Intraoperative Diagnosis and Eradication of Tumors with Gap-enhanced Raman Tags

Author:Zhang Yu Qing

Supervisor:ye jian


Degree Year:2018





Malignant tumors have become one of the leading causes of death in the world.The traditional treatment is based on surgical resection,supplemented by drug therapy,physiotherapy and other comprehensive treatment methods.However,the borders of many malignant tumors are irregular and fuzzy,showing invasive growth or distant metastasis,which makes it difficult to remove all tumor foci by surgical treatment.At present,intraoperative imaging methods include intraoperative MRI,ultrasound and fluorescence imaging,but all methods have certain defects.Postoperative radiotherapy and chemotherapy for residual tumors will cause significant side effects to patients.Taking into account the above two aspects of intraoperative and postoperative treatment,there is an urgent need for new theranostics methods that can rapidly recognize and treat resectable or unresectable tumor lesions during surgery.Therefore,in this dissertation,we designed Gap-Enhanced Raman tags(GERTs)with strong surface-enhanced Raman scattering(SERS)and ultraphotostability as a theranostic probe for tumors.The probes are used in tumors of different types to achieve detection and elimination of residual tumors quickly,accurately,with high sensitivity,high resolution,and high specificity during surgery.In Chapter 2,we investigated the performance of GERTs and assessed its biomedical application potential.Using the off-resonance near-infrared laser excitation,the embedded BDT molecules were well protected by the solid metallic shell and mesoporous silica coating during laser irradiation,and can achieve ultraphotostability.Significantly,GERTs exhibited strongRaman signals by combining chemical and electromagnetic enhancement effects,so that sensitive and fast SERS-based cell and tumor imaging can be achieved.More specifically,GERTs exhibited high storage,pH,serum,and photostabilities;strong Raman signals;and favorable biocompatibility.Thus,they were particularly suitable for high-speed,long-term,and real-time bioimaging under the continuous laser irradiation.In Chapter 3,we used GERTs for high-contrast sentinel lymph nodes(SLNs)Raman imaging.SLNs imaging based on GERTs has many advantages compared to the blue dyes commonly used in clinical practice,including strong Raman enhancements,high photostability,super-long retention time(up to 24 h)in the SLNs,easy usage(injection 2 h prior to surgery),and large imaging depth(up to 2 mm).We also studied dynamic migration behavior of GERTs towards the SLNs: partially entering the SLNs 2 h after injection and staying there for 24 h,leaving sufficient time to perform surgery.Moreover,the location of SLNs could be realized via a cost-effective commercial portable Raman scanner.Therefore GERTs-based Raman spectroscopy technique exhibits great potential for intraoperatively pinpointing the SLNs more accurately.In Chapter 4,we further studied the photothermal conversion capabilities of GERTs,and explored the feasibility of GERTs based Raman imaging guided intraoperative real-time diagnosis and eradication of residual microtumors.The results showed that GERTs can identify the infiltrative tumor margins and microscopic satellite metastases ultrasensitively and specifically,and then eliminate them with photothermal therapy.This strategy for intraoperative diagnosis and treatment of residual tumors reduces the possibility of existence of residual tumors and the side effects of postoperative radiotherapy and chemotherapy.These findings highly facilitate the utilization of GERTs as a robust platform for residual microtumor-complicated surgeries,helping to achieve complete removal of residual tumors.In Chapter 5,in order to diagnose and treat unresectable and disseminated tumor foci,we presented cisplatin-loaded GERTs(C-GERTs)for intraoperative Raman-guided synergistic chemo-photothermal therapy of multiple lesions of advanced ovarian cancer.Both in vitro and in vivo results demonstrated C-GERTs-based chemo-photothermal therapy could better inhibit tumors and prolong survival of mice.Thanks to the unique Raman signal of the probe,we could detect microtumors with a diameter of only 1 mm in the experiment.C-GERTs are particularly suitable for advanced ovarian cancer which has multiple tumor foci.C-GERTs based detection can not only discover most of the lesions,but also enable the localized chemo-photothermal therapy to minimize the damage to normal tissues.