Mussel-inspired Biomimetic Nanoplatform For Enhance Photothermal Treatment Against Breast Cancer

The cure of cancer has always been one of the biggest challenges in modern medicine.Compared to traditional cancer treatment,photothermal therapy（PTT）has been recognised as one of the most promising cancer treatment methods in recent years.The PTA can be used to treat tumours by converting the absorbed light energy into thermal energy.PTT uses a photothermal conversion nano-material（PTA）with strong absorption in the near infrared（NIR）region,which effectively converts the absorbed light energy into heat energy under the irradiation of the NIR laser,causing the local tumour tissue to increase in temperature and thus leading to tumour cell degeneration and necrosis,thus achieving the purpose of tumour treatment.PTT is also known as“green therapy”due to its advantages of rapid targeted killing,minimal invasiveness and minimal toxic side effects,and has great potential as an alternative to surgical excision.However,tumour cells can increase cell viability and resistance to heat damage through upregulation of heat shock proteins（HSPs）,resulting in acquired heat resistance in cells,leading to reduced efficacy and poor prognosis of PTT.HSPs are a group of highly conserved chaperone proteins induced by various environmental or pathophysiological stresses in which they not only protect cells from heat stress injury but also inhibit PTT and chemotherapy-mediated apoptosis by directly inhibiting Caspase-3 activation.Therefore,down-regulation of HSPs can effectively enhance the efficacy of therapies such as PTT and chemotherapy.In recent years,many new nanomaterials have been developed as PTAs for photothermal therapy of tumors,however,most PTAs are still difficult to achieve clinical application due to their easy aggregation,poor photostability and high toxic side effects.Therefore,the selection of suitable PTAs is crucial to improve the efficacy of PTT.Dopamine is a mussel mucin-inspired melanin mimetic that can self-assemble to form polydopamine（PDA）nanoparticles under alkaline conditions.Compared to conventional PTAs,PDA is biocompatible,biodegradable and biosafe and can respond to one or more external stimuli,making it a promising nanoplatform for drug delivery and PTT.In the chapter two of this thesis,we have used the stimulus responsiveness,differential adsorption to single/double-stranded DNA and fluorescence quenching properties of PDA to synthesise PDA-engineered nanomolecular beacons（D/CP-MB）for the fluorescence detection of intracellular HSP90 m RNAs and fluorescence imaging-guided NIR-triggered chemo-photothermal enhanced therapy.In this theranostics nanobeacon,HSP90 MBs not only detect intracellular HSP90 m RNAs by fluorescence,but also down-regulate HSP90 expression and reduce cellular heat resistance.With the guidance of fluorescence imaging and the assistance of NIR,the photothermal effect can be achieved by triggering the spatio-temporal release of chemotherapeutic agents（DOX）,thus enabling precise combined chemotherapy and photothermal treatment.In addition,the dual photothermal effect of the hollow mesoporous copper sulphide（HCu S）core and the PDA allows for better photothermal performance.In vitro and in vivo experiments demonstrated that D/CP-MB nanobeacons significantly inhibited tumor proliferation and enhanced apoptosis both in vitro and in vivo compared to other controls,thus demonstrating highly effective chemo-photothermal enhancement of the therapeutic effect.In summary,this work provides novel theranostic nanobeacons that integrate imaging and therapy in a single nanoparticle,this strategy of imaging-guided therapy can enable precise tumor treatment and effectively improve tumor treatment efficacy.Based on the first system,and in order to better down-regulate the expression of HSPs,in Chapter three of this thesis we have developed a stimulated detonation bionic“nanobomb”for gas-photothermal enhanced treatment of breast cancer,the developed nanoplatform can down-regulate the expression of HSP90 in breast cancer cells through the release of HSP90 inhibitors and gas treatment-mediated mitochondrial dysfunction.This nanoplatform was fabricated by the load of manganese carbonyl（Mn CO,CO donor）in dendritic mesoporous silicon（DMS）,followed by the coating with PDA,and loading of epigallocatechin gallate（EGCG,HSP90 inhibitor）.Upon NIR irradiation,the photothermal effect of PDA not only induces apoptosis of tumor cells but also triggers the controlled drug release of Mn CO and EGCG.Moreover,the acidity and H₂O₂-rich tumor microenvironment can render the degradation of released Mn CO,followed by triggering the release of CO gas.CO-initiated gas therapy can realize to disrupt the mitochondrial function,which can accelerate cell apoptosis and downregulate HSP90expression by decreasing intracellular ATP.The combination of EGCG and Mn CO effectively can reduce the thermo-resistance of tumor and improve the PTT sensitivity.In addition,the released Mn²⁺enables T₁-weighted magnetic imaging of tumors.The nanoplatform’s anti-breast cancer efficacy was systematically evaluated and validated in vitro and in vivo.In summary,this thesis has developed two PDA-based bionanoplatforms for enhancing the therapeutic effect of PTT on tumors.In vitro and in vivo experiments have demonstrated that both bionanoplatforms can effectively enhance the therapeutic effect of PTT on breast cancer.The construction of these two nanotherapeutic systems provides new ideas and insights into the use of PDA-based bionanoplatforms for enhancing the efficacy of PTT in breast cancer.