title: Improved tumor targetability of Tat-conjugated PAMAM dendrimers as a novel nanosized anti-tumor drug carrier.
abstract: The generation 4-poly-amidoamine-dendrimers (PAMAM G4 dendrimer, P) was conjugated to Tat peptide (Tat, T), a cell-penetrating peptide, in search of an efficient anti-tumor drug delivery vehicle for cancer therapy. In this study, we synthesized BODIPY-labeled Tat-Conjugated PAMAM dendrimers (BPTs) as a novel nanosized anticancer drug carriers and systemically investigated their biodistribution and the tumor accumulation in Sarcoma 180-bearing mice. In addition, the uptake and the cytotoxicity to S180 cells of BPTs thereof were evaluated. The unmodified dendrimer (BP) showed a soon clearance from the blood stream and nonspecific accumulation in tumor. In contrast, the Tat-modified dendrimer, BPT(64) with appropriate particle size showed a better retention in blood and could be accumulated effectively in tumor tissue via the enhanced permeability and retention (EPR) effect. Moreover, BPTs with a high Tat modification rate was accumulated more effectively in tumor tissue. In vitro experiments, these BPTs displayed low cytotoxicity on S180 cells and high uptake to S180 cells. These findings indicate that the nanoparticulate system on the basis of Tat-conjugated PAMAM dendrimers is safer and effective in the concentration range (below 20 μg/ml) to be used as a carrier of anti-tumor drugs for tumor targeting by intravenous administration.
authors.affiliation: College of Pharmacy, Guilin Medical University , Guilin, Guangxi , People's Republic of China .
authors.forename: Chengyun
authors.initials: C
authors.lastname: Yan
authors.forename: Jiwei
authors.initials: J
authors.lastname: Gu
authors.forename: Daping
authors.initials: D
authors.lastname: Hou
authors.forename: Hongying
authors.initials: H
authors.lastname: Jing
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Guo
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sakane
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D065567:Absorption, Physiological; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000009:adverse effects / Q000737:chemistry*; D055598:Chemical Phenomena; D050091:Dendrimers / Q000009:adverse effects / Q000737:chemistry*; D016503:Drug Delivery Systems; D005456:Fluorescent Dyes / Q000737:chemistry; D007275:Injections, Intravenous; D008297:Male; D008807:Mice, Inbred BALB C; D049329:Nanostructures / Q000009:adverse effects / Q000737:chemistry*; D010316:Particle Size; D010446:Peptide Fragments / Q000009:adverse effects / Q000737:chemistry; D012510:Sarcoma 180 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D014018:Tissue Distribution; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000009:adverse effects / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D050091:Dendrimers; D005456:Fluorescent Dyes; C104700:PAMAM Starburst; D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: Biodistribution; PAMAM dendrimer; Tat peptide; nanoparticles; tumor targeting