Polydopamine Nanocomposites Camouflaged By Stem Cell Membranes For The Treatment Of Bone Tumors

Malignant bone tumors include invasive tumors that originate in bone tissue and metastasize to bone tissue from tumors in other parts.Malignant bone tumors have the characteristics of rapid growth,high recurrence rate and high mortality rate,and the prognosis is often very poor.The treatment of malignant bone tumors is still a huge clinical challenge.The current methods used to treat malignant bone tumors mainly include surgical treatment,chemotherapy and radiotherapy.Even if surgery alone can resect the tumor,it is still prone to tumor recurrence and distant metastasis.The bone marrow microenvironment induces dormancy of tumor cells and causes them to resist chemotherapy and radiotherapy,which makes it difficult to eliminate tumor cells.Therefore,it is urgent to develop new therapies to treat malignant bone tumors.Nanomedicine is an emerging discipline in the treatment of tumors.Nanoparticles(NPs)synthesized by using the advantages of nanotechnology have become an effective drug delivery system.NPs-based drug delivery system can combine different tumor treatment strategies and show good prospects in tumor diagnosis and treatment research.However,the synthetic nanomaterials is treated as a foreign antigen substance in the body to produce immune clearance,resulting in a short circulation time of the nanomaterials in the body and cannot effectively target to the tumor site.Therefore,it is important to design and develop nanomaterials that reduce immune clearance and target tumorsBecause the nanomaterials camouflaged by the cell membrane can reduce the elimination of the body's immune system,increase the circulation time in the blood,and increase the accumulation in the tumor area,it is considered to be a very promising tumor treatment method.Among various types of cell membranes,stem cell membranes(SCM)inherit the low immunogenicity of stem cells and tumor tropism ability,but they do not have the risk of promoting tumor development and metastasis like stem cells.This biomimetic nanocomposite does not require complicated production of targeting molecules and incorporating them into NPs.This is a very simple and close to clinical application method,which can reduce immune system clearance,overcome vascular barriers and actively target to the tumor tissue.Therefore,the technology of using SCM to camouflage the nanocomposite can effectively solve the above problems.In this study,polydopamine nanoparticles(PDA NPs)were used as the carrier and the SCM was camouflaged on the outer layer of the NPs by extrusion.The obtained PDA NPs camouflaged by the stem cell membrane(PDA@SCM NPs)could be combined with different treatment methods for synergistic anti-tumor.This paper consists of the following two parts:(1)Chemo-photothermal therapy based on nano-delivery systems has been proven to be an effective non-invasive anti-tumor treatment.However,synthetic nano-delivery systems have been facing problems that need to be solved urgently:clearance of the body's immune system and the inability to effectively target tumor tissue sites.In order to solve these problems,we use PDA as the core and load the hydrophobic anticancer drug 7-ethyl-10-hydroxycamptothecin(SN38).The stem cell membrane camouflaged PDA NPs loaded with SN38(PDA-SN38@SCM NPs)were obtained by co-extrusion for chemo-photothermal treatment of osteosarcoma.After characterizing PDA@SCM NPs,it was verified that SCM was successfully disguised to PDA NPs,and the obtained PDA@SCM NPs had good biocompatibility.The photothermal experiment showed that PDA-SN38@SCM NPs still retained the excellent photothermal effect.The drug release of PDA-SN38@SCM NPs could be triggered by 808 nm near infrared(NIR)radiation and acidic stimulation.The anti-macrophage phagocytosis experiment found that compared with the PDA NPs,macrophages had lower uptake of PDA@SCM NPs.Laser scanning confocal microscope(LSCM)and flow cytometry showed that compared with PDA-SN38 NPs,MG63 cells could uptake more PDA-SN38@SCM NPs.In vivo pharmacokinetics and biodistribution studies showed that compared with PDA NPs,PDA@SCM NPs prolonged the circulation time in the blood,reduced the distribution in the liver,spleen and lungs,and enhanced the ability to target tumor sites.In vitro and in vivo anti-tumor studies have proved that PDA-SN38@SCM NPs have a strong anti-tumor effect under 808 nn NIR and can reduce the amount of chemical drugs and the side effects of photothermal therapy.PDA-SN38@SCM NPs excellent chemophotothermal therapy may become one of the most promising strategies for the treatment of osteosarcoma.(2)Chemotherapy can reduce the number of regulatory immunosuppressive T cells in tumors and provide a favorable immune microenvironment for killing tumor cells.Chemo-immunotherapy,which combines chemotherapy and immunotherapy,is more effective in treating tumors than using one of the therapies alone.We further studied the anti-tumor effects of PDA@SCM NPs in prostate cancer bone metastasis models.We used PDA@SCM NPs to co-deliver the chemotherapy drug doxorubicin(DOX)and programmed cell death ligand 1(PD-L1)siRNA(PDA-DOX/ siPD-L1@SCM NPs)for targeted treatment of prostate cancer bone metastases.We characterized PDA-DOX/siPD-L1@SCM NPs and evaluated the loading of DOX and siRNA.Gene and protein level detection of PDA-DOX/siPD-L1@SCM NPs effectively knocked out PD-L1 in PC-3 cells.LSCM and flow cytometry proved that PDA-DOX/siPD-L1@SCM NPs can target PC-3 cells in vitro.In vivo pharmacokinetics and biodistribution studies have shown that PDA-DOX/siPD-L1 @SCM NPs can effectively prolong blood circulation time and increase tumor accumulation.In vitro and in vivo anti-tumor experiments found that compared with the PDA-DOX/siPD-L1 NPs group,the PDA-DOX/siPD-L1@SCM NPs group had better anti-tumor effects.Therefore,our synthesized PDA-DOX/siPD-L1@SCM NPs is a biomimetic multifunctional nanocomposite for the treatment of prostate cancer bone metastasis,and it can play a good synergistic effect in the chemotherapy and immunotherapy of prostate cancer bone metastasis.In this paper,a nano-drug delivery platform targeting malignant bone tumors is constructed by camouflaging the stem cell membrane on the outside of PDA NPs.After the delivery platform is loaded with different therapeutic molecules,it not only has good biocompatibility,but also can reduce the body's immune clearance,prolong blood circulation time and enhance the ability to target tumor sites.The delivery platform exhibits strong anti-tumor effects in two malignant bone tumor animal models of osteosarcoma and prostate cancer bone metastasis,and provides a powerful treatment method for the treatment of malignant bone tumors.