Coaxial double-walled microspheres for drug and gene delivery applications

[摘要] Polymeric double-walled microspheres were developed by coaxial electrohydrodynamic atomization (CEHDA) and precision particle fabrication (PPF) techniques. Here, we focus on double-walled microspheres consisting of a poly(D,L-lactic-co-glycolic acid) (PLGA) core surrounded by a poly(D,L-lactic acid) (PDLLA) or poly(L-lactic acid) (PLLA) shell layer.The first study involves bridging the experimental work on the fabrication of double-walled microspheres from CEHDA and the simulation work on the generation of compound droplets from the same process. Process conditions and solution parameters were investigated to ensure the formation of double-walled microspheres with a doxorubicin-loaded PLGA core surrounded by a relatively drug-free PDLLA shell layer. Numerical simulation of CEHDA process was performed based on a computational fluid dynamics (CFD) model in Fluent. The simulation results were compared with the experimental work to illustrate the capability of the CFD model to predict the production of consistent double-walled microspheres.The second study involves drug release and degradation behavior of two double-walled microsphere formulations consisting of a doxorubicin-loaded PLGA core surrounded by a PDLLA shell layer. It was postulated that different molecular weights of the shell layer could modulate the erosion of the outer coating and limit the occurrence of water penetration into the inner drug-loaded core on various time scales, and therefore control the drug release from the microspheres. For both microsphere formulations, the drug release profiles were observed to be similar. Interestingly, both microsphere formulations exhibited occurrence of bulk erosion of PDLLA on a similar time scale despite different PDLLA molecular weights forming the shell layer. The shell layer of the double-walled microspheres served as an effective diffusion barrier during the initial lag phase period and controlled the release rate of the hydrophilic drug independent of the molecular weight of the shell layer.The third study involves designing and evaluating double-walled microspheres loaded with chitosan-p53 nanoparticles (chi-p53, gene encoding p53 tumor suppressor protein) and/or doxorubicin in the shell and core phases, respectively, for combined gene therapy and chemotherapy. The microspheres were monodisperse with a mean diameter of 65 to 75 μm and uniform shell thickness of 8 to 17 μm. The encapsulation efficiency of doxorubicin was significantly higher when it was encapsulated alone compared to co-encapsulation with chi-p53. However, the encapsulation efficiency of chi-p53 was not affected by the presence of doxorubicin. As desired, chi-p53 was released first, followed by simultaneous release of chi-p53 and doxorubicin at a near zero-order rate. Next, the therapeutic efficiencies of doxorubicin and/or chi-p53 in microsphere formulations were compared to free drug(s) and evaluated in terms of growth inhibition, and cellular expression of tumor suppressor p53 and apoptotic caspase 3 proteins in human hepatocellular carcinoma HepG2 cells. Overall, the combined doxorubicin and chi-p53 treatment exhibited enhanced cytotoxicity as compared to either doxorubicin or chi-p53 treatments alone. Moreover, the antiproliferative effect was more substantial when cells were treated with microspheres than those treated with free drugs. Overall, double-walled microspheres present a promising dual anticancer delivery system for combined chemotherapy and gene therapy.

[效力级别] Double-Walled Microspheres

[关键词] Drug Delivery;Double-Walled Microspheres;Drug;Gene