Davis Yohanes Arifin

The use of submicron/nanoscale PLGA implants to deliver paclitaxel with enhanced pharmacokinetics and therapeutic efficacy in intracranial glioblastoma in mice

Pharmacokinetics and therapeutic efficacy of submicron/nanoscale, intracranial implants were evaluated for treating malignant glioblastoma in mice. 9.1% (w/w) paclitaxel-loaded polylactide-co-glycolide (PLGA) nanofiber discs (F3) were fabricated and characterized for morphology and size distribution. Along with F3, three other formulations, 9.1% (w/w) paclitaxel-loaded PLGA submicron-fiber discs (F2), 16.7% (w/w) paclitaxel-loaded PLGA microspheres entrapped in hydrogel matrices (H80 and M80) were intracranially implanted in BALB/c mice and the coronal brain sections were analyzed for bio-distribution of paclitaxel on 14, 28 and 42 days post-implantation. BALB/c nude mice with intracranial human glioblastoma (U87 MG-luc2) were used in the therapeutic efficacy study. Animals were randomized to intracranial implantation of F3 and H80 with paclitaxel dose of 10mg/kg, placebo F3, placebo H80, weekly intratumoral injection of Taxol (10mg/kg) or no treatment and the treatment response was analyzed by bioluminescence imaging and histological (H&E, Ki-67) examinations. Enhanced, therapeutic paclitaxel penetration (approximately 1 microm) in the mouse brain up to 5mm from the implant site even after 42 days post-implantation from F3 and H80 was confirmed and deduced to be diffusion/elimination controlled. F3 and H80 demonstrated significant (approximately 30 fold) tumor inhibition and significantly low tumor proliferation index after 41 days of treatment in comparison to sham and placebo controls. The submicron/nanoscale implants are able to demonstrate optimal paclitaxel pharmacokinetics in the brain/tumor with significant tumor inhibition in a glioblastoma xenograft model in mice and hence could be potentially useful to treat highly recurrent GBM.

Core/shell microspheres via coaxial electrohydrodynamic atomization for sequential and parallel release of drugs

Herein, it is demonstrated that coaxial electrohydrodynamic atomization can be used for the fabrication of microspheres with distinct core/shell structure. This allows the encapsulation of two different types of drugs in different compartments in one single step. In Group A, we prepared microspheres in which the core and the shell contain hydrophobic and hydrophilic drugs, respectively. In contrast, in Group B, the opposite is prepared. While the former can be achieved by using amphiphilic polymers in aqueous environment, the latter is difficult to be prepared. The release patterns of the two groups are significantly different. The release of drugs from Group A microspheres is rather sequential, whereas group B microspheres release drugs in a parallel (co-release) manner. Nevertheless, in both groups, we found that the release of drugs can be easily tailored by altering outer/inner flow ratios. These findings present the advantages and possible application of this multi-drug release system in chemotherapy. Moreover, cell culture experiments have been performed to testify the performances of different microspheres in cytotoxicity and cellular apoptosis in vitro.

Chemotherapeutic drug transport to brain tumor.

Implantation of polymeric wafers to deliver a chemotherapeutic drug is the most popular strategy against a brain tumor, but the understanding on local drug transport to influence the treatment efficacy is often overlooked. In this work, we employ a computational fluid dynamics simulation to study the suitability of four chemotherapeutic agents from a transport perspective, which specifically are carmustine, paclitaxel, 5-fluorouracil (5-FU), and methotrexate (MTX). The study is based on the diffusion/reaction/convection model, in which Darcys law is used to account the convective contribution of the interstitial fluid. A realistic three-dimensional (3D) tissue geometry is extracted from magnetic resonance images (MRI) of a brain tumor. Our analysis explains how the distribution of the drug in the brain tumor is sensitively coupled to its physico-chemical properties. For the postulated conditions, only paclitaxel exhibits minimal degradation within the cavity: its effective cavity concentration is at least two times higher than those of others. It also exhibits the best penetration of the remnant tumor, so that the tumor is exposed to higher effective concentration up to two orders of magnitude as compared to others. It is also found that tumor receives uneven distribution of drug concentration, in which, even paclitaxel fails to provide adequate penetration on that part of the cavity surface nearest to the ventricles. In addition, we consider antiangiogenic treatment, which has been postulated to be a way to avoid drug loss from the treatment region by convection. It is shown that convection is of only marginal importance and that renormalization has little effect.

Mathematical Modelling of Convection Enhanced Delivery of Carmustine and Paclitaxel for Brain Tumour Therapy

ABSTRACTPurposeConvection enhanced delivery (CED) is a promising method of anticancer treatment to bypass the blood–brain barrier. This paper is aimed to study drug transport under different CED operating conditions.MethodsThe convection enhanced delivery of chemotherapeutics to an intact and a remnant brain tumour after resection is investigated by means of mathematical modelling of the key physical and physiological processes of drug transport. Realistic models of brain tumour and its holding tissue are reconstructed from magnetic resonance images. Mathematical modelling is performed for the delivery of carmustine and paclitaxel with different infusion rates, solution concentrations and locations of infusion site.ResultsModelling predications show that drug penetration can be improved by raising the infusion rate and the infusion solution concentration. The delivery of carmustine with CED is highly localised. High drug concentration only can be achieved around the infusion site. The transport of paclitaxel is more sensitive to CED-enhanced interstitial fluid as compared to carmustine, with deeper penetration into tumour interior. Infusing paclitaxel in the upstream of interstitial fluid flow leads to high spatial averaged concentration and relatively uniform distribution.ConclusionResults obtained in this study can be used to guide the design and optimisation of CED treatment regimens.

Novel ultrafiltration membranes from low-fouling copolymers for RO pretreatment applications

AbstractFor a consistent and reliable ultrafiltration (UF) membrane operation, the membrane flux level has always been determined conservatively so that fouling rate is controllable, and therefore, chemical cleaning requirements are minimized. A better solution is to prevent the fouling to happen in the first place by modifying the surface properties of the membrane materials. This paper presents novel approaches to improve the fouling-propensity performance of existing UF membranes based on polyethersulfone. More hydrophilic membranes and anti-adhesive membranes were developed by using various novel copolymers as base membrane materials or as an additive in the spinning process. Incorporating these copolymers, improved Multibore® fibers were produced and validated in multiple pilot trials for various applications, namely surface and wastewater purification and seawater reverse osmosis pretreatment for desalination. The paper demonstrates that, for each application, a reduced fouling propensity performanc...