Preparation Of Vaterite CaCO₃ Particles By Flash Nano-precipitation Technique For Targeted And Extended Anticancer Drug Delivery

An ideal drug release system for anticancer therapy is designed to release drugs over a prolonged period to achieve stable and higher therapeutic potential while minimizing the initial burst release to significantly reduce the side effects and the number of medications to improve patient’s adherence.However,the current controlled drug-release system still suffers from several shortcomings,including poor drug selectivity,carriers with poor biocompatibility,low drug utilization,and low specificity.Vaterite calcium carbonate,possessing outstanding advantages such as good biocompatibility,good biodegradability,high specific surface area and mild synthetic conditions,has attracted great attention in the field of drug carriers in recent years.With the aim to attain an ideal anticancer-drug-delivery system,the flash nano-precipitation(FNP)method is applied to the synthesis of the inorganic drug carrier,vaterite CaCO3 particles.The reaction of sodium carbonate(Na2CO3)and calcium chloride(CaCl2),in the presence of food-grade or pharmaceutical grade additives,is performed in a home-made multi-inlet-vortex-mixer-typed FNP reactor.First,three typical drug/food additives,sodium dodecyl sulfate(SDS),hydroxypropyl methyl cellulose(HPMC)and sodium caseinate(NaCas),are investigated in the FNP process for the synthesis of CaCO3 particles,respectively.It is found that SDS and NaCas can effectively prevent particle agglomeration and HPMC can remarkably improve the mono-dispersity of CaCO3 particles.After screening of combinations of two kinds of additives,the additive "couple" of HPMC+SDS is opted as the best combination for the synthesis of CaCO3 particles in FNP process.The effect of different factors including HPMC-to-SDS ratio and reactant concentration on the morphology,crystalline type,size and size distribution of the CaCO3 particles in FNP process,is examined.The combination of HPMC+SDS is found to act as not only additives for CaCO3 crystallization to promote the formation of vaterite,but also stabilizers for CaCO3 particles to control particle growth and prevent particle aggregation.Stable and convex-disc-like CaCO3 particles are prepared with single crystalline type(vaterite),with a proper size dimension between typical nano-size and typical micro-size(average diameter 800-1600 nm),and with a narrow size distribution(PDI～0.1).The as-prepared CaCO3 particles are furtherly loaded with anticancer drug DOX(Doxorubicin} and a satisfactory drug loading capacity(～0.1 mg DOX/mg CaCO3)is achieved.It is founded that the CaCO3-DOX drug delivery system is able to achieve drug release targeting tumor extracellular pH(～6).Prolonged drug release is also realized(～40%within 8 days at pH=6.0)with very low initial release(below 10%within 1 day at pH=6.0).Moreover,zero-order or approximately zero-order release kinetics is achieved(R2>0.97 before 36 h and R2>0.99 after 36 h)is achieved with the as-prepared vaterite CaCO3 drug carrier.In this thesis,FNP technique is proved to be a simple and efficient method for preparing stable,uniform and monomorphic CaCO3 particles.The nano-/micro-sized non-spherical vaterite CaCO3 particles prepared in this thesis could be a potential candidate drug carrier for anticancer drug,capable of achieving targeted release in a prolonged period with minimized initial burst and a constant drug releasing rate.