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: Chengyun Yan, Jiwei Gu, Daping Hou, Hongying Jing, Jing Wang, Yuzhi Guo, Hidemasa Katsumi, Toshiyasu Sakane, Akira Yamamoto
• Journal: Drug development and industrial pharmacy (Drug Dev Ind Pharm) Vol. 41 Issue 4 Pg. 617-22 (Apr 2015) ISSN: 1520-5762 [Electronic] England
• PMID: 24564798 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cell-Penetrating Peptides
• Dendrimers
• Fluorescent Dyes
• PAMAM Starburst
• Peptide Fragments
• tat Gene Products, Human Immunodeficiency Virus

Topics

• Absorption, Physiological
• Animals
• Antineoplastic Agents (administration & dosage, metabolism, pharmacokinetics, pharmacology)
• Biological Availability
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cell-Penetrating Peptides (adverse effects, chemistry)
• Chemical Phenomena
• Dendrimers (adverse effects, chemistry)
• Drug Delivery Systems
• Fluorescent Dyes (chemistry)
• Injections, Intravenous
• Male
• Mice, Inbred BALB C
• Nanostructures (adverse effects, chemistry)
• Particle Size
• Peptide Fragments (adverse effects, chemistry)
• Sarcoma 180 (blood, drug therapy, metabolism)
• Tissue Distribution
• tat Gene Products, Human Immunodeficiency Virus (adverse effects, chemistry)