title: Synthesis and evaluation of folate-based chlorambucil delivery systems for tumor-targeted chemotherapy.
abstract: The development of tumor-targeting drug delivery systems, able to selectively transport cytotoxic agents into the tumor site by exploiting subtle morphological and physiological differences between healthy and malignant cells, currently stands as one of the most attractive anticancer strategies used to overcome the selectivity problems of conventional chemotherapy. Owing to frequent overexpression of folate receptors (FRs) on the surface of malignant cells, conjugation of cytotoxic agents to folic acid (FA) via suitable linkers have demonstrated to enhance selective drug delivery to the tumor site. Herein, the chemical synthesis and biological evaluation of two novel folate-conjugates bearing the anticancer agent chlorambucil (CLB) tethered to either an aminoether (4,7,10-trioxa-1,13-tridecanediamine) or a pseudo-β-dipeptide (β-Ala-ED-β-Ala) linker is reported. The two drug delivery systems have been prepared in high overall yields (54% and 34%) through straightforward and versatile synthetic routes. Evaluation of cell specificity was examined using three leukemic cell lines, undifferentiated U937 (not overexpressing FRs, FR(-)), TPA-differentiated U937 (overexpressing FRs, FR(+)), and TK6 (FR(+)) cells. Both conjugates exhibited high specificity only to FR(+) cells (particularly TK6), demonstrating comparable antitumor activity to CLB in its free form. These data confirm the reliability of folate-based drug delivery systems for targeted antitumor therapy; likewise, they lay the foundations for the development of other folate-conjugates with antitumor potential.
authors: Dipartimento di Chimica Organica e Biochimica, Università di Napoli Federico II, via Cinthia 4, Naples, Italy. annalisa.guaragna@unina.it
authors: Annalisa
authors: A
authors: Guaragna
authors: Angela
authors: A
authors: Chiaviello
authors: Concetta
authors: C
authors: Paolella
authors: Daniele
authors: D
authors: D'Alonzo
authors: Giuseppe
authors: G
authors: Palumbo
authors: Giovanni
authors: G
authors: Palumbo
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002699:Chlorambucil / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D020298:U937 Cells
chemical_list: D002699:Chlorambucil; D005492:Folic Acid