Antibody targeting of camptothecin-loaded PLGA nanoparticles to tumor cells.
Antibody targeting of drug substances can improve the efficacy of the active molecule, improving distribution and concentration of the drug at the site of injury/disease. Encapsulation of drug substances into polymeric nanoparticles can also improve the therapeutic effects of such compounds by protecting the molecule until its action is required. In this current study, we have brought together these two rationales to develop a novel immuno-nanoparticle with improved therapeutic effect against colorectal tumor cells. This nanoparticle comprised a layer of peripheral antibodies (Ab) directed toward the Fas receptor (CD95/Apo-1) covalently attached to poly(lactide-co-glycolide) nanoparticles (NP) loaded with camptothecin. Variations in surface carboxyl density permitted up to 48.5 microg coupled Ab per mg of NP and analysis of nanoparticulate cores showed efficient camptothecin loading. Fluorescence visualization studies confirmed internalization of nanoconstructs into endocytic compartments of HCT116 cells, an effect not evident in NP without superficial Ab. Cytotoxicity studies were then carried out against HCT116 cells. After 72 h, camptothecin solution resulted in an IC 50 of 21.8 ng mL (-1). Ab-directed delivery of NP-encapsulated camptothecin was shown to be considerably more effective with an IC 50 of 0.37 ng mL (-1). Calculation of synergistic ratios for these nanoconstructs demonstrated synergy of pharmacological relevance. Indeed, the results in this paper suggest that the attachment of anti-Fas antibodies to camptothecin-loaded nanoparticles may result in a therapeutic strategy that could have potential in the treatment of tumors expressing death receptors.
McCarron
Paul A
PA
School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, U.K.
Marouf
Waleed M
WM
Quinn
Derek J
DJ
Fay
Francois
F
Burden
Roberta E
RE
Olwill
Shane A
SA
Scott
Christopher J
CJ
D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D058846:Antibodies, Monoclonal, Murine-Derived; D002166:Camptothecin / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism* / Q000633:toxicity; D042541:Intracellular Space / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000276:immunology*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D004337:Drug Carriers; D018796:Immunoconjugates; C411023:anti-Fas monoclonal antibody; D019014:fas Receptor; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D002166:Camptothecin