Poly(amidoamine) dendrimer-based multifunctional engineered nanodevice for cancer therapy.
Multifunctional cancer therapeutic nanodevices have been designed and synthesized using the poly(amidoamine) (PAMAM) dendrimer as a carrier. Partial acetylation of the generation 5 (G5) PAMAM dendrimer was utilized to neutralize a fraction of the primary amino groups, provide enhanced solubility of the dendrimer during the conjugation reaction of fluorescein isothiocyanate (FITC) (in dimethyl sulfoxide (DMSO)), and prevent nonspecific targeting interactions (in vitro and in vivo) during delivery. The remaining nonacetylated primary amino groups were utilized for conjugation of the functional molecules fluorescein isothiocyanate (FITC, an imaging agent), folic acid (FA, targets overexpressed folate receptors on specific cancer cells), and methotrexate (MTX, chemotherapeutic drug). The appropriate control nanodevices have been synthesized as well. The G5 PAMAM dendrimer molecular weight and number of primary amino groups were determined by gel permeation chromatography (GPC) and potentiometric titration for stoichiometric design of ensuing conjugation reactions. Additionally, dendrimer conjugates were characterized by multiple analytical methods including GPC, nuclear magnetic resonance spectroscopy (NMR), high performance liquid chromatography (HPLC), and UV spectroscopy. The fully characterized nanodevices can be used for the targeted delivery of chemotherapeutic and imaging agents to specific cancer cells. Here, we present a more extensive investigation of our previously reported synthesis of this material with improvements directed toward scale-up synthesis and clinical trials (Pharm. Res. 2002, 19 (9), 1310-1316).
Majoros
István J
IJ
Center for Biologic Nanotechnology, University of Michigan, 200 Zina Pitcher Place, 4027 Kresge II, Ann Arbor, Michigan 48109-0533, USA. majoros@umich.edu
Thomas
Thommey P
TP
Mehta
Chandan B
CB
Baker
James R
JR
D000107:Acetylation; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D050091:Dendrimers; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D005492:Folic Acid / Q000737:chemistry; D008727:Methotrexate / Q000737:chemistry; D049329:Nanostructures; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry; D020005:Propanols / Q000737:chemistry
D000970:Antineoplastic Agents; D050091:Dendrimers; D004337:Drug Carriers; D004852:Epoxy Compounds; C104700:PAMAM Starburst; D011073:Polyamines; D020005:Propanols; D005492:Folic Acid; D016650:Fluorescein-5-isothiocyanate; C004312:glycidol; D008727:Methotrexate