Novel water-soluble polyurethane nanomicelles for cancer chemotherapy: physicochemical characterization and cellular activities.
BACKGROUND
Efficient delivery of anticancer chemotherapies such as paclitaxel (PTX) can improve treatment strategy in a variety of tumors such as breast and ovarian cancers. Accordingly, researches on polymeric nanomicelles continue to find suitable delivery systems. However, due to biocompatibility concerns, a few micellar nanoformulations have exquisitely been translated into clinical uses. Here, we report the synthesis of novel water-soluble nanomicelles using bioactive polyurethane (PU) polymer and efficient delivery of PTX in the human breast cancer MCF-7 cells.


RESULTS
The amphiphilic polyurethane was prepared through formation of urethane bounds between hydroxyl groups in poly (tetramethylene ether) glycol (PTMEG) and dimethylol propionic acid with isocyanate groups in toluene diisocyanate (TDI). The free isocyanate groups were blocked with phenol, while the free carboxyl groups of dimethylol propionic acid were reacted with triethylamine to attain ionic centers in the polymer backbone. These hydrophobic PTMEG blocks displayed self-assembly forming polymeric nanomicelles in water. The PTX loaded PU nanomicelles showed suitable physical stability, negative zeta potential charge (-43) and high loading efficiency (80%) with low level of critical micelle concentration (CMC). In vitro drug release profile showed a faster rate of drug liberation at pH 5.4 as compared to that of pH 7.4, implying involvement of a pH-sensitive mechanism for drug release from the nanomicelles. The kinetic of release exquisitely obeyed the Higuchi model, confirming involvement of diffusion and somewhat erosion at pH 5.4. These nanomicelles significantly inhibited the growth and proliferation of the human breast cancer MCF-7 cells, leading them to apoptosis. The real time RT-PCR analysis confirmed the activation of apoptosis as result of liberation of cytochrome c in the cells treated with the PTX loaded PU nanomicelles. The comet assay analysis showed somewhat DNA fragmentation in the treated cells.


CONCLUSIONS
Based upon these findings, we propose that the bioactive waterborne polyurethane nanomicelles can be used as an effective nanocarrier for delivery of anticancer chemotherapies such as paclitaxel.
Faculty of Bioscience, Tarbiat Modares University, Tehran, Iran.
Ahmad Yari
AY
Khosroushahi
Hossein
H
Naderi-Manesh
Hamid
H
Yeganeh
Jaleh
J
Barar
Yadollah
Y
Omidi
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics; D053453:Caspase 9 / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006018:Glycols / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010316:Particle Size; D011140:Polyurethanes / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D014867:Water
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D006018:Glycols; D008823:Micelles; D011140:Polyurethanes; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014867:Water; C047554:polytetramethylene glycol; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D017239:Paclitaxel