Abstract |
To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-α- tocopherol polyethylene glycol succinate ( TPGS) based PTX prodrug ( TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of ∼140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/ necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration-time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors.
|
Authors | Yuling Bao, Yuanyuan Guo, Xiangting Zhuang, Dan Li, Bolin Cheng, Songwei Tan, Zhiping Zhang |
Journal | Molecular pharmaceutics
(Mol Pharm)
Vol. 11
Issue 9
Pg. 3196-209
(Sep 02 2014)
ISSN: 1543-8392 [Electronic] United States |
PMID | 25102234
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents
- Drug Carriers
- Micelles
- Prodrugs
- Vitamin E
- Polyethylene Glycols
- tocophersolan
- Paclitaxel
|
Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(metabolism)
- Animals
- Antineoplastic Agents
(chemistry, pharmacology)
- Apoptosis
(drug effects)
- Cell Line, Tumor
- Chemistry, Pharmaceutical
(methods)
- Drug Carriers
(chemistry)
- Drug Resistance, Multiple
(drug effects)
- Drug Resistance, Neoplasm
(drug effects)
- Female
- G2 Phase Cell Cycle Checkpoints
(drug effects)
- Half-Life
- Humans
- Mice
- Micelles
- Ovarian Neoplasms
(drug therapy, metabolism)
- Oxidation-Reduction
- Paclitaxel
(chemistry, pharmacology)
- Polyethylene Glycols
(chemistry)
- Prodrugs
(chemistry, pharmacology)
- Rats
- Rats, Sprague-Dawley
- Vitamin E
(analogs & derivatives, chemistry)
|