Abstract
To optimize the anti-tumor efficacy of combination therapy with paclitaxel (PTX) and imatinib (IMN), we used coaxial electrospray to prepare sequential-release core–shell microparticles composed of a PTX-loaded sodium hyaluronate outer layer and an IMN-loaded PLGA core. The morphology, size distribution, drug loading, differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, PLGA degradation, cellular growth inhibition, in vivo vaginal retention, anti-tumor efficacy, and local irritation in a murine orthotopic cervicovaginal tumor model after vaginal administration were characterized. The results show that such core–shell microparticles were of spherical appearance, with an average size of 14.65 μm and a significant drug-loading ratio (2.36% for PTX, 19.5% for IMN, w/w), which might benefit cytotoxicity against cervical-cancer-related TC-1 cells. The DSC curves indicate changes in the phase state of PTX and IMN after encapsulation in microparticles. The FTIR spectra show that drug and excipients are compatible with each other. The release profiles show sequential characteristics in that PTX was almost completely released in 1 h and IMN was continuously released for 7 days. These core–shell microparticles showed synergistic inhibition in the growth of TC-1 cells. Such microparticles exhibited prolonged intravaginal residence, a >90% tumor inhibitory rate, and minimal mucosal irritation after intravaginal administration. All results suggest that such microparticles potentially provide a non-invasive local chemotherapeutic delivery system for the treatment of cervical cancer by the sequential release of PTX and IMN.
Highlights
By means of coaxial electrospray, drugs can be conveniently loaded in different areas microparticles to achieve precise control of the drug release [43,44,45]
The mean size of the PHIPMPs shown by DLS was about saline solution after 5 min
The PHIPMPs showed the strongest synergy effect, as the combined index (CI) was was 0.09, indicating that the combina0.09, indicating that the combination tion of PTX and IMN in the form of a core–shell microparticle can exert a better synergistic of PTX and IMN in the form of a core–shell microparticle can exert a better synergistic effect
Summary
Many micron/nano preparations have been designed for the co-administration of different anti-tumor drugs [5,6,7]. To improve antitumor effects and reduce side effects, sequential-release core–shell microparticles were designed by coaxial electrospray (Figure 1), fabricated with a PTX-loaded hyaluronate (HA) outer layer and an IMN PLGA core. This core–shell microparticle was expected to first release the PTX quickly and, subsequently, release the IMN slowly, which acted upon the highly expressed PDGF induced by the treatment with. To the best of our knowledge, this is the first report on micron preparations fabricated by electrospray for sequential-release anti-tumor drugs.
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