Multi-drug-loaded Microcapsules with Controlled Release for Management of Parkinson's Disease

Parkinson's disease (PD) is a progressive disease of the nervous system, and is currently managed through commercial tablets that do not sufficient enable controlled, sustained release capabilities. It is hypothesized that a drug delivery system that provides controlled and sustained release of PD drugs would afford better management of PD. Hollow microcapsules composed of poly-L-lactide (PLLA) and poly (caprolactone) (PCL) were prepared through a modified double-emulsion technique. They were loaded with three PD drugs, i.e. levodopa (LD), carbidopa (CD) and entacapone (ENT), at a ratio of 4:1:8, similar to commercial PD tablets. LD and CD were localized in both the hollow cavity and PLLA/PCL shell, while ENT was localized in the PLLA/PCL shell. Release kinetics of hydrophobic ENT was observed to be relatively slow as compared to the other hydrophilic drugs. It was further hypothesized that encapsulating ENT into PCL as a surface coating onto these microcapsules can aid in accelerating its release. Now, these spray-coated hollow microcapsules exhibited similar release kinetics, according to Higuchi’s rate, for all three drugs. The results suggest that multiple drug encapsulation of LD, CD and ENT in gastric floating microcapsules could be further developed for in vivo evaluation for the management of PD.ASTAR (Agency for Sci., Tech. and Research, S’pore)NMRC (Natl Medical Research Council, S’pore)MOH (Min. of Health, S’pore)Accepted versio

Poly(ethylene oxide)- block

There has been an increasing interest to develop new types of stimuli-responsive drug delivery vehicles with high drug loading and controlled release properties for chemotherapeutics. An acid-labile, polyphosphoester-based degradable, polymeric paclitaxel (PTX) conjugate containing ultra-high levels of PTX loading has been improved significantly, in this second generation development, which involves connection of each PTX molecule to the polymer backbone via a pH-sensitive β-thiopropionate linkage. The results for this system indicate that it has great potential as an effective anti-cancer agent. Poly(ethylene oxide)-block-polyphosphoester-graft-PTX drug conjugate (PEO-b-PPE-g-PTX G2) was synthesized by organocatalyst-promoted ring-opening polymerization of 2-(but-3-en-1-yloxy)-1,3,2-dioxaphospholane-2-oxide from a PEO macroinitiator, followed by thermo-promoted thiolene click conjugation of a thiol-functionalized PTX prodrug to the pendant alkene groups of the block copolymer. The PEO-b-PPE-g-PTX G2 formed well-defined nanoparticles in aqueous solution, by direct dissolution into water, with a number-averaged hydrodynamic diameter of 114 ± 31 nm. The conjugate had PTX loading capacity as high as 53 wt%, and a maximum PTX concentration of 0.68 mg/mL in water (vs. 1.7 μg/mL for free PTX). Although the PTX concentration is ca. 10× less than for our first generation material, its accelerated release allowed for similar free PTX concentrations vs. time. The PEO-b-PPE-g-PTX G2 exhibited accelerated drug release under acidic conditions (~50 wt% PTX released in 8 d) compared to neutral conditions (~20 wt% PTX released in 8 d) and compared to the first generation analog that contained ester linkages between PTX and the polymer backbone (<5 wt% PTX released in 4 d), due to their acid-sensitive hydrolytically-labile β-thiopropionate linkages between PTX molecules and the polymer backbone. The positive cell-killing activity of PEO-b-PPE-g-PTX G2 against two cancer cell lines was demonstrated, and the presence of pendant reactive functionality provides a powerful platform for future work to involve conjugation of multiple numbers and/or types of targeting ligands, other drugs and imaging agents to achieve chemotherapy and bioimaging. Compared to our previously reported polyphosphoester-based PTX drug conjugates, PEO-b-PPE-g-PTX G1 without the β-thiopropionate linker, the PEO-b-PPE-g-PTX G2 showed pH-triggered drug release property and 5-to-8-fold enhanced in vitro cytotoxcity against two cancer cell lines