Protease-Triggered, Integrin-Targeted Cellular Uptake of Recombinant Protein Micelles.
Targeting nanoparticles for drug delivery has great potential for improving efficacy and reducing side effects from systemic toxicity. New developments in the assembly of materials afford the opportunity to expose cryptic targeting domains in tissue-specific microenvironments in which certain proteases are expressed. Here, recombinant proteins are designed to combine the responsiveness to environmental proteases with specific targeting. Materials made recombinantly allow complete control over amino acid sequence, in which each molecule is identically functionalized. Previously, oleosin, a naturally occurring plant protein that acts as a surfactant, has been engineered to self-assemble into spherical micelles-a useful structure for drug delivery. To make oleosins that are locally activated to bind receptors, oleosin is genetically modified to incorporate the integrin-binding motif RGDS just behind a domain cleavable by thrombin. The resulting modified oleosin self-assembles into spherical micelles in aqueous environments, with the RGDS motif protected by the thrombin-cleavable domain. Upon the addition of thrombin, the RGDS is exposed and the binding of the spherical micelles to breast cancer cells is increased fourfold.
Department of Chemical and Biomolecular Engineering, University of Pennsylvania, 311A Towne Building, 220 S. 33rd Street, Philadelphia, PA, 19104, USA.
Chen
C
Gao
Department of Chemical and Biomolecular Engineering, University of Pennsylvania, 311A Towne Building, 220 S. 33rd Street, Philadelphia, PA, 19104, USA.
Kevin B
KB
Vargo
Department of Chemical and Biomolecular Engineering, University of Pennsylvania, 311A Towne Building, 220 S. 33rd Street, Philadelphia, PA, 19104, USA. hammer@seas.upenn.edu.
Daniel A
DA
Hammer
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008823:Micelles; D018613:Microscopy, Confocal; D008958:Models, Molecular; D009842:Oligopeptides / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism*; D010940:Plant Proteins / Q000737:chemistry; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology
D016023:Integrins; D008823:Micelles; D009842:Oligopeptides; D010940:Plant Proteins; D011994:Recombinant Proteins; C079350:oleosin, Helianthus annuus; C046617:arginyl-glycyl-aspartyl-serine; D010447:Peptide Hydrolases; D013917:Thrombin
enzyme-sensitive; protein surfactants; self-assembly; targeted drug delivery; thrombin