Kinetic limitations of cooperativity-based drug delivery systems.
We study theoretically a novel drug delivery system that utilizes the overexpression of certain proteins in cancerous cells for cell-specific chemotherapy. The system consists of dendrimers conjugated with "keys" (ex: folic acid) which "key-lock" bind to particular cell-membrane proteins (ex: folate receptor). The increased concentration of "locks" on the surface leads to a longer residence time for the dendrimer and greater incorporation into the cell. Cooperative binding of the nanocomplexes leads to an enhancement of cell specificity. However, both our theory and detailed analysis of in vitro experiments indicate that the degree of cooperativity is kinetically limited. We demonstrate that cooperativity and hence the specificity to particular cell type can be increased by making the strength of individual bonds weaker, and suggest a particular implementation of this idea.
Department of Physics and Michigan Center for Theoretical Physics, University of Michigan, 450 Church Street, Ann Arbor, MI 48109, USA.
Nicholas A
NA
Licata
Alexei V
AV
Tkachenko
D000327:Adsorption; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000008:administration & dosage / Q000493:pharmacokinetics; D050091:Dendrimers; D016503:Drug Delivery Systems / Q000379:methods*; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics; D008954:Models, Biological; D008956:Models, Chemical; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011073:Polyamines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D013816:Thermodynamics
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004277:DNA, Single-Stranded; D050091:Dendrimers; D058973:Folate Receptors, GPI-Anchored; D009363:Neoplasm Proteins; C104700:PAMAM Starburst; D011073:Polyamines; D011956:Receptors, Cell Surface; D005492:Folic Acid