / Q000378:metabolism*; D005492:Folic Acid / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D061848:Optical Imaging / Q000379:methods; D010778:Photochemotherapy / Q000379:methods; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D013267:Stilbenes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D058973:Folate Receptors, GPI-Anchored; D011355:Prodrugs; D013267:Stilbenes; D005492:Folic Acid; C058728:fosbretabulin