Construction And Antitumor Properties Of Paclitaxel Self-assembled Nanomedicines

Paclitaxel(Taxol)is an active diterpene compound extracted from Pacific yew bark.It is one of the most excellent natural anticancer drugs in clinic,which has been widely used in the therapy of breast cancer,ovarian cancer,some head and neck cancer and lung cancer.Due to the poor water solubility of paclitaxel,Cremophor EL(Cr EL)and ethanol are usually introduced to increase its solubility.However,Cr EL has obviousdrawbacks,it would cause serious allergic side effects.Thus,it is necessary to develop new dosage forms to increase the bioavailability of paclitaxel,enhance its anti-tumor activity and reduce toxicity.In recent years,the development of nanomedicines has provided the efficient methods to solve the problems above.There are some delivery systems based on nanotechnology including protein-bound paclitaxel,polymer micellar paclitaxel,polymer-paclitaxel conjugate,liposome-encapsulated paclitaxel.These paclitaxel nanomedicines not only improve the water solubility of paclitaxel,but also enhance anti-tumor properties and reduce toxic side effects.In the methods of preparation nanostructures,the self-assembly provides a convenient method in preparing nanostructures with functionalized modifications.Molecules as structural components can form ordered nanostructures by non-covalent interactions.In nanomedicine field,self-assembly strategies have been widely used in the research and development of nanocarriers for chemotherapeutic drugs,proteins and gene therapy drugs.In this dissertation,three kinds of PTX drug delivery systems with anti-cancer prospects were constructed by molecular self-assembly technology:(1)PTX and chitosan(CS)molecules can be assembled formed by hydrophobic interaction and hydrogen bonding(2)PTX,hydroxyapatite(HA)and bovine serum albumin(BSA)can be assembled by co-precipitation during the synthesis process(3)PTX molecules have modifiable sites that can form amphiphilic molecules with tyroserleutide(YSL)by ester bonding.Meanwhile,combining the different types of tumor administration and the characteristics of assembled nanoassemblies,the anti-tumor properties of three nanomedicines for bladder cancer,osteosarcoma and liver cancer were studied.1.Preparation of paclitaxel/chitosan nanosuspensions and evaluation for bladder cancer infusion systemBladder perfusion therapy is an important method to reduce the recurrence rate significantly in the postoperative treatment of bladder cancer.The paclitaxel/chitosan(PTX/CS)nanosuspensions were used as a sustained release system of bladder infusion drugs.It has the advantages of sustained and prolonged delivery of paclitaxel and enhanced intravesical bladder cancer therapy.The positive charged PTX/CS nanosuspensions exhibited a rod shape with mean diameter about 200 nm.They can stably disperse in water without any protective agents,and the positive charged properties make them easily adsorbed on the inner mucosa of the bladder through electrostatic adsorption.PTX/CS nanosuspensions also had drug-loading efficiency of 40.2 wt.% and PTX sustained release could be prolonged over 10 days.Cell experiments in vitro demonstrated that PTX/CS nanosuspensions had good biocompatibility and effective cancer cell proliferation inhibition.The significant anti-cancer efficacy against intravesical bladder cancer was verified by nude mice in situ bladder cancer model.The PTX/CS nanosupensions could provide improved chemotherapeutic delivery with significant anti-cancer efficacy against bladder cancer.2.Preparation of hydroxyapatite-bovine serum albumin-paclitaxel nanoparticles and evaluation for osteosarcoma in situ drug delivery systemOsteosarcoma is the most common primary bone and the combination of chemotherapy and surgery can make patients long-term survival about 60-70 %.Hydroxyapatite-bovine serum albumin-paclitaxel(HA-BSA-PTX)nanoparticles,as an in situ drug delivery system for osteosarcoma,have the advantages of slow drug release,enhanced anti-tumor effect and inhibition of osteosarcoma metastasis.HA-BSA-PTX nanoparticles were spherical and had a diameter of approximately 55 nm.HA-BSA-PTX nanoparticles also had drug-loading efficiency of 32.2 wt.% and PTX sustained release could be prolonged over 5 days.The cell experiments in vitro showed that HA-BSA-PTX nanoparticles had good biocompatibility and effective inhibition of osteosarcoma cell proliferation.The nude mice in situ osteosarcoma model in demonstrated the significant anticancer and metastatic effects of HA-BSA-PTX nanoparticles on osteosarcoma.3.Preparation of paclitaxel-tyroserleutide self-assembled nanoparticles and evaluation for liver cancer administration systemThe self-assembly of small molecule drug conjugates can realize the self-transport without carrier.At the same time,the thermodynamics of the assemblies is more stable,and the long circulation in vivo promotes their enrichment at the tumor site.The structure of paclitaxel-tyrogliadin molecule(PTX-YSL)was clear,and the synthesis process was relatively simple.The amphipathic PTX-YSL conjugate was synthesized through hydrolyzed ester linkage,it can be self-assembled into PTX-YSL nanoparticles with size about 40-100 nm.The amphipathic PTX-YSL conjugate could be hydrolyzed in the tumor's slightly acidic environment to release two drug molecules simultaneously.Cell study in vitro indicated that conjugation of PTX-YSL nanoparticles had low cytotoxicity and could facilitate cellular uptake by SK-HEP-1 cells.In vivo animal experiment result showed the PTX-YSL nanoparticles have longer blood retention which can enhance the accumulation of tumor tissue through the high permeability and retention effect of solid tumors.PTX-YSL nanoparticles were expected to become a simple,safe and effective nanoscale paclitaxel drug delivery system,and have the potential to treat liver cancer.