Fabrication And Drug Delivery Research For Multi-Functional Drug-Loaded Micro/Nano Carriers

Cancer is a major health problem and largest cause of death worldwide with an increasing morbidity year by year.Treatment effect of conventional cancer therapies remains unsatisfactory due to their existing drawbacks such as low specificity,high recurrence rate,strong toxicity and adverse effect.To overcome these limitations,we developed multi-functional nano/micro carriers of therapeutics for a variety of drug delivery requirements,such as sustained drug release and remotely triggered drug delivery.The pharmacokinetic properties of these nano/micro carriers were characterized by a series of bench experiments and their therapeutic effects were compared with those of conventional chemotherapies in order to demonstrate their anti-cancer potential.First,we designed paclitaxel(PTX)-laden solid lipid microparticles and established in vivo phannacokinetics and cell cytotoxicity models to verify their advantages in sustained release and cancer treatment.We explored a single-step coaxial electrospray process to synthesize core-shell structure of PTX-SLMPs with a particle size of 1.76±0.37 ?m,encapsulation efficacy of 94.73%and sustained drug release profile.In vitro evaluation of PTX-SLMPs in SKOV-3 ovarian cancer cells yielded significant enhancement in cytotoxicity when compared with Taxol.In vivo pharmacokinetic study demonstrated slower absorption of PTX into the systemic circulation after intraperitoneal(i.p.)administration of PTX-SLMPs in Wistar rats implying that the PTX-SLMPs formulation remained in the peritoneal cavity for sustained release of PTX for a prolonged period of time.Through these studies,we have demonstrated that the core-shell structured PTX-SLMPs can potentially enhance sustained release of PTX to the tumor for more effective treatment of ovarian cancer and other peritoneal malignancies.Second,we engineered PTX-laden hybrid microparticles(PTX-Hyb-MPs)with controlled particle size,tunable thickness,uniform size distribution,and high encapsulation rate(92.17±6.9%)for improved delivery of chemotherapy in ovarian cancer.Same co-axial electrospray process was used for one-step and scalable production of the PTX-Hyb-MP formation comprised of a lipid-coated shell of PLGA encapsulating PTX.We developed several experimental models such as cell uptake model and xenograft tumor model following other biological models and bench experiments mentioned above to evaluate the passive targeting cancer treatment effect of PTX-Hyb-MPs compared with Taxol and normal drug loaded PLGA microparticles.Our studies revealed that PTX-Hyb-MPs formation can be potentially applied in locoregional treatment passively targeting ovarian cancer and other tissue malignancies with sustained drug release,tunable release profiles,enhanced drug uptake and reduced systemic toxicity.Finally,we conjugated doxorubicin(DOX)laden magnetoliposomes(DOX-ML)with microbubbles to form DOX-ML-MBs complex for controlled delivery and sustained release of chemotherapy.DOX-ML-MBs were self-assembled perflurocarbons(PFC)gas loaded microbubbless surrounded by liposomes composed of DOX and oligolamellar-coated citrate stabilized iron oxide nanoparticles(MN)at the size of 5-10 nm.The particle size,magnetic properties and drug carrying efficiency of DOX-ML-MBs were characterized.In vitro studies in both Bxpc3 and Panc02 pancreatic cancer cells showed the greater anti-cancer potent for this formulation in comparison with conventional chemotherapies.In vivo studies in mice showed that intravenous administration of DOX-ML-MBs in presence of external magnetic field followed by selective application of ultrasound(US)pulses yielded greater drug accumulation at the targeted site.These results demonstrate the superiority of the DOX-ML-MB formulation over other formulations in tumor specific drug delivery and remotely controlled drug release.Our study opens a new avenue for systemic delivery and locoregionally stimulated release of anti-cancer therapies in the treatment of pancreatic cancer and other tissue malignancies.In summary,our research work manifested the advantages of our multi-functional nano/micro carriers over conventional formulations in remotely controlled delivery and sustained release of anti-cancer therapies.Further development and optimization of our multi-functional nano/micro carriers may shift the current paradigm for more effective and safe treatment of cancer and other tissue malignancies.