Polyplex micelles from triblock copolymers composed of tandemly aligned segments with biocompatible, endosomal escaping, and DNA-condensing functions for systemic gene delivery to pancreatic tumor tissue.
OBJECTIVE
For systemic gene delivery to pancreatic tumor tissues, we prepared a three-layered polyplex micelle equipped with biocompatibility, efficient endosomal escape, and pDNA condensation functions from three components tandemly aligned; poly(ethylene glycol) (PEG), a poly(aspartamide) derivative with a 1,2-diaminoethane moiety (PAsp(DET)), and poly(L-lysine).


METHODS
The size and in vitro transfection efficacy of the polyplex micelles were determined by dynamic light scattering (DLS) and luciferase assay, respectively. The systemic gene delivery with the polyplex micelles was evaluated from enhanced green fluorescence protein (EGFP) expression in the tumor tissues.


RESULTS
The polyplex micelles were approximately 80 nm in size and had one order of magnitude higher in vitro transfection efficacy than that of a diblock copolymer as a control. With the aid of transforming growth factor (TGF)-beta type I receptor (TbetaR-1) inhibitor, which enhances accumulation of macromolecular drugs in tumor tissues, the polyplex micelle from the triblock copolymer showed significant EGFP expression in the pancreatic tumor (BxPC3) tissues, mainly in the stromal regions including the vascular endothelial cells and fibroblasts.


CONCLUSIONS
The three-layered polyplex micelles were confirmed to be an effective gene delivery system to subcutaneously implanted pancreatic tumor tissues through systemic administration.
Miyata
Kanjiro
K
Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
Oba
Makoto
M
Kano
Mitsunobu R
MR
Fukushima
Shigeto
S
Vachutinsky
Yelena
Y
Han
Muri
M
Koyama
Hiroyuki
H
Miyazono
Kohei
K
Nishiyama
Nobuhiro
N
Kataoka
Kazunori
K
D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage*; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D010190:Pancreatic Neoplasms / Q000628:therapy*; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry; D011107:Polylysine / Q000737:chemistry; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014162:Transfection
D001672:Biocompatible Materials; D008823:Micelles; C539404:PAsp(DET); D010455:Peptides; D011108:Polymers; D018125:Receptors, Transforming Growth Factor beta; D011107:Polylysine; D011092:Polyethylene Glycols; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
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