The Application Of Nanomaterials In The Diagnosis And Therapy Of Breast Cancer

With the improvement of the quality of life, people are increasingly aware of the importance of physical health. However, as a serious threat to human life and health, cancer has been a difficult problem for medical and scientific researchers. For women in the world, breast cancer is the highest incidence of cancer. The different subtypes of breast cancer could be real-timely diagnosed and selectively treated which can effectively prolong the patient’s life length and improve the quality of life of patients. Therefore, the research on breast cancer has great practical clinical significance.In recent years, nanomaterials as biological imaging probes and drug carriers have attracted wide attention. The biomedical problems are solved using the characteristics and advantages of nanomaterials which is an emerging discipline-Nano Biomedical. At present, nano biomedical research focuses on two aspects of disease diagnosis and treatment. In this paper, we designed and constructed a fluorescent tracer and drug delivery systems for the screening of different breast cancer subtypes and the treatment of drug-resistant breast cancer. The main contents are as follows:1. Screening of HER2 Overexpressed Breast Cancer Subtype In Vivo by the Validation of High-Performance, Long-Term, and Noninvasive Fluorescence TracerThe high-performance and noninvasive screening of heterogeneous tumor subtypes in vivo is particularly desirable for the diagnosis and symptomatic treatment of cancer. Therefore, we report a near-infrared (NIR) fluorescence tracer "smartly identified HER2" (SI-HER2) for rapid, accurate, and highly specific screening of HER2 overexpressed breast cancer. An antibody against HER2 protein receptor, EP1045Y, was conjugated with NIR emitting CdSeTe/CdS/ZnS QDs via polyhistidine-driven self-assembly approach. The further adsorption of black hole quencher 3 on antibody enabled a "turn on" fluorescence response of the fluorescence tracer to HER2 protein receptor. Aside from the capability of differentiating the HER2 overexpressed MCF-7 cells from its counterparts, the fluorescence tracer can also accurately and rapidly identify the HER2 overexpressed breast tumor subtype in two tumors-bearing mouse model, providing a platform for the investigation of advanced pathways to distinguish the different breast cancer subtypes.2. Tumor-Homing Cell-Penetrating Peptide Linked to Colloidal Mesoporous Silica Encapsulated (-)-Epigallocatechin-3-gallate as Drug Delivery System for Breast Cancer Therapy in VivoChemotherapy uses chemical drugs to prevent cancer cell proliferation, invasion, and metastasis, but a serious obstacle is that chemotherapeutics strikes not only on cancerous cells, but also on normal cells. Thus, anticancer drugs without side effects should be developed and extracted. (-)-Epigallocatechin-3-gallate (EGCG), a major ingredient of green tea, possesses excellent medicinal values, such as anticancer effects, DNA-protective effects, etc. However, EGCG will be mostly metabolized if it is directly orally ingested. Here, we report a drug delivery system (DDS) for loading EGCG to enhance its stability, promising target and anticancer effects in vitro and in vivo. The designed DDS is composed of three main moieties: anticancer drug, EGCG; drug vector, colloidal mesoporous silica (CMS); target ligand, breast tumor-homing cell-penetrating peptide (PEGA-pVEC peptide). Based on the results of CCK-8 assay, confocal imaging, cell cycle analysis, and Western blot, the anticancer effect of EGCG was increased by loading of EGCG into CMS and CMS@peptide. In vivo treatment displayed that CMS had a not obvious influence on breast tumor bearing mice, but CMS@peptide@EGCG showed the greatest tumor inhibition rate, with about 89.66%. H&E staining of organs showed no tissue injury in all experimental groups. All the above results prove that EGCG is an excellent anticancer drug without side effects and CMS@peptide could greatly promote the efficacy of EGCG on breast tumors by targeted accumulation and release, which provide much evidence for the CMS@peptide as a promising and targeting vector for DDS.3. Hyaluronidase-triggered anticancer drug and siRNA delivery from cascaded targeting nanoparticles for drugresistant breast cancer therapyDrug resistance renders standard chemotherapy ineffective in the treatment of connective tissue growth factor (CTGF)-overexpressing breast cancer. By co-embedding the breast tumor cell-penetrating peptide (PEGA-pVEC) and hyaluronic acid (HA) as a targeting media, novel cascaded targeting nanoparticles (HACT NPs) were created on a rattle mesoporous silica (rmSiO2) scaffold for the pinpoint delivery of siRNAs along with an anticancer drug, aiming at overcoming the drug resistance of CTGF-overexpressing breast cancer in vivo. The targeting nanoparticles selectively accumulated in the vasculature under the guidance of the PEGA-pVEC peptide, cascaded by receptor-mediated endocytosis with the aid of another targeting agent, HA, presenting a greater in vivo tumor targeting ability than single targeting ligand vectors. In addition, an HA shell prevented the leakage of therapeutic drugs during the cargo transport process, until the hyaluronidase (HAase)-triggered degradation upon lysosomes entering, guaranteeing a controllable drug release inside the target cells. When the protective shell disintegrates, the released siRNA took charge to silence the gene associated with drug resistance, CTGF, thus facilitating doxorubicin-induced apoptosis. The cascaded targeting media (PEGA-pVEC and HA) advances precision-guided therapy in vivo, while the encapsulation of siRNAs into a chemotherapy drug delivery system provides an efficient strategy for the treatment of drug resistance cancers.4. Self-assembled Nanogel Comprising (-)-epigallocatechin gallate and siRNA for drug-resistant breast cancer therapyGene therapy has the potential to treat various human genomic disorders, especially when it is associated with chemotherapy. However, the species and quantities of carriers should be carefully considered when designing a drug delivery system (DDSs), because the use of high quantities carriers can cause body toxicity as a result of poor metabolism and tissue residue. This issue would be solved if the carrier could be omitted, which means the therapeutic gene directly combine with drug by valence bond to form therapeutic compound. Here, we show that sequential and simple self-assembly of (-)-Epigallocatechin-3-O-gallate (EGCG) with small interfering RNA (siRNA) leads to the formation of a nanogel, which is used to treat drug-resistant three negative breast cancer (TNBC). The nanogel is a core-shell structure which obtained by complexation among siRNA, protamine sulfate and subsequently EGCG form the core, followed by encapsulation of hyaluronic acid (HA) to form the shell. The half-maximal inhibition concentration of nanogel is 10.58 μg/mL in MDA-MB-231 cells (TNBC cells), a 15-fold increase in the cytotoxicity compared with that of free EGCG. Equipped with a specific tumor-targeting ligand, the siRNA- and EGCG-loaded nanogel demonstrates better tumor selectivity and growth reduction than free EGCG in xenograft MDA-MB-231 tumor-bearing mice. Overall, this design strategy provides a versatile method that could be adopted for delivering other drug and therapeutic gene.