Preparation Of Nanoparticles And Nanocrystalline Taxol Modified By Polydopamine

Osteosarcoma is the most common primary bone tumor and predominantly affects children and adolescents.According to the National Cancer Institute database of the USA,patients with metastasis at diagnosis exhibited 5-year survival rates less than 20%.Although adjuvant chemotherapy has significantly improved the survival of osteosarcoma patients,some serious problems continue to exist,including severe side effects,and relapse or metastatic disease.Furthermore some patients do not respond to chemotherapy and others exhibit features of multidrug resistance.Thus,improving the targeting of chemotherapeutic drugs is a important pathway to treatment osteosarcoma.Paclitaxel(PTX)is a new type of microtubule stabilizer,which has good clinical effect on many cancers such as breast cancer and osteosarcoma clinically.In this experiment,paclitaxel was made into nanoparticles and nanocrystals to improve the water solubility and bioavailability of paclitaxel.At the same time,new polymeric materials of polymerize dopamine were used in this topic.The simple and efficient connection of albite phosphate allantoin(ALN)by Michael addition and Schiff reaction,which targeting osteosarcoma surface protein tyrosine phosphatase is expected to provide a new theoretical basis and thinking for the targeted therapy of osteosarcoma.The first part of the experiment,to enhance the treatment effects of chemotherapy on osteosarcoma,we synthesized a novel nanoparticles(NPs)PTX-PDA-ALN-NPs based on dopamine polymerization(PDA)as a way of functionalizing NPs surfaces.Dopamine polymerization is a simple and versatile modification technique,will not be limited by the lack of functional groups on the surface of the compound and not change the chemical properties of the polymer what may lead to polymer lose the ability to encapsulate drug as chemically reactive.The novel nanoparticles(NPs)PTX-PDA-ALN-NPs average particle size of 255.12±1.560 nm,a PDI value of 0.193± 0.026,a zeta potential of-17.4±3.27.By means of transmission electron microscopy(TEM),X ray electron spectroscopy(XPS)and Fourier transform infrared spectroscopy(FTIR),we further know the spherical morphology and surface element characteristics of the prepared nanoparticles,which further proves that the target ALN has been successfully connected.Because it stability in phosphate buffer saline(PBS,PH 7.4),5%glucose,normal saline and plasma,We can use intravenous injection to conduct animal studies.The nanoparticles displayed sustained drug release behavior in vitro release experiments.Furthermore,the targeting PTX-PDA-ALN-NPs nanoparticles has a stronger in vitro cytotoxicity against K7M2 wt osteosarcoma cell compared to free PTX-NPs In vivo study the targeting NPs could much more accumulate in the tumor than naked nanoparticles.In addition,demonstrated that prominently decreased the side effects of PTX and achieved a better therapeutic efficacy as PTX injection(8 mg/kg,i.v.)(82.51%versus 66.63%).Therefore,these results indicate that alendronate modified polydopamine-coated PTX nanoparticles is a potential drug for osteosarcoma targeted therapy.In the second part of the experiment,poloxamer P188 and docusate sodium were used as stabilizers to make paclitaxel nanocrystalline,we engineered a novel paclitaxel(PTX)nanocrystals modified with dopamine polymerization(PDA)and functionalized by alendronate(ALN)as ligand(PTX-PDA-ALN-NCs).Different stabilizers were used for prescription screening and process optimization.The resultant nanocrystals had an average particle size of 290.6±2.19 nm,a PDI value of 0.183±0.036 and a zeta potential of-13.4±2.67.By means of transmission electron microscopy(TEM),X ray electron spectroscopy(XPS)and Fourier transform infrared spectroscopy(FTIR),we further know the spherical morphology and surface element characteristics of the prepared nanoparticles,which further proves that the target ALN has been successfully connected.It is suitable for intravenous administration,because it is stable in phosphate buffer saline(PBS,PH 7.4),5%glucose or plasma.In vitro release of nanoparticles conforms to the first-order release equation,which can be released in PBS for 120 h(cumulative release rate of 69.6%).In vitro assay demonstrated the targeting nanocrystals(PTX-PDA-ALN-NCs)had stronger cytotoxicity against K7M2 wt osteosarcoma cell than the non-targeting nanocrystals PTX-NCs and PTX-PDA-NCs.And in vivo distribution study showed they could much more accumulate in the tumor than naked nanocrystals.Establish a tumor-burdened Balb/C mice model,the related research of the pharmacodynamics,targeted nanocrystalline PTX-PDA-ALN-NCs replication has a 72.09%inhibitory rate and lower kidney toxicity.Nanocrystallines(PTX-PDA-ALN-NCs)are much simpler to prepare than nanoparticles(PTX-PDA-ALN-NPs).PTX-PDA-ALN-NCs only need to stir the organic phase(contained the drug)into the water phase.The simple operation is beneficial to industrial production.The nanocrystalline organic phase is ethanol,and the nanoparticle organic phase is acetone.From the perspective of drug safety,nanocrystals are still better.In vitro release and cell experiments,there is no significant difference between NPs and NCs,but from the anti-tumor efficacy test in vivo,the efficacy of nanoparticles is better(inhibition rate:82.51%vs 72.09%).Both PTX-PDA-ALN-NCs and PTX-PDA-ALN-NPs are promising nanomedicines with potential and research value,why there is a pharmacodynamic difference between them,and whether the differences are related to polydopamine.These issues deserve further exploration and investigation.