Synthesis Of Bone-Targeted Nanoparticles And Their Application In The Therapy Of Malignant Bone Tumors

The incidence of bone metastasis is steadily increasing owing to the extended survival in cancer patients.Bone metastasis occurs in 30-80% of patients with cancer,and up to 65-80% of patients with advanced breast and prostate cancers are diagnosed with bone metastasis.Once cancer cells metastasize to bone and form malignant bone tumors,a vicious cycle between bone and tumor cells will be established under the control of bone microenvironment.Devastating consequences,such as osteolysis,hypercalcaemia,pathological fractures,considerable pain,and nerve compression may occur,greatly reducing patients’ quality of life,diminishing the possibility of cure,even causing death.There still remains a formidable challenge in clinical therapy of bone tumor.Surgical resection is the main therapy currently,but fails to clear the multiple focal lesions of bone tumors.The chemotherapies and radiotherapies are always troubled with bone marrow microenvironment-associated therapeutic resistance,achieve poor therapeutic outcomes,cause adverse effects to the patients.A large number of targeted agents have been developed to improve the therapuetic efficacy of malignant bone tumors by researchers.Orthotopic and metastatic bone tumors can be treated with these tumor targeted or bone targeted nanoparticles for chemotherapy,photothermal therapy,gene therapy and combination therapy.However,there still remains some disadvantages between them.Firstly,bone targeting moieties need to be decorated on the surface of nanoperticles by extra reaction,making the synthesis process of these nanoparticles sophisticated.Moreover,the literature-reported bone targeting moieties only includes bisphosphonates,aspartic acid-related oligopeptides and aptamers.They are either involved with complex syntheses or troubled by safety issues,resulting their limited application.Meanwhile,most of targeting nanoparticles can only bind to bone surfaces or bone tumor cells.Tumor eclls targeted nanoparticles fail to gather on the tumor sites by enhanced permeability and retention(EPR)effect due to the lack of circulating systems in skeletal tissues,and bone targeted nanoparticles can not escape from the bone,making them fail to increase the accumulation of therapeutic angets in the tumors.Therefore the application of these targeting agents in the therapy of bone tumors are limited.Based on the above isuues,three moieties were introduced to help the fabrication of three nanoparticles with inherent bone targeting capacity via facile reduction reaction or simple formulation in this dissertation.Experiment in vitro and in vivo demonstrated their therapeutic efficacy to bone tumors.Detailed methods and results are summarized as follows:(1)Platinum nanoparticles with ultrasmall size were synthesized in the hollow interior of carboxyl-terminated dendrimer via a simple reduction reaction to obtain the bone targeting nanoparticles.The plentiful carboxyl groups on the dendrimer surface endowed them the strong bone-binding ability.There is no need to decorate extra bone targeting moieties on the nanoparticles surfaces.They represented high affinity to hydroxyapatite and bone fragments in vitro,and were able to selectively recognize the osteolytic bone lesions in vivo.The accumulation of these nanoparticles in the tumorbearing tibias was 10 times than in the healthy ones.When using these bone targeting nanoparticles for photothermal therapy,the temperature of tumor sites rapidly increased to the therapeutic level under the irradiation of a near-infrared light(NIR)laser.And finally the bone tumors growth and tumor-associated osteolysis were regressed.Moreover,these bone targeting nanoparticles had low toxicity to blood cells and main organs of mice,maintained an excellent biocompatibility(2)PA-coated platinum nanoparticles were synthesized by reducing chloroplatinic acid with SC in the presence of PA to obtain the bone targeting nanoparticles.There is also no need to decorate extra bone targeting moieties on the nanoparticles surfaces,PA significantly enhanced the amount of nanoparticles bound on hydroxyapatite and increased their accumulation at the tumor-bearing bone lesions by 5 times.Pt NPs in the nanoparticles had excellent photothermal effect and can be used for efficient photothermal therapy of malignant bone tumors.PA above on the nanoparticles made them possess inherent anticancer activity and be a remarkable nanoplatform for targeted combination therapy of bone tumors.The therapeutic results in vivo showed that the combination therapy associated by the nanoparticles efficiently suppressed bone tumors and reduced osteolysis.(3)The bone targeting nanoparticles were obtained by two steps.First,boronate-rich dendrimer(GP)mixed with saporin in distilled water to form binary complexes and then Poly-(α,β)-DL-aspartic acid peptides(PASP)were added into the the complex solution to obtain ternary nanoformulations.The nanoparticles also contained no added bone targeting moieties on the surfaces.PASP endowed them high binding affinity to hydroxyapatite and bone fragment in vitro,and enhanced their accumulation at tumorassociated bone lesions for 48 h.When the nanoparticles accumulated at the bone tumor sites,PASP could be protonated by the acidic extracellular compartment in the tumor tissues,and then detached from the ternary nanoformulation surfaces,thus exposing the binary complexes for protein therapy of bone tumors.The protein therapy conducted by the bone targeting nanoparticles could not only suppress the orthotopic bone tumors,but also the metastatic ones,and finally restrained the osteolysis induced by bone resorption and decreased the bone damage.