title: Novel tumor-targeted RGD peptide-camptothecin conjugates: synthesis and biological evaluation.
abstract: Five RGD peptide-camptothecin (CPT) conjugates were designed and synthesized with the purpose to improve the therapeutic index of this antitumoral drug family. New RGD cyclopeptides were selected on the basis of their high affinity to alpha(v) integrin receptors overexpressed by tumor cells and their metabolic stability. The conjugates can be divided in two groups: in the first the peptide was attached to the drug through an amide bond, in the second through a hydrazone bond. The main difference between the two spacers lies in their acid stability. Affinity to the receptors was maintained for all conjugates and their internalization into tumor cells was demonstrated. The first group conjugates showed lower in vitro and in vivo activity than the parent drug, probably due to the excessive stability of the amide bond, even inside the tumor cells. Conversely, the hydrazone conjugates exhibited in vitro tumor cell inhibition similar to the parent drug, indicating high conversion in the culture medium and/or inside the cells, but their poor solubility hampered in vivo experiments. On the basis of these results, information was acquired for additional development of derivatives with different linkers and better solubility for in vivo evaluation.
authors: Istituto di Ricerche Chimiche e Biochimiche G.Ronzoni, via G Colombo 81, 20133 Milano, Italy. dalpozzo@ronzoni.it
authors: Alma
authors: A
authors: Dal Pozzo
authors: Ming-Hong
authors: MH
authors: Ni
authors: Emiliano
authors: E
authors: Esposito
authors: Sabrina
authors: S
authors: Dallavalle
authors: Loana
authors: L
authors: Musso
authors: Alberto
authors: A
authors: Bargiotti
authors: Claudio
authors: C
authors: Pisano
authors: Loredana
authors: L
authors: Vesci
authors: Federica
authors: F
authors: Bucci
authors: Massimo
authors: M
authors: Castorina
authors: Rosanna
authors: R
authors: Foderà
authors: Giuseppe
authors: G
authors: Giannini
authors: Concetta
authors: C
authors: Aulicino
authors: Sergio
authors: S
authors: Penco
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D002166:Camptothecin