Design and Characterization of Multifunctional Self-Assembling Lecithin/Amphiphilic Polymers Mixed Micellar Delivery Systems

The solubility of active pharmaceutical ingredients (APIs) has always been a concern for clinical application because poor solubility may hamper the development of commercial products and limit their bioavailability. Self-assembling mixed polymeric micelles (SAMPM) consists of a core and shell structure by amphiphilic polymers; the inner core is the hydrophobic part, which incorporates the poorly water-soluble drug, while the outer shell of the hydrophilic block protects the drug from the aqueous environment and stabilizes for longer duration. The SAMPM is attractive for drug delivery because of its multifunction, such as, enhanced solubility and stability, smaller particle size leading to passive targeting, potential active targeting by ligands conjugating, and simple preparation. In this study, we combine the concept of lecithin phospholipid complex and amphiphilic polymers to form lecithin-based SAMPM; in the hypothesis that the addition of co-polymers could spontaneously form micelles, while the initial incorporation of lecithin in the core may increase the concentration of hydrophobic API with reducing the amount of co-polymers. Our preliminary data show that quercetin SAMPM had particle size of 78.7 nm, entrapment efficiency of 88.07%, drug loading of 11.01%; moreover, it possessed better stability. Similarly, amphotericin B and docetaxel also formed SAMPM. Compared to previous study, SAMPM is novel and worthy for further develop. The purpose is to develop an effective anti-cancer drug lecithin-based SAMPM to reduce toxicity and increase selectivity, and set up a database regarding the effect on polymer types and ratio as an evaluation platform. Year 1 study: Formulate, physiochemical characterize lecithin-based SAMPM formulation, and create an mathematic model Different lecithin (derived from egg, soybean or sunflower) and lysolecithin are applied as a core to increase the concentration of APIs. As to the shell, more types and different ratio of co-polymers (TPGS; DSPE-PEG1000, DSPE-PEG2000, and DSPE-PEG5000; Pluronic® P188, P237, P338, P407, P403, and P401; Kolliphor®RH40 and ELP) even with combination use are formulated. These SAMPM are characterized by particle size, zeta potential, drug loading, entrapment efficiency, critical micelle concentration, differential scanning calorimetry and NMR. A mathematic model of SAMPM to predict the impact (particle size, encapsulation efficacy and drug loading) on the types and amount of these polymers in the six hydrophobic anti-cancer model APIs (docetaxel, paclitaxel, amphotericin B, curcumin, resveratrol, and quercetin) is set up. The complete database could provide an evaluation platform for future API use. Year 2 study: In vitro characterization of optimized lecithin-based SAMPM formulation and investigate the parental and oral formulation The optimized lecithin-based SAMPM formulation is determined by in vitro drug release and cytotoxicity. The oral dosage form is formulated by adsorbent and other commonly used exciepients. The availability of parenteral and oral formulation is to test the ability of self-assembling and stability in medium. Year 3 study: In vivo characterization of the optimized lecithin-based SAMPM formulation, and bispecific HER2 antibody conjugating and characterization of HER2 targeting ability In vivo pharmacokinetic, tissue biodistribution, and antitumor effect of the optimized SAMPM are conducted. A bispecific antibody is inserted to the DSPE-PEG SAMPM; while it can recognize the methoxy group of DSPE-PEG and display anti-HER2 targeting outside which is able to specific bind HER2 over-expreesion breast cancer.