Multimodoal Therapies Of Triple Negative Breast Cancer Based On Single-walled Carbon Nanohorns

Triple-negative breast cancer has high metastatic and recurrence-prone properties,resulting in poor prognosis and high risk of death.The intrinsic limits of conventional cancer therapies promote the development and application of various nanotechnologies for more effective and safer cancer treatment.However,the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the heterogeneity and complexities of tumor biology and the incomplete understanding of nano-biology interactions.A growing number of clinical trials have shown that a single traditional treatment model is difficult to effectively eradicate triple-negative breast cancer.Therefore,multi-modal synergistic therapies based on nanomaterials have received widespread attention in clinical trials.The unique physical and chemical properties of nanomaterials show great promises in clinical translation,which not only serve as a drug carrier to strengthen traditional therapies?combined drug delivery,combined radiotherapy with chemotherapy?,but also introduce some emerging treatment methods?photodynamic therapy and photothermal therapy?.This combination of conventional treatment with novel therapies show a strong inhibitory effect on primary tumors,however,they always play a powerless role in tumor metastases and recurrence.Immunotherapy has been proved to have great promises in cancer treatment,and once further combined with phototherapy,they would demonstrate strong pre-clinical promise to treat metastatic cancers.Therefore,the combination of nanotechnology and immunotherapy,which not only retains the inherent characteristics of nanomaterials,but also stimulates immune responses,could efficiently eradicate tumor metastases and prevent cancer recurrence.Therefore,nanomaterials can play a role to enhance the specific effects of both immunotherapeutic and phototherapeutic approaches for cancer treatments simultaneously.Based on the above background,we systematically research the therapeutic efficiency of single-walled carbon nanohorns?SWNHs?-based nanomaterials in spontaneous 4T1 metastasis models.The SWNHs-based versatile system is first designed to enhance conventional chemotherapies.When appropriate photosensitizer is loaded,the SWNHs system could both serve as photodynamic therapy?PDT?agent and photothermal therapy?PTT?agent.In vivo results indicated that both chemotherapy-PTT and PDT-PTT exhibited synergistic anti-tumor effects in 4T1 tumor-bearing animal model.And we further explore the mechanism of synergistic immune effects introduced by the two phototherapy modalities.In chapter 2,we designed a highly potent theranostic platform,doxorubicin?DOX?and cisplatin dual chemo-drug-loaded SWNHs,termed as SWNHs/C₁₈PMH/mPEG-PLA-DOX-Pt.Above-mentioned SWNHs system was developed for photoacoustic imaging?PAI?-guided chemo-photothermal combination antitumor therapy.SWNHs were first modified simultaneously with poly?maleic anhydride-alt-1-octadecene?(C₁₈PMH)and methoxypolyethyleneglycol-b-poly-D,L-lactide?mPEG-PLA?to form a"high-low"hierarchy surface structure.DOX and cisplatin were sequentially loaded onto the modified nanohorns in a noninterfering way.The dual chemo-drug-loaded SWNHs demonstrated pH-sensitive,tandem and sustainable drug release,and exerted both dual drug chemotherapeutic and chemo-photothermal synergistic antitumor effects.Notably,SWNHs-based nanosystem had a long blood half-life?10.9 h?in vivo and could simultaneously target both primary tumors and their lung metastases after intravenous administration.Consequently,chemo-photothermal combination therapy guided by PAI completely ablated the primary tumors and simultaneously eradicated the metastatic lung nodules.In chapter 3,we disclosed a simple synthesis method of nanoplatforms which combined PDT with PTT strategies,namely,the system was prepared by the coating of dual amphiphilic polymers and followed by loading with the photosensitizer chlorin e6?Ce6?on the SWNHs.Efficient tumor-homing effect and the potential to penetrate into the tumor were proved by enhanced NIR-II photoacoustic and optical imaging.As-prepared SWNHs nano complex under 650 nm and 808 nm excitation could successively trigger ROS?PDT?and hyperthermia?PTT?destruction of primary tumors.Meanwhile,the release of tumor-associated antigens,damage associated molecular patterns?DAMPs?and cell debris with the assistance of SWNHs nano-vehicle could trigger a synergistic antitumor immune response to effectively eliminate both irradiated tumors and metastases.Furthermore,such the cancer immunotherapy strategy showed a strong long-term immune memory effect to protect the cured mice against pathogens rechallenge.In chapter 4,we systematically explained the action mechanism of synergistic host immune response triggered by combination PDT with PTT.Specifically,diversity and multi-sources of DAMP formation induced by PDT/PTT provided a promising synergistic way for stimulating the host immunotherapy.With the assisted of SWNHs nano adjuvant,combined photo-immunotherapy?PIT?could be considered as personalized tumor therapies.An overall consideration of the activation path of the immune cycle in vivo,we could comprehensive understanding of the actions for SWNHs-strengthened the immune response.First,prominent therapeutic efficiency caused by locally PIT was benefited from the nanosystem efficiently targeted tumors via long blood circulation time?18.9 h?.Then sufficient elements caused cells to die through necrosis,which the cell rapidly lost membrane integrity,or apoptosis,which programmed cell death was triggered.Second,ICD induced by different approaches gave rise to a wide variety of immune antigen releasing.What?s more,SWNHs-based nanosystem both as an immune adjuvant and a container which could capture these antigens to enlarge the recognition of antigen presenting cells?APCs?.Third,APCs,such as DCs,not only was quickly recruited into the tumor and efficiently matured in a short time,but also maintained this state supported by SWNHs-contained tumor antigens migrating from tumor to lymph node at a longer time.In return,more cytotoxic lymphocyte?CTLs?were recruited into the distant tumor without photo treatment.Finally,robust and sustainable immune effects occurred the abscopal effect on suppressing the distant metastatic.It is worth noting that,the systemic synergistic immune response induced by locally PDT with PTT based SWNHs nanosystem was to be demonstrated for the first time in vivo in this study.In conclusion,SWNHs system exhibited high biocompatibility and could simultaneously target to the primary breast cancer tumors and lung metastases in vivo.A systemic immune response was induced based on enhanced local phototherapy of the primary tumor under the premise of stimulation and regulation of multiple aspects in the immune cycle.Then the enhancement of photo-immune therapy introduced by SWNHs nanosystem successfully inhibit the formation of spontaneous lung metastases and re-invasion of cancer cells without the addition of additional immune adjuvants.These new insights provide a simple and potent treatment for triple-negative breast cancer in clinical.