Hydrogel Matrix Entrapping PLGA-Paclitaxel Microspheres: Drug Delivery with Near Zero-Order Release and Implantability Advantages for Malignant Brain Tumour Chemotherapy
To develop paclitaxel-delivering PLGA microspheres entrapped in a gel matrix with sustained drug release properties and implantability advantages for local glioma chemotherapy.
Paclitaxel-loaded PLGA microspheres were fabricated using electrohydrodynamic atomization and entrapped by electrospray and gelation. The physicochemical characterizations were performed using scanning electron microscopy and differential scanning calorimetry. The influence of various parameters on the disintegration time was investigated. In vitro release of paclitaxel was quantified using high performance liquid chromatography. Cytotoxicity of the formulations was assessed by the quantification of IC50 and caspase-3 activity against C6 glioma cells in vitro. The formulations were tested against a subcutaneous C6 glioma tumour in mice.
Highly monodisperse gel beads containing a uniform microsphere distribution were obtained. Gelation using Ca2+ ions ensured entrapment of microspheres with high loading efficiency. With an increase in the gelation time, gelling bath concentration and decrease in microsphere loading, it was more difficult to disintegrate the beads and release the microspheres. The formulations demonstrated sustained drug release for more than 60 days at a near-constant rate and a low initial burst. Cell culture studies proved the cytotoxicity against C6 glioma and improved performance in comparison to Taxol®. The formulations could reduce subcutaneous tumour volume to a greater extent compared to Taxol® and the control.
Paclitaxel-loaded PLGA microspheres entrapped in an alginate gel matrix could be potential local chemotherapy implants to treat malignant glioma with critical advantages of implantability and sustained drug release with low initial burst.
KEY WORDSchemotherapy electrohydrodynamic atomization glioma hydrogel microspheres PLGA-paclitaxel
The authors acknowledge the Biomedical Research Council (BMRC), A*STAR and the National University of Singapore for providing support under the grant numbers BMRC/07/1/21/19/508 and R279-000-257-731, respectively. The authors thank Alvin Yang, Ying Ying Chan, Jinghan Huang and Hui Yian Tan for technical assistance in the preparation of this manuscript and Dr. Yilong Fu for his assistance in the animal experiments.
- 3.Limentani SA, Asher A, Heafner M, Kim JW, Fraser R. A phase I trial of surgery, Gliadel wafer implantation, and immediate postoperative carboplatin in combination with radiation therapy for primary anaplastic astrocytoma or glioblastoma multiforme. J Neuro-Oncol. 2005;72:241–244.CrossRefGoogle Scholar
- 8.Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-Brain Tumor Treatment Group. Lancet. 1995;345:1008–1012.PubMedCrossRefGoogle Scholar
- 13.Lesniak MS, Upadhyay U, Goodwin R, Tyler B, Brem H. Local delivery of doxorubicin for the treatment of malignant brain tumors in rats. Anticancer Res. 2005;28(6B):3825–3831.Google Scholar
- 18.Chang SM, Kuhn JG, Robins HI, Schol SC Jr, Spence AM, Berger MS, et al. A phase II study of paclitaxel in patients with recurrent malignant glioma using different doses depending upon the concomitant use of anticonvulsants: a North American Brain Tumor Consortium report. Cancer. 2001;91:417–422.PubMedCrossRefGoogle Scholar
- 34.Soares JP, Santos JE, Chierice GO, Cavalheiro ETG. Thermal behavior of alginic acid and its sodium salt. Ecletica Quimica. 2004;29(2):53–56.Google Scholar
- 37.Donth EJ. Relaxation and thermodynamics in polymers. Glass transition. Berlin: Akademie Verlag; 1992.Google Scholar