Multifunctional Nanoparticles For Photothermal Therapy Of Bone Tumors

Malignant bone tumors are frequenty dignosed and difficult to cure,of which metastatic bone tumors are most common.65-80%of patients with advanced prostate and breast cancer have bone metastases.The incidence of liver cancer,lung cancer,kidney cancer,and bladder cancer is also 30-40%.In addition,malignant bone tumors are accompanied by various complications such as pain,osteolysis,pathological fractures,and hypercalcemia,which cause great suffering to patients and also consume a large amount of medical resources.At present,the methods of clinical treatment of bone tumors include surgical treatment,radiotherapy and chemotherapy.Surgical treatment is the main method of clinical treatment of bone tumors,but surgical treatment cannot remove tiny tumor lesions.Chemotherapy is a commonly used postoperative adjuvant therapy,but chemotherapy has serious toxic and side effects,and it will produce resistance,which leads to the failure of treatment.Most bone tumors are insensitive to radiation,and there is a great risk of radiotherapy in the spine.Therefore,it is very important and urgent to design and develop new bone tumor treatment methods.Photothermal therapy?PPT?is a kind of therapy that uses photothermal materials to convert light energy into heat energy,and kills tumor cells by local overheating and its secondary effects.Photothermal therapy has been considered as a very promising cancer treatment method,because it can control the time and space of treatment,and avoid the damage of non-target areas.It has been successfully applied to treat various tumors.The U.S.Food and Drug Administration has approved a phase II clinical study of photothermal therapy?Auro Lase?Therapy?for head and neck cancer and metastatic lung cancer.However,photothermal therapy has some problems in the treatment of bone tumors.Photothermal nanoparticles provide low concentration efficiency in bone tumors by way of system administration.As a result,local temperature does not reach the level of killing tumor cells.Even if the photothermal nanoparticles have been modified tumor targeting molecules on the surface,the enrichment rate is still less than10%at bone tumors.If the dosage of nanoparticles is to be increased,it may cause toxic and side effects.If the laser power is to be raised,it will produce an inflammatory response,causing serious damage to the healthy tissue.Based on the above issues,this paper aims to design and develop a series of bone-targeted photothermal nanoparticles for solving the difficulties in photothermal therapy of bone tumors.The specific research contents are as follows:?1?The target study of bone tumor is still in a very primary stage,and there is no molecule that can target bone tumors directly.Due to the vicious circle between the bone tumors and the bone marrow microenvironment,there are a large number of bone resorption interfaces at the bone tumors.We modified bone-targeting peptide?Asp?₈that could target bone resorption interfaces on the surface of photothermal nanoparticles.The binding rate of modified?Asp?₈ photothermal nanoparticles and hydroxyapatite increased by 14 times than?Gly?₈ photothermal nanoparticles without bone targeting effect in vitro.In vivo,bone targeted photothermal nanoparticles accumulated more efficiently in bone tumors than the non-targeted group,making the temperature of photothermal treatment up to about 8?.The bone targeted photothermal nanomaterials could be effectively enriched in bone tumor areas by systematic administration.Asp-DPCN-mediated photothermal therapy not only effectively inhibited the growth of osteoclasts,but also reduced the destruction of bone by tumors.?2?Individual photothermal treatment of bone tumors requires higher temperatures,whereas hyperthermia treatment temperatures?above 45°C?can lead to cell necrosis.In contrast,mild photothermic treatment temperature?42-45°C?can make tumor cells sensitive to many chemotherapeutic drugs.Photothermal therapy combined with chemotherapy can significantly improve the efficacy of photothermal therapy.Therefore,we designed a kind of bone-targeted photothermal nanomaterials loading chemotherapy drugs on the surface.The chemo-photothermal therapy?CPT?in bone tumor areas could inhibit the growth of bone tumors at mild temperature.Experiments show that alendronate-anchored polydopamine nanoparticle loaded with anticancer drugs 7-ethyl-10-hydroxycamptothecin?SN38?on the surface was more effective in inhibiting tumor growth compared with photothermal therapy alone.The fluorescence of bone tumors remained unchanged before and after CPT,however it increased by 5.5 times after PPT.Moreover,CPT can more effectively reduce bone tumors damage to bone.?3?Chemo-photothermal therapy can inhibit bone tumor growth under mild temperature conditions.However,chemotherapy has serious toxic and side effects,and it will produce drug resistance.The vicious circle between bone tumor and bone marrow microenvironment has always been a difficult point in the treatment of bone tumors.In order to break the vicious cycle and maximize osteolysis inhibition in the treatment of bone tumors,we designed bone-targeted photothermal nanomaterials loading with an autophagy inhibitor on the surface for inhibiting osteoclast differentiation and maturation in the bone marrow microenvironment.The autophagy inhibitor chloroquine could enhance the sensitivity of photothermal therapy by inhibiting autophagy in tumor cells during PPT,thereby inhibiting the growth of bone tumors at moderate temperatures.At the same time,chloroquine could also inhibit osteoclast differentiation,osteoclast activity and osteolysis in the bone tumor region.Under the joint action of two aspects,the vicious circle between the bone marrow microenvironment and the tumor was broken down,osteolysis in the bone tumor area was reduced,and bone integrity was preserved to the greatest extent.In this thesis,photothermal therapy had opened up a very promising therapy for the treatment of bone tumors by modifying the bone-targeting molecules on the surface of nanoparticles.In addition,photothermal therapy mediated by nanoparticles loading with chemotherapy drugs or autophagy inhibitors,inhibit the growth of bone tumors under mild photothermotherapy conditions.This alleviated photothermal therapy damage to normal tissues and could effectively inhibit osteolysis in the bone tumor area.