Novel self-associating poly(ethylene oxide)- b-poly(ɛ-caprolactone) based drug conjugates and nano-containers for paclitaxel delivery

• Published in: International journal of pharmaceutics 2010-04, Vol.389 (1), p.213-222
• Main Authors: Shahin, Mostafa, Lavasanifar, Afsaneh
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; Cell Line, Tumor; Chemotherapy; Drug Carriers - chemical synthesis; Drug Delivery Systems; General pharmacology; Humans; Hydrogen-Ion Concentration; Inhibitory Concentration 50; Lactones - chemistry; Medical sciences; Micelles; Nanoparticles; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - pharmacology; Particle Size; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Poly(ethylene oxide)- block-poly(ɛ-caprolactone); Polyethylene Glycols - chemistry; Polymeric micelles; Polymer–drug conjugate; Solubility; Time Factors
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2010.01.015

Poly(ethylene oxide)- block-poly(ɛ-caprolactone) (PEO- b-PCL) copolymers bearing paclitaxel (PTX) side groups on PCL (PEO- b-P(CL-PTX) were synthesized and assembled to particles of 123 nm average diameter. At 20% (w/w) PTX to polymer conjugation, PEO- b-P(CL-PTX) demonstrated only 5.0 and 6.7% PTX release after 72 h incubation at pH 7.4 and 5.0, respectively, but revealed signs of chain cleavage at pH 5.0. The cytotoxicity of PEO- b-P(CL-PTX) against MDA-MB-435 cancer cells increased as incubation time was raised from 72 to 96 h (IC 50 of 680 and 475 ng/mL, respectively), but it was still significantly lower than the cytotoxicity of free PTX (IC 50 of 3.5 ng/mL at 72 h). In further studies, micelles of PEO- b-PCL and those bearing benzyl or PTX on PCL were used for physical encapsulation of PTX, where maximum level of loading was achieved by PEO- b-P(CL-PTX) (2.22%, w/w). The release of PTX from this carrier was rapid; however. The in vitro cytotoxicity of physically loaded PTX was independent of carrier and similar to that of free PTX. This was attributed to the low concentration of polymers which fell below their critical micellar concentration in the cytotoxicity study. The results point to the potential of chemically tailored PEO- b-PCL for optimum PTX solubilization and delivery.