Hydrogel matrix entrapping PLGA-paclitaxel microspheres: drug delivery with near zero-order release and implantability advantages for malignant brain tumour chemotherapy.

PURPOSE: To develop paclitaxel-delivering PLGA microspheres entrapped in a gel matrix with sustained drug release properties and implantability advantages for local glioma chemotherapy. METHODS: 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 IC(50) and caspase-3 activity against C6 glioma cells in vitro. The formulations were tested against a subcutaneous C6 glioma tumour in mice. RESULTS: Highly monodisperse gel beads containing a uniform microsphere distribution were obtained. Gelation using Ca(2+) 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. CONCLUSIONS: 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.

Development of Nanoparticles for Drug Delivery to Brain Tumor: The Effect of Surface Materials on Penetration Into Brain Tissue.

Surface-modified poly(d,l-lactic-co-glycolic acid) PLGA nanoparticles (NPs) were fabricated via nanoprecipitation for obtaining therapeutic concentration of paclitaxel (PTX) in brain tumor. The cellular uptake and cytotoxicity of NPs were evaluated on C6 glioma cells in vitro, and BALB/c mice were used to study the brain penetration and biodistribution upon intravenous administration. Results showed that by finely tuning nanoprecipitation parameters, PLGA NPs coated with surfactants with a size around 150 nm could provide a sustained release of PTX for >2 weeks. Surface coatings could increase cellular uptake efficiency when compared with noncoated NPs, and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) showed the most significant enhancement. The in vivo evaluation of TPGS-PLGA NPs showed amplified accumulation (>800% after 96 h) of PTX in the brain tissue when compared with bare NPs and Taxol®. Therefore, PLGA-NPs with PLGA-TPGS coating demonstrate a promising approach to efficiently transport PTX across blood-brain barrier in a safer manner, with the advantages of easy formulation, lower production cost, and higher encapsulation efficiency.

Controlling injectability and in vivo stability of thermogelling copolymers for delivery of yttrium-90 through intra-tumoral injection for potential brachytherapy.

Intra-tumoral injection of radiopharmaceuticals such as yttrium-90 (90Y) or phosphorus-32 (32P) is an important route for brachytherapy in unresectable solid tumors such as locally advanced hepatocellular carcinoma. However, the injected radiopharmaceuticals can potentially leak out from the tumor site due to high intra-tumoral pressure. In this study, we demonstrated the use of thermogelling copolymers that can be injected into tumor and subsequently solidify as hydrogels within the tumor that can potentially overcome the above problem. To this end, a series of thermogelling polyurethane copolymers with varying compositions were designed and synthesized from Pluronic F127, poly(3-hydroxylbutyrate), and poly(propylene glycol), which were characterized in terms of their molecular structures, compositions, phase diagrams, rheological properties, and injectability and body temperature stability in vitro and in vivo. The analyses of our data elucidated the injectability of the copolymer solutions at low temperatures, and the stability of the hydrogels at the body temperature. This provided the basis on which we could identify one copolymer with balanced composition as the most suitable candidate for intra-tumoral injection and for prevention of the leakage. Finally, the injectability and in vivo stability of the copolymer solution and hydrogel loaded with 90Y were further demonstrated in a mouse tumor model, and the in vivo biodistribution of 90Y showed that the radionuclide could be retained at the tumor site, indicating that the 90Y-loaded copolymer has a great potential for tumor radio-brachytherapy.

Development of a gene/drug dual delivery system for brain tumor therapy: potent inhibition via RNA interference and synergistic effects.

Malignant brain tumors are characterized by three major physiological processes: proliferation, angiogenesis, and invasion. Traditional cytotoxic chemotherapies (e.g. Paclitaxel) control the tumor by blocking growth and proliferation mechanisms, but leave angiogenesis and invasion unchecked. We identified Matrix metalloproteinase-2 (MMP-2), an essential proteinase regulating brain tumor invasion and angiogenesis, as one of the therapeutic target. A designer RNAi plasmid was developed, and complexed with the gene carrier polyethylenimine (PEI), in an effort to specifically suppress MMP-2 expression in tumor cells. The gene and a cytotoxic drug Paclitaxel were then dual-encapsulated in PLGA based submicron implants to achieve a sustained release of both agents. Potent inhibition effects on MMP-2 mRNA and protein expression, in vitro cell angiogenesis and invasion were demonstrated both on the PEI/DNA nanoparticles alone, and on the PEI/DNA nanoparticles embedded in microfibers. Most importantly, through in vivo test on intracranial xenograft tumor model in BALB/c nude mice, it was proved that the gene/drug dual delivery microfibers are able to impose significant tumor regression compared with single drug delivery microfibers and commercial drug treatment, showing evidence for synergistic therapeutic efficacy.