Design And Performance Study Of Novel Formulations: Polymorphic Drug-based Multi-mode Drug Delivery System

Conventional small-molecule hydrophobic drugs are limited in clinical application due to their low aqueous solubility,lack of selectivity and high toxicity.Therefore,how to improve the solubility of hydrophobic drugs and how to to design the nanometer/micron scale drug delivery systems become important issues.Recently,nano-drug delivery systems(nano-DDS)have attracted widely attention because of their excellent abilities such as the longer drug half-life in blood circulation,improvment of drug biodistribution and alleviation of drug toxicity.However,current drug delivery systems still encounter several challenges,including(a)slow or incomplete release of hydrophobic drugs in diseased region;(b)complexity of carrier surface modification by coupling various target ligands;(c)safety of drug delivery carriers,etc.Taking this into account,in this thesis,we proposed the nanotechnology or micronization associated with a crystal engineering approach to construct multimodal drug delivery systems,by integrating optimal polymorphic nanocrystals and inorganic and/or organic materials into a single nano/micro-scale platform for achieving better therapeutic efficacies.The key research contents are described below:(1)10-hydroxycamptothecin polymorphic nanoparticle dispersions(HCPT-PNDs)were prepared using the supercritical anti-solvent(SAS)technique coupled with the high-pressure homogenization method.The effect of morphology and crystal form on the biological efficiency of HCPT-PNDs was investigated.The results showed that needle-shaped HCPT-PND had a large surface-to-volume ratio,which is beneficial to improve the solubility of HCPT.When compared to pancake-like and prismatic ones,the needle-shaped HCPT-PND,which with longer blood retention time and more effective cellular uptake,makes it possible to accumulate drug in tumor tissues and exhibit higher antitumor efficiecy.No severe systemic toxicity was observed in normal tissues under a low dosage of needle HCPT-PND.These results indicate that the needle-shaped HCPT-PND is a promising nano-formulation.(2)With the aim of designing multi-mode drug delivery systems,a novel nanocarrier that integrates inorganic(AuNPs)and organic(Zein)into a single nanoscale platform was fabricated by BUDP method.Dopamine polymerization method was introduced to functionalize the surface of AuNPs-Zein with the targeted ligand,FA,which is a facile approach for surface functionalization and did not require modification of Zein or chemical activation of the carrier surface.The resultant nanocarrier,AuNPs-Zein-PFA,showed superior dispersibility and stability in physical conditons due to the good hydrophilicity of PDA layer.Also,the designed nanocarrier exerted FA-mediated active targeting delivery to folate receptor(FR)-expressed cells.Zein-based shell structure is biocompatible and biodegradable,in which hydrophobic drugs could be effectively encapsulated.The AuNPs in the core can realize the intracellular localization and be accurately determinated,which is beneficial to the tracer and localization of nano-carriers in the organism.(3)Based on the above-mentioned work,a versatile nano-drug delivery system(HCPT @ AuNPs-Zein-PFA)were fabricated via the combination of SAS technique and BUDP method,which displays high drug-loading efficiency for needle-shaped hydroxycamptothecin(HCPT)nanocrystals.In vitro cytotoxicity and celluar uptake results displayed that the folate-conjugated nanoparticles facilitate selective cellular internalization via FA-mediated endocytosis,leading to more HCPT released in tumor cell and thus highly improving the antitumor efficiency.Compared to free HCPT and its non-targeting equivalent,HCPT@AuNPs-Zein-PFA is capable of effectively accumulation in tumor sites and exerted a superior tumor suppression capacity in vivo.HE results exhibited that tumor cells appear large areas of necrosis after treated by HCPT@AuNPs-Zein-PFA,while no significant side effects was observed in normal tissues.These results suggested that this targeted nano-DDS encapsulated HCPT nanocrystals holds great promise to improve cancer therapy with high selectivity and low toxicity in the clinic.(4)A polymorph modification associated with a delayed release approach was proposed for improving the solubility of hydrophobic drugs for developing a Zein-based colon-targeted delivery system.A microcarrier system based on self-assembled structures of Zein was fabricated via a BUDP method,which displayed high encapsulation efficiency(89.1±1.4%)of a model drug indomethacin(Indo)with its optimal crystal form(α form).The α form Indo at the microscale featured with higher solubility and dissolution rate in comparison with other crystal forms of Indo.The microspheres Zein-Indo@PDA with a surface coating of PDA,rendered them enhanced stability and also effectively hindered the premature drug release at undesired sites.In vitro drug release results demostrated that Zein-Indo@PDA was gastric acid resistant and enable them to time-and region-dependent release,thus offering better chances of colon-targeted delivey.