Transferrin-containing, cyclodextrin polymer-based particles for tumor-targeted gene delivery.
Transferrin is a well-studied ligand for tumor targeting due to upregulation of transferrin receptors in numerous cancer cell types. Here, we report the development of a transferrin-modified, cyclodextrin polymer-based gene delivery system. The delivery system is comprised of a nanoparticle (formed by condensation of a cyclodextrin polycation with nucleic acid) that is surface-modified to display poly(ethylene glycol) (PEG) for increasing stability in biological fluids and transferrin for targeting of cancer cells that express transferrin receptor. A transferrin-PEG-adamantane conjugate is synthesized for nanoparticle modification. The transferrin conjugate retains high receptor binding and self-assembles with the nanoparticles by adamantane (host) and particle surface cyclodextrin (guest) inclusion complex formation. At low transferrin modification, the particles remain stable in physiologic salt concentrations and transfect K562 leukemia cells with increased efficiency over untargeted particles. The increase in transfection is eliminated when transfections are conducted in the presence of excess free transferrin. The transferrin-modified nanoparticles are appropriate for use in the systemic delivery of nucleic acid therapeutics for metastatic cancer applications.
Bellocq
Nathalie C
NC
Insert Therapeutics, Inc., Pasadena, California, USA.
Pun
Suzie H
SH
Jensen
Gregory S
GS
Davis
Mark E
ME
D000218:Adamantane / Q000737:chemistry; D002240:Carbohydrate Sequence; D002241:Carbohydrates / Q000737:chemistry; D045744:Cell Line, Tumor; D003505:Cyclodextrins / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D020014:K562 Cells; D008239:Lysine / Q000737:chemistry; D008297:Male; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009696:Nucleic Acids / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism; D014162:Transfection; D014168:Transferrin / Q000737:chemistry* / Q000378:metabolism
D002241:Carbohydrates; D003505:Cyclodextrins; D004337:Drug Carriers; D009696:Nucleic Acids; D014168:Transferrin; D011092:Polyethylene Glycols; D008239:Lysine; D000218:Adamantane