Enhancement in anti-proliferative effects of paclitaxel in aortic smooth muscle cells upon co-administration with ceramide using biodegradable polymeric nanoparticles.
OBJECTIVE
Using a combination of paclitaxel (PTX), and the apoptotic signaling molecule, C6-ceramide (CER), the enhancement in anti-proliferative effect of human aortic smooth muscle cells (SMC) was examined by administering in polymeric nanoparticles.


METHODS
PTX- and CER-loaded poly(ethylene oxide)-modified poly(epsilon caprolactone) (PEO-PCL) nanoparticles were formulated by solvent displacement and characterized. The uptake and intracellular localization of the nanoparticle in SMC was examined using Z-stack fluorescent confocal microscopy. Anti-proliferative and pro-apoptotic effects of SMC were determined upon administration of PTX and CER, either as single agent or in combination, in aqueous solution and in PEO-PCL nanoparticle formulations.


RESULTS
High encapsulation efficiencies (i.e., >95%) of PTX and CER at 10% (w/w) loading were attained in the PEO-PCL nanoparticles of around 270 nm in diameter. Fluorescence confocal analysis showed that nanoparticle delivery did facilitate cellular uptake and internalization. Additionally, combination of PTX and CER delivery in PEO-PCL nanoparticles was significantly more effective in decreasing the proliferation of SMC, probably by enhancing the apoptotic response.


CONCLUSIONS
The results of this study show that combination of PTX and CER when administered in PEO-PCL nanoparticles can significantly augment the anti-proliferative effect in SMC. This strategy may potentially be useful in the treatment of coronary restenosis.
Deshpande
Dipti
D
Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 110 Mugar Life Sciences Building, Boston, MA 02115, USA.
Devalapally
Harikrishna
H
Amiji
Mansoor
M
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D002208:Caproates; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000008:administration & dosage / Q000494:pharmacology*; D004563:Electrochemistry; D005079:Excipients; D006801:Humans; D066298:In Vitro Techniques; D007783:Lactones; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects; D053758:Nanoparticles; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010316:Particle Size; D011092:Polyethylene Glycols; D011108:Polymers
D000972:Antineoplastic Agents, Phytogenic; D002208:Caproates; D002518:Ceramides; D005079:Excipients; D007783:Lactones; D011108:Polymers; D011092:Polyethylene Glycols; C121056:caprolactone; D017239:Paclitaxel