The therapeutic efficiency of FP-PEA/TAM67 gene complexes via folate receptor-mediated endocytosis in a xenograft mice model.
To circumvent carrier related obstacles, we developed a biodegradable, folate conjugated poly (ester amine) (FP-PEA) that mediates high level folate receptor (FR) mediated endocytosis in vitro as well as in vivo. We report the efficacy of a therapeutic strategy that combines the potency of FP-PEA based on polycaprolactone (PCL) and low molecular weight polyethylenimine (LMW-PEI) with the tumor targeting potential of receptor mediated endocytosis. When tested on cells in culture, FP-PEA was found to retain high affinity for FR-positive cells compared with PEA without folate moiety (P-PEA). The FR specific activity of FP-PEA was drastically decreased in the presence of an excess free folic acid and very less significant transfection was detected against FR-negative cells. FP-PEA showed marked anti-tumor activity against FR-positive human KB tumors in nude mice with no evidence of toxicity during and after therapy using TAM67 gene. Furthermore, the therapeutic effect occurred in the apparent absence of weight loss or noticeable tumor apoptosis. In contrast, no significant anti-tumor activity was observed in P-PEA treated mice which were co dosed with an excess of FR, thus demonstrating the target specific gene delivery. Furthermore, anti-tumor activity with PEA without folic acid moiety (P-PEA) proved not to be effective against xenograft mice model with KB cells when administered at the same dose to that of FP-PEA. Taken together, these results indicate that FP-PEA is highly effective gene carrier capable of producing therapeutic benefit in xenograft mice model without any sign of toxicity.
Arote
Rohidas B
RB
Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea.
Hwang
Soon-Kyung
SK
Lim
Hwang-Tae
HT
Kim
Tae-Hee
TH
Jere
Dhananjay
D
Jiang
Hu-Lin
HL
Kim
You-Kyoung
YK
Cho
Myung-Haing
MH
Cho
Chong-Su
CS
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism*; D018014:Gene Transfer Techniques; D006801:Humans; D008297:Male; D008422:Materials Testing; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics*; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism*; D011091:Polyesters / Q000737:chemistry / Q000378:metabolism*; D011094:Polyethyleneimine / Q000737:chemistry / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D002352:Carrier Proteins; D004337:Drug Carriers; D058973:Folate Receptors, GPI-Anchored; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D011073:Polyamines; D011091:Polyesters; D016755:Proto-Oncogene Proteins c-jun; D011956:Receptors, Cell Surface; C439528:TAM67 peptide; C516446:poly(caprolactone-block-ethyleneimine); D019716:Tissue Inhibitor of Metalloproteinase-2; C016240:polycaprolactone; D011094:Polyethyleneimine; D005492:Folic Acid; D020782:Matrix Metalloproteinases