Polyester dendritic systems for drug delivery applications: in vitro and in vivo evaluation.
High molecular weight polymers (> 20 000 Da) have been widely used as soluble drug carriers to improve drug targeting and therapeutic efficacy. Dendritic polymers are exceptional candidates for the preparation of near monodisperse drug carriers due to their well-defined structure, multivalency, and flexibility for tailored functionalization. We evaluated various dendritic architectures composed of a polyester dendritic scaffold based on the monomer unit 2,2-bis(hydroxymethyl)propanoic acid for their suitability as drug carriers both in vitro and in vivo. These systems are both water soluble and nontoxic. In addition, the potent anticancer drug, doxorubicin, was covalently bound via a hydrazone linkage to a high molecular weight 3-arm poly(ethylene oxide)-dendrimer hybrid. Drug release was a function of pH, and the release rate was more rapid at pH < 6. The cytotoxicity of the DOX-polymer conjugate measured on multiple cancer lines in vitro was reduced but not eliminated, indicating that some active doxorubicin was released from the drug polymer conjugate under physiological conditions. Furthermore, biodistribution experiments show little accumulation of the DOX-polymer conjugate in vital organs, and the serum half-life of doxorubicin attached to an appropriate high molecular weight polymer has been significantly increased when compared to the free drug. Thus, this new macromolecular system exhibits promising characteristics for the development of new polymeric drug carriers.
Padilla De Jesús
Omayra L
OL
Department of Chemistry, University of California, Berkeley 94720-1460, USA.
Ihre
Henrik R
HR
Gagne
Lucie
L
Fréchet
Jean M J
JM
Szoka
Francis C
FC
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006863:Hydrogen-Ion Concentration; D008657:Metabolic Clearance Rate; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010084:Oxidation-Reduction; D011091:Polyesters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011108:Polymers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D011091:Polyesters; D011108:Polymers; D004317:Doxorubicin