A Study On The Treatment Of Breast Cancer Based On Photothermal Therapy Combined With Intratumoral Injection Of Annosin Nanoparticles

Annonaceous acetogenins(ACGs)are a kind of long-chain fatty acid lactone compounds extracted from the Annonaceous plants.They are promising natural anticancer active ingredients after paclitaxel.Compared with other common anticancer drugs,ACGs have stronger activities and unique pharmacological mechanism,and they can reverse multidrug resistance.However,their side effects and narrow treatment window have limited their application.To overcome this problem,a local drug delivery system that combines chemotherapy and photothermal therapy(PTT)has been constructed in this study.The principle is that local administration can reduce the distribution of ACGs in non-target sites.And under laser irradiation,the photothermal conversion material can increase the temperature of tumor to ablate the tumor and promote the release and penetration of ACGs nanoparticles(ACGs NPs).At the same time,the dosage of ACGs can be further reduced due to the synergistic effect of PTT and chemotherapy.Finally,it is expected to enhance efficiency and reduce toxicity of ACGs to achieve effective drug delivery.Polydopamine(PDA)is widely used as a photothermal material due to its good photothermal conversion performance,biocompatibility,easy preparation and modification.Therefore,we use PDA nanoparticles(PDA NPs)as photothermal conversion materials for PTT.The research contents are as follows:First,ACGs NPs were prepared using PCL2000-mPEG2000 as a stabilizer,and PDA NPs were prepared by oxidative self-polymerization method using dopamine hydrochloride.In order to improve the stability in physiological media,PDA NPs were modified with polyethylene glycol(PEG)to obtain PEGylated PDA NPs(PDA-PEG NPs).Subsequently,the nanoparticles(NPs)were characterized by measuring the particle size,zeta potential,Fourier transform infrared spectroscopy(FTIR),X-ray photoelectron spectroscopy(XPS),and photothermal conversion performance of the corresponding NPs.ACGs NPs have a particle size of 103.70±0.87 nm.PDA NPs and PDA-PEG NPs have small particle sizes(64.42±0.32,70.96±2.55 nm).PDA-PEG NPs can stably exist in a variety of physiological media,and when 1.5 mg/mL PDA-PEG NPs were irradiated under an 808 nm NIR laser at a power density of 5 W/cm2 for 330 s,the temperature could be raised to above 42℃,which can kill tumor cells.FTIR and XPS confirmed the successful modification of PEG on PDA NPs.In vitro cytotoxicity assays have proved that:(1)4T1 cells were more sensitive to ACGs NPs than B16 cells,so we adopted the 4T1 cell model later.(2)PDA-PEG NPs had good biocompatibility and could be used as photothermal conversion materials.(3)PDA-PEG NPs at a given concentration could kill more than half of 4T1 cells under NIR laser irradiation.(4)ACGs NPs and PDA-PEG NPs showed excellent synergistic effects under laser irradiation,making the survival rate of 4T1 cells only 1%.In vivo studies showed that:(1)PDA-PEG NPs had good biocompatibility in mice.(2)The tumor inhibition rate of the photothermal therapy group treated with PDA-PEG NPs plus NIR laser irradiation was 63.49%.(3)The antitumor effects of ACGs NPs injected intratumorally(0.2 mg/kg)and intravenously(0.4 mg/kg)were similar(69.87%vs 72.81%).However,compared with ACGs NPs injected intravenously which caused the death of 4 mice,ACGs NPs injected intratumorally had significantly higher safety and more drug distribution in tumor site.(4)More interestingly,the drug distribution in tumor site of ACGs NPs injected intratumorally would be further improved after combining with PTT.(5)The local drug delivery system that combined ACGs NPs with PDA-PEG NPs had excellent antitumor effects under laser irradiation,and the tumor inhibition rate can reach 82.65%.Although it may damage the spleen to a certain extent,it had no obvious effects on body weight,and it can achieve stronger antitumor effects and higher safety than a high dose of ACGs NPs injected intravenously when the dosage and administration frequency of ACGs were reduced,indicating that the drug delivery system plays a role in enhancing efficiency and reducing toxicity of ACGs.In summary,the local drug delivery system that combined PTT(based on PDA)and chemotherapy(based on ACGs)has excellent antitumor effects,enhances the efficiency and reduces the toxicity of ACGs.And this good drug delivery system is expected to explore new methods for the therapy of breast cancer.