title: Molecular targeting of drug delivery systems to ovarian cancer by BH3 and LHRH peptides.
abstract: Novel targeted proapoptotic anticancer drug delivery systems were developed and evaluated. Poly(ethyleneglycol) (PEG) conjugates were used as carriers. Camptothecin (CPT) was used as an anticancer agent-apoptosis inductor. Two types of molecular targets were investigated: (1) an extracellular membrane receptor specific to ovarian cancer and (2) intracellular controlling mechanisms of apoptosis. Synthetic peptides similar to luteinizing hormone-releasing hormone (LHRH) and BCL-2 homology 3 (BH3) peptide were used as a targeting moiety and a suppressor of cellular antiapoptotic defense, respectively. Three different conjugates (CPT-PEG, CPT-PEG-BH3 and CPT-PEG-LHRH) were synthesized and examined in A2780 human ovarian cancer cells. Cytotoxicity, expression of genes encoding BCL-2, BCL-XL, SMAC, APAF-1 proteins and caspases 3 and 9, the activity of caspases 3 and 9 and apoptosis induction were studied. Taken together the results indicate much higher cytotoxicity and apoptosis-inducing activity of PEG-CPT conjugates when compared to free CPT. Moreover, the effects of targeted CPT-PEG-BH3 and CPT-PEG-LHRH conjugates were more pronounced than the non-targeted PEG-CPT conjugate. The results confirmed the feasibility of this new two-tier molecular targeting strategy for enhancing the efficacy of cancer chemotherapy.
authors.affiliation: Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Dharap
authors.forename: B
authors.initials: B
authors.lastname: Qiu
authors.forename: G C
authors.initials: GC
authors.lastname: Williams
authors.forename: P
authors.initials: P
authors.lastname: Sinko
authors.forename: S
authors.initials: S
authors.lastname: Stein
authors.forename: T
authors.initials: T
authors.lastname: Minko
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000008:administration & dosage* / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D017931:DNA Primers; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006801:Humans; D008856:Microscopy, Fluorescence; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000596:Amino Acids; D000972:Antineoplastic Agents, Phytogenic; C474007:Bax protein (53-86); D017931:DNA Primers; D004337:Drug Carriers; D010446:Peptide Fragments; D014677:Pharmaceutical Vehicles; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D007987:Gonadotropin-Releasing Hormone; D011092:Polyethylene Glycols; D020169:Caspases; D002166:Camptothecin