Targeted Nano-bioconjugates For The Study And Application In Image, Diagnoses, Drug Transportation And Therapy Of Cancer Cell

Malignant tumor (cancer) has a reputation as a deadly disease, and successful cure of most cancers depends on early detection and timely treatment. It is difficult to discover tumor in the early stage, because of the relatively low sensitivity and specificity of conventional diagnostic methods. Usually, the undetected metastasis has already occurred in patients before initial diagnosis, which leads to missing the opportunity to cure disease. Although the clinical arsenal in treating cancer has been greatly extended in recent years with the application of new drugs and therapeutic modalities, the three main approaches still to be surgical resection, radiation, and chemotherapy. Most research focus on how to improve the efficacy of chemotherapy which is a promising approach in cancer therapy. The challenges encountered by chemotherapy make it still difficult to achieve the desired therapeutic effect, including untargeted transport, serious side effects on healthy tissue and drug resistance. Therefore, it is significant to develop simple, sensitive and effective detection approaches and targeted, safe, effective antitumor drugs system for cancer diagnosis and therapy.Fluorescent probes and drug carriers based on nano-materials has been widely used in biochemistry, especially in imaging diagnosis and treatment of cancer. The gold nanoparticle (AuNP) has an extraordinary intracellular stability and biocompatibility that makes it useful for intracellular imaging, molecular diagnostics and drug delivery. AuNP-based probes and drug carriers has been widely reported. However, most current probes detect usually a single tumor marker, which often result in "false positive" results for cancer diagnosis. The realease of drug from delivery carrier lacks the consistent correlations with tumor progression and usually results in unpredictable release, resulting in serious side effects. In addition, the single traditional therapy can not achieve satisfactory therapeutic effects. Thus, sensitive and specific fluorescent probes for simultaneous detecting several tumor markers, controlled and targeted drug carrier and combined antitumor therapy have become research focus in the field of cancer diagnosis and therapy.In this study, based on the biocompatible AuNP, molecular beacon (MB), antitumor Doxorubicin (Dox), the gold nanorod (GNR) and photosensitizer (PS), we developed a series of fluorescent nanoprobes and drug nano-carriers for cancer diagnosis and therapy as follows:1. We demonstrated an effective and controlled drug carrier for the delivery of Dox based on AuNP-MB. It could target cyclin D1 mRNA, which is a tumor mRNA of breast cancer. When MB bound selectively to cyclin D1 mRNA, fluorescent Dox released effectively from AuNP–MB(Dox) and induced apoptosis, which occurred in breast cancer cells (cyclin D1+) but not in normal cells (cyclin D1-). Significantly, the release of Dox was correlated positively with the quantities of tumor mRNA. This drug carrier released Dox according to various stages of tumor progression in a controlled manner which could decrease effectively side effects of Dox.2. Based on AuNP and bi-MB, we developed a bi-color fluorescence imaging agent AuNP-bi-MB to detect simultaneously intracellular tumor mRNAs in breast cancer. The AuNP was assembled with bi-MB which targeted specifically to two kinds of tumor mRNAs. This novel approach could prevent effectively"false positive"results and provide comprehensive and dependable information for early detection of cancer compared with single tumor mRNA testing. It would be beneficial to identify the stage of tumor progression and assess treatment decisions by real-time detection of relative expression level of tumor mRNAs in cancer cells.3. Based on GNR, MB and PS, we developed a light-triggered drug nano-carrier GNR-MB-Ce6 targeting survivin mRNA which is a tumor mRNA of breast cancer. GNR-MB-Ce6 was assembled by Ce6-labeled MB and GNR. GNR-MB-Ce6 could detect survivin mRNA and be used in cancer cell imaging. Under the irradiation of NIR light, Ce6 generated singlet oxygen as photodynamic theray (PDT) agent, GNR generated photothermal effect and damage cancer cell. Combination of PDT and photothermal effect could induce effectively apoptosis in cancer cell and avoid the limitations of single therapy.