title: Synthesis and preliminary biological evaluation of high-drug-load paclitaxel-antibody conjugates for tumor-targeted chemotherapy.
abstract: The goal of this study was to design paclitaxel (PTX)-monoclonal antibody (mAb) prodrug conjugates (PTXMAbs) with the ability to deliver therapeutically significant doses of the drug to the tumor while avoiding the previously observed solubility limitations of conjugates with PTX:mAb molar ratios of >3. New PTX conjugates were synthesized using the discrete poly(ethylene glycol) (dPEG) as linkers. These compounds, PTX-L-Lys[(dPEG12)(3)-dPEG4]-dPEG6-NHS (9a and 9b, for L = GL or SX, respectively), were then conjugated to the antiepidermal growth factor receptor mAb, C225 at increasing PTX:C225 ratios, producing completely soluble conjugates. Unlike the earlier PTXMAbs, buffered solutions of these conjugates remained homogeneous for extended periods of time. Fluorescence-activated cell sorting (FACS) analysis indicated preserved immunogenicity of the conjugates at all four substitution ratios, while cytotoxicity studies in MDA-MB-468 breast cancer cells indicated preservation of drug cytotoxicity. These conjugates may have potential in the development of high-drug-load tumor-targeting taxanes.
authors: Department of Radiation Oncology, School of Medicine, University of Alabama at Birmingham,Birmingham, Alabama 35294, USA.
authors: Sherly
authors: S
authors: Quiles
authors: Kevin P
authors: KP
authors: Raisch
authors: Leisa L
authors: LL
authors: Sanford
authors: James A
authors: JA
authors: Bonner
authors: Ahmad
authors: A
authors: Safavy
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D066246:ErbB Receptors / Q000276:immunology; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D017239:Paclitaxel / Q000008:administration & dosage*; D011092:Polyethylene Glycols
chemical_list: D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D018796:Immunoconjugates; D011092:Polyethylene Glycols; D066246:ErbB Receptors; D017239:Paclitaxel