Introduction: In situ-forming gels, with a phase transition temperature near to body temperature, appear particularly interesting as platforms for drug delivery applications. Being liquid at room temperature, indeed, they can be simply injected into the body but, once in place, they gelify thus allowing a time-controlled release of the active. In this context, due to their ability to undergo thermal gelation, thermosensitive amphiphilic block copolymers, namely polyethylene oxide– polypropylene oxide copolymers (pluronic PPO-PEO-PPO), have been widely used in biomedical field, particularly as a dispersing medium for drugs. However, to encapsulate hydrophobic drugs and/or to obtain a controlled release the use of a protective matrix for the drug is more convenient. To this aim Mesoporous Silica Nanoparticles (MSNs) with their highly-ordered structures having uniform but size-adjustable pores have shown high efficiency either for loading or controlled drug release[1]. The main target of this work is to design composite injectable in situ forming gels based on blends of PPO-PEO-PPO copolymers reinforced by a natural polysaccharide, hyaluronic acid (HA), and mesoporous silica nanoparticles (MSNs) as platforms for the controlled release of chemotherapeutics. Thanks to their gel nature these platforms could be potentially used to fill the cavity after tumour resection. Drug loading efficiency onto MSNs was optimised and in vitro release kinetics of a widely employed chemotherapeutic (Irinotecan) was also studied.
Experimental Methods: The platforms were prepared by mixing Pluronic F127 and F68 with different amounts of HA at different molecular weight (low MW: 150KDa and high Mw: 1200KDa). The composition of the platforms was optimised to obtain a gelification temperature (Tgel) around body temperature. The platforms with and without MSNs were characterised for the rheological properties and assessed for its capability of suspending efficiently MSNs.
The MSNs were synthesized according to Yu et al.[2], then characterized in terms of morphology, size and porous dimensions, through N2 adsorption/desorption isotherms SAXS and TEM techniques[3].
The drug entrapment experiments were performed by suspending the MSNs particles in a DMSO solution of Irinotecan. In vitro release experiments were performed placing the platforms containing MSNs in dialysis membrane. Phosphate buffer solutions (PBS) was used as release medium at 37 °C and the drug was quantified by spectrophotometric assay.
Results and Discussion: Separate Pluronic F127 and F68 solutions do not show a gelling temperature close to the body one in the concentration range from 10 to 30% w/w (gelling temperatures higher than 40°C or lower than 25°C). By formulating Pluronic F127/F68 blends at specific concentrations, it was possible to obtain a medium with a Tgel close to the body temperature. The addition of low molecular weight HA at different concentrations had only a slight influence on Tgel, but very interestingly, improved significantly the viscoelastic properties of the final gel as determined through rheological measurements. The presence of MSNs did not alter the rheological properties of the platforms and their gelling temperatures. The Irinotecan loading efficiency was optimized in terms of dissolving medium and was found to be the highest (about 5%) for the medium 50% DMSO-50% ethanol. Stable suspensions of Irinotecan loaded MSNs in the new thermosensitive platforms were achieved. In vitro drug release experiments, showed that the optimized platforms containing MSNs were able to control the Irinotecan release up to about 7 days.
Conclusions: We formulated injectable composite hydrogels potentially useful as vehicle for sustained chemotherapeutic delivery made up of pluronics, HA and MSNs.
References:
[1] Jie Lu et al. Mesoporous Silica Nanoparticles as a Delivery System for Hydrophobic Anticancer Drugs. Small 2007, 3, No. 8, 1341 – 1346
[2] Yu M. et al. Hyaluronic Acid Modified Mesoporous Silica Nanoparticles for Targeted Drug Delivery to CD44-Overexpressing Cancer Cells. Nanoscale 2013, 5, 178–183
[3] Salis A et al. Adsorption of Lysozyme on Hyaluronic Acid Functionalized SBA-15 Mesoporous Silica: A Possible Bioadhesive Depot System. Langmuir 2014, 30, 12996-13004