Design Of Theranostic Raman Nanoprobes For Intraoperative Detection And Eradication Of Residual Tumors

The inability to completely eliminate residual tumors represents a significant challenge in cancer surgery.In many aggressive or metastasis cancers,tumors are poorly demarcated and indistinctly distributed,and tumor growth infiltrates into surrounding crucial organs or neurological structures.In these circumstances,even for an experienced surgeon,it is almost impossible to completely resect these tumors,leaving residual tumors behind.These residual tumors may comprise just tens of cancer cells,but they are sufficient to cause lethal recurrence and metastases.Surface-enhanced Raman scattering(SERS)-based imaging is a novel intraoperative imaging method.It can achieve intraoperative tumor detection with higher specificity and sensitivity than other imaging technologies(e.g.,magnetic resonance imaging,fluorescence,positron emission computed tomography and ultrasound imaging).Because of the “fingerprint” scattering signals of reporter molecules,Raman imaging is capable of specifically distinguishing the reporter molecule-contained tumors from the surrounding normal tissues.The Raman scattering of reporter molecules can be massively amplified by interacting with SERS nanoprobes,allowing for sensitive tumor detection.Previous studies have focused on employing SERS nanoprobes for intraoperative imaging-guided surgical resection of bulk solid tumors with clear boundary,while none of the investigations illustrate its application in intraoperative detection and real-time elimination of unresectable residual tumors.To achieve this goal,the SERS nanoprobes are desirable to possess the following features:(i)ultrahigh sensitivity for delineating the very few residual tumor cells;(ii)simultaneous incorporation of therapeutic functionality without interfering the Raman signals,allowing for intraoperative real-time elimination of the detected residual tumors.Additionally,currently reported SERS nanoprobes are nondegradable and thus they would raise concerns of potential toxicity.To solve this problem,we need to explore new degradable SERS materials for biomedical applications.Herein,we have designed two generations of novel SERS nanoprobes capable of fulfilling these features.The first generation is gap-enhance Raman tags(GERTs)featuring gold core-shell nanostructures,with Raman reporters embedding inside the interior gap junction.The gap junction of GERTs creates a great amount of “hot spots”for ultrahigh sensitivity,thus enabling intraoperatively precise detection of residual tumors.Simultaneously,GERTs elicit strong photothermal transition effect,capable of intraoperative ablation of detected tumors in a real-time manner.The second generation of SERS nanoprobe is designed by degradable Cu S nanoparticles,termed as Cu S SERS.Besides excellent Raman and photothermal performance,Cu S SERS show unique photodegradable properties,and thus they can be disseminated into small clusters upon NIR laser irradiation,facilitating their post-imaging clearance from the tissues.In the orthotopic prostate metastasis tumor model,the two generations of SERS nanoprobes enable precise imaging and real-time ablation of residual malignant lesions around the surgical bed without damaging normal tissues,thus prolonging the survival of the mice.Additionally,Cu S SERS can be dissociated into small particles in tissues,facilitating their self-clearance from imaging tissues.In summary,our study expands the application of SERS nanoprobes towards intraoperatively real-time detection and elimination of residual tumors.Meanwhile,we identify,for the first time,the Raman enhancement effects of Cu S nanoparticles,thus serving as degradable SERS nanoprobes for intraoperative detection and eradication of residual tumors.Our intraoperative strategy for detecting and eradicating residual tumors would broaden the avenues to apply SERS-based bioimaging toward a wide arrange of theranostics-related in vivo applications.