Novel tumor-targeted RGD peptide-camptothecin conjugates: synthesis and biological evaluation.
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.
Dal Pozzo
Alma
A
Istituto di Ricerche Chimiche e Biochimiche G.Ronzoni, via G Colombo 81, 20133 Milano, Italy. dalpozzo@ronzoni.it
Ni
Ming-Hong
MH
Esposito
Emiliano
E
Dallavalle
Sabrina
S
Musso
Loana
L
Bargiotti
Alberto
A
Pisano
Claudio
C
Vesci
Loredana
L
Bucci
Federica
F
Castorina
Massimo
M
Foderà
Rosanna
R
Giannini
Giuseppe
G
Aulicino
Concetta
C
Penco
Sergio
S
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
D000972:Antineoplastic Agents, Phytogenic; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D002166:Camptothecin