Research On The Drug Delivery System With PH Sensitivity And Synergistic Effect Of Calcium Ions For Breast Cancer

Breast cancer is one of the malignant tumors that seriously threatens women's health.Chemotherapy is still the main treatment.Due to the poor selectivity and large side effects of chemotherapeutic drugs,how to efficiently accumulate drug molecules in the tumor site,reduce the loss of circulation in the body and play a role in the tumor location,have been the key to disease treatment.In addition,it is also important for cancer therapy to seek an integrated treatment that can synergistically enhance therapeutic effect with chemotherapy.For the above issues,here we intend to build a composite and multi-functional nano-drug delivery system as multi-functional carrier for tumor therapy.This multi-functional and composite nano-drug delivery system can produce calcium ion,response to the slightly acidic environment of tumor to control the release of anti-tumor drugs and achieve thermal therapy after irradiating with Near Infrared(NIR)light,which not only improves the release and accumulation of anti-tumor drugs at the tumor site,but also achieves the combination of chemotherapy,photothermal therapy and the overloaded of calcium in mitochondria,which synergistically enhance the treatment of breast cancer.Hollow mesoporous copper sulfide Nano-Particles(HMCuS NPs)are kinds of NIR light absorption materials,which have the advantage of high photothermal conversion efficiency,large specific surface area,good dispersibility and high drug loading capacity.However,it's well known that the degradation of pure HMCuS NPs is quite slow due to their stable structure,so it's hard to release active drugs quickly when it arrives at tumor tissues.What's more terrible is that HMCuS NPs will accumulate in living organs which is really harmful to human body.So the poor degradability of HMCuS NPs limits their biomedical applications.In this paper,we got a novel muti-functional Nano-particals(HMCuS@CaP NPs)by incorporating calcium phosphata(CaP)into HMCuS NPs homogeneously.The HMCuS@CaP NPs enabled to response to the slight acidic environment of tumor site to control the release of anti-tumor drugs and had the ability of photothermal conversion.The incorporation of CaP improved the pH sensitivity of HMCuS NPs.In addition,the disintegration of HMCuS@CaP NPs led to a significant increase of intracellular calcium ion.On the other hand,due to the disintegration,HMCuS@CaP NPs turned into smaller nano-particles,which improved the degradability of nano-particals and reduced the residence time of copper sulfide in vivo,thereby reducing the carrier toxicity.Then we loaded the nature anti-tumor drug-curcumin into HMCuS@CaP NPs by physical adsorption method.To improve the water dispersibility and biocompatibility of the muti-functional nanoparticles and avoid the earlier leakage of Cur during the body circulation,we used polymer Pluronic F68 with low toxicity to modify the surface of HMCuS@CaP-Cur to efficiently seal the pores of HMCuS@CaP NPs.Thus we finally obtained a pH-responsive and calcium generational drug delivery system(HMCuS@CaP-Cur-F68)that integrated chemotherapy,ion damage therapy and thermotherapy.Calcium ion as a large intracellular signaling molecule,regulates the physiological functions of cells,such as cell cycle,apoptosis and cell proliferation and so on.Overloading of calcium ions in mitochondeia is believed to be the cause of tumor cytotoxicity and always leads to cell necrosis and apoptosis.The pH-sensitive and muti-functional Nano-drug delivery system(HMCuS@CaP-Cur-F68)would rapidly disintegrate when it arrived at the tumor site,and release the anti-tumor drug of Cur and produce a large amount of calcium ions leading to the remodeling of calcium signal which contributed to continuous increase of intracellular calcium.Calcium ions released from the disintegration of the carrier deposited in tumor mitochondria,which acted synergistically with curcumin to accelerate the release of cytochrome c from the mitochondria to the cytoplasm and reduced the mitochondrial membrane potential(??),which induced the apoptosis of tumor cells.In addition,the muti-functional nano-drug delivery system had the good ability of photo-themal conversion under the irradiation of NIR light.It was not only achieved thermal therapy effect,but also destroied the lattice of HMCu S NPs to accelerate the disintegration of HMCuS@CaP NPs,thus improved the release of antitumor drug Cur and calcium ions to induce the deposition of calcium ions in mitochondrial.Therefore,HMCuS@CaP-Cur-F68 acted as a synergistic treatment that combined chemotherapy,ion damage therapy and thermotherapy to enhance breast cancer treatment.In this subject,we have approved that we incorporated CaP into HMCuS NPs successfully by series of characterization analysis,such as transmission electron microscopy(TEM),scanning electron microscopy(SEM),atomic force microscope(AFM),Energy Disperse Spectroscopy(EDS)and Nitrogen adsorption and desorption experiments.Based on the above characterization analysis,we demonstrated that we had got the multifunctional nanodrug delivery system(HMCuS@CaP-Cur-F68)which presented uniformly dispersed spheres and processed the average size about 100-200nm,specific surface area about 123.68 m~2/g,average pore size about 3.5 nm.The results of UV-visible scanning and drug loading results showed that HMCuS@CaP NPs were successfully and efficiently loaded with the anti-tumor drug of Cur.The loading efficiency of Cur achieved 64.86%.The pH sensitivity experiments and drug release curves at different pH indicated that HMCuS@CaP-Cur-F68 had extremely sensitive pH response.At pH 6.5 and 5.0,HMCuS@CaP-Cur-F68 collapsed to release abundant drugs.The cumulative release rate of Cur in 12 hours highly achieved 52.8%and 84%respectively,and existed burst release phenomenon within 2 hours.However,the cumulative release rate of Cur in physical condition(pH about 7.4)was less than 20%in 12 hours.The heating curves after NIR light irradiation and heat experiment in vivo proved that HMCuS@CaP NPs had good photothermal conversion efficiency which could efficiently convert light energy into heat.Meanwhile,in vivo and in vitro experiments showed that the multifunctional drug delivery system(HMCuS@CaP-Cur-F68)had the following characteristics:1.Synergistically increasing intracellular calcium ion by disintegrating of carriers and the induction of Cur,thus inducing tumor cells apoptosis and achieved the efficient,accurate and low-toxic treatment for breast cancer through mitochondrial pathway such as the induction of mitochondrial membrane potential,the reduction of ATP content,the increase of cytochrome c and other factors.2.Specially responded to the tumor slightly acidic environment,which not only promoted carriers to collapse and rapidly releases antitumor drugs,but also accelerated the carrier's metabolism thus reducing side effects to human body.3.Integrate chemotherapy,ion damage therapy and photothermal therapy to improve the therapeutic effect of breast cancer.4.Good biocompatibility and stability.