Temozolomide/PLGA microparticles and antitumor activity against Glioma C6 cancer cells in vitro
Introduction
A major factor limiting intracranial therapeutic levels of systemically administered chemotherapeutic agents is the physiologic barriers of the brain (Gallia et al., 2005). The presence of the blood–brain barrier (BBB) restricts permeability of certain drug molecules within the brain and prevents diffusion of these agents into the brain tumor (Kornblith and Walker, 1988). Temozolomide(3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide, TM) is one of the most effective antineoplastic agents for malignant glial tumor, partially due to its ability to cross the BBB (Reni and Mason, 2004). However, TM must be administered in high systemic doses to achieve therapeutic brain levels due to its short half-life of about 1.8 h in plasma (Baker et al., 1999). Furthermore, prolonged systemic administration is associated with some side effects such as nausea, vomiting, fatigue and headache.
Recent reports have shown that polymeric devices implanted into the brain can release locally neuroactive substances for extended periods of time (Menei et al., 1996, Menei et al., 1997). In this manner, the brain implantation of polymeric devices has been achieved in men for the treatment of malignant cerebral tumors (Brem et al., 1995). Poly(d,l-lactide-co-glycolide) (PLGA) is a well-known biodegradable polymer, which has long history of safe use in pharmaceutical and medical applications (Hutchison and Furr, 1990). Furthermore, the study have demonstrated the biocompatibility and biodegradability of blank poly(d,l-lactide-co-glycolide) (PLGA) microspheres implanted in the brain tissue (Emerich et al., 1999, Menei et al., 1993).
The present research report describes the in vitro release of TM from PLGA-based microparticles fabricated using the emulsifying-solvent evaporation method. The influences of several preparation parameters, such as initial drug loading, polymer concentration, and stirring rate were investigated. The physical characteristics of TM-loaded PLGA microparticles were studied using scanning electron microscopy (SEM), powder X-ray diffraction (XRD), and differential scanning calorimetry (DSC). The in vitro antitumor activity of TM released from the microparticles was assessed against Glioma C6 cancer cells in comparison with that of TM powder.
Section snippets
Materials
PLGA (75:25 mole ratio of lactide to glycolide) having molecular weight of 20,000 g/mol were purchased from Shandong Medical Equipment Research Institute (China). TM was supplied by Friend Pharmaceutical Co. Ltd. (Beijing, China). Polyvinyl alcohol (PVA) (88% hydrolyzed, Beijing, China) was used as the emulsifying agent. The methylene chloride (CH2Cl2) was used without further purification (Shanghai, China). All other chemicals were reagent grade. Deionized water was prepared by a Milli-Q
Microparticle preparation
TM-loaded PLGA microparticles were prepared using emulsifying-solvent evaporation method. In the process, aqueous phase containing 2% (w/v) PVA was saturated with TM beforehand to improve the encapsulation efficiency of TM. It was found that when aqueous phase was not saturated with TM, TM in the organic phase was almost diffused into the aqueous phase and the encapsulation efficiency was only about 30%. The encapsulation efficiency was significantly improved when aqueous phase was saturated
Conclusions
TM-loaded PLGA microparticles were prepared by emulsifying-solvent evaporation method in reproducible manner. Several preparation parameters, such as initial drug loading, polymer concentration, and stirring rate played a predominant role in the preparation. Microparticles had spherical shape, i.e. microspheres. From SEM, X-ray and DSC results, it appeared that TM trapped in the microparticles existed in an amorphous or disordered-crystalline status in the polymer matrix. The release profiles
Acknowledgements
The authors are very grateful to Professor Zhi-Jian Yue for many helpful discussions and technical support. They also express their appreciation to Professor Ding-Jian for providing the C6 glioma cell line samples.
References (19)
- et al.
The preparation and characterization of microspheres containing the anti-inflammatory agents indomethacin, ibuprofen and ketoprofen
J. Contr. Rel.
(1989) - et al.
Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas
Lancet
(1995) - et al.
The preparation and characterization of poly(lactide-co-glycolide) microparticles 1: oil-in-water emulsion solvent evaporation
Int. J. Pharm.
(1991) - et al.
Biodegradation and brain tissue reaction to poly(d,l-lactide-co-glycolide) microspheres
Biomaterials.
(1993) - et al.
Salvage chemotherapy with temozolomide in primary CNS lymphomas: preliminary results of a phase II trial
Eur. J. Cancer
(2004) - et al.
BCNU-loaded poly(d,l-lactide-co-glycolide) wafer and antitumor activity against XF-498 human CNS tumor cells in vitro
Int. J. Pharm.
(2003) - et al.
Preparation of biodegradable poly(lactic-co-glycolic) acid microspheres and their in vitro release of timolol maleate
Int. J. Pharm.
(1993) - et al.
Absorption, metabolism and excretion of 14C-temozolomide following oral administration to patients with advanced cancer
Clin. Cancer. Res.
(1999) Thermoanalysis of microspheres
Thermochim. Acta
(1995)
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