Development of a nonviral gene delivery vehicle for systemic application.
Polycation vehicles used for in vitro gene delivery require alteration for successful application in vivo. Modification of polycations by direct grafting of additional components, e.g., poly(ethylene glycol) (PEG), either before or after DNA complexation, tend to interfere with polymer/DNA binding interactions; this is a particular problem for short polycations such as linear, beta-cyclodextrin-containing polycations (betaCDPs). Here, a new method of betaCDP polyplex (polycation/DNA composite structures) modification is presented that exploits the ability to form inclusion complexes between cyclodextrins and adamantane. Surface-PEGylated betaCDP polyplexes are formed by self-assembly of the polyplexes with adamantane-PEG conjugates. While unmodified polyplexes rapidly aggregate and precipitate in salt solutions, the PEGylated betaCDP polyplexes are stable at conditions of physiological salt concentration. Addition of targeting ligands to the adamantane-PEG conjugates allows for receptor-mediated delivery; galactosylated betaCDP-based particles reveal selective targeting to hepatocytes via the asialoglycoprotein receptor. Galactosylated particles transfect hepatoma cells with 10-fold higher efficiency than glucosylated particles (control), but show no preferential transfection in a cell line lacking the asialoglycoprotein receptor. Thus, surface modification of betaCDP-based polyplexes through the use of cyclodextrin/adamantane host/guest interactions endows the particles with properties appropriate for systemic application.
Pun
Suzie Hwang
SH
Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Davis
Mark E
ME
D000218:Adamantane / Q000378:metabolism; D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry; D003505:Cyclodextrins / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D005260:Female; D005690:Galactose / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism; D000071228:Polyelectrolytes; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism*
D000218:Adamantane; D037263:Asialoglycoprotein Receptor; D003505:Cyclodextrins; D004247:DNA; D004337:Drug Carriers; D005690:Galactose; D005947:Glucose; D011073:Polyamines; D000071228:Polyelectrolytes; D011092:Polyethylene Glycols