Bispecific fibrous glue synergistically boosts vascular normalization and antitumor immunity for advanced renal carcinoma therapy.

Immune checkpoint blockade therapy represented by programmed cell death ligand 1 (PD-L1) inhibitor for advanced renal carcinoma with an objective response rate (ORR) in patients is less than 20%. It is attributed to abundant tumoral vasculature with abnormal structure limiting effector T cell infiltration and drug penetration. We propose a bispecific fibrous glue (BFG) to regulate tumor immune and vascular microenvironments simultaneously. The bispecific precursor glue peptide-1 (pre-GP1) can penetrate tumor tissue deeply and self-assemble into BFG in the presence of neuropilin-1 (NRP-1) and PD-L1. The resultant fibrous glue is capable of normalizing tumoral vasculature as well as restricting immune escape. The pre-GP1 retains a 6-fold higher penetration depth than that of antibody in the multicellular spheroids (MCSs) model. It also shows remarkable tumor growth inhibition (TGI) from 19% to 61% in a murine advanced large tumor model compared to the clinical combination therapy. In addition, in the orthotopic renal tumor preclinical model, the lung metastatic nodules are reduced by 64% compared to the clinically used combination. This pre-GP1 provides a promising strategy to control the progression and metastasis of advanced renal carcinoma.

Inducing mitochondriopathy-like damages by transformable nucleopeptide nanoparticles for targeted therapy of bladder cancer.

Mitochondriopathy inspired adenosine triphosphate (ATP) depletions have been recognized as a powerful way for controlling tumor growth. Nevertheless, selective sequestration or exhaustion of ATP under complex biological environments remains a prodigious challenge. Harnessing the advantages of in vivo self-assembled nanomaterials, we designed an Intracellular ATP Sequestration (IAS) system to specifically construct nanofibrous nanostructures on the surface of tumor nuclei with exposed ATP binding sites, leading to highly efficient suppression of bladder cancer by induction of mitochondriopathy-like damages. Briefly, the reported transformable nucleopeptide (NLS-FF-T) self-assembled into nuclear-targeted nanoparticles with ATP binding sites encapsulated inside under aqueous conditions. By interaction with KPNA2, the NLS-FF-T transformed into a nanofibrous-based ATP trapper on the surface of tumor nuclei, which prevented the production of intracellular energy. As a result, multiple bladder tumor cell lines (T24, EJ and RT-112) revealed that the half-maximal inhibitory concentration (IC50) of NLS-FF-T was reduced by approximately 4-fold when compared to NLS-T. Following intravenous administration, NLS-FF-T was found to be dose-dependently accumulated at the tumor site of T24 xenograft mice. More significantly, this IAS system exhibited an extremely antitumor efficacy according to the deterioration of T24 tumors and simultaneously prolonged the overall survival of T24 orthotopic xenograft mice. Together, our findings clearly demonstrated the therapeutic advantages of intracellular ATP sequestration-induced mitochondriopathy-like damages, which provides a potential treatment strategy for malignancies.

An adhesive peptide specifically induces microtubule condensation.

Cell function-associated biomolecular condensation has great potential in modulation of molecular activities. We develop a microtubule-trapping peptide that first self-assembles into nanoparticles and then in situ transforms into nanofibers via ligand-receptor interactions when targeted to tubulin. The nanofibers support the increased exposed targets for further adhering to microtubules and induce the self-assembly of microtubules into networks due to multivalent effects. Microtubule condensation with prolonged retention in cells for up to 24 h, which is 6 times longer than that of the non-transformable nanoparticle group, efficiently induces in vitro cell apoptosis and inhibits in vivo tumour growth. These smart transformable peptide materials for targeted protein condensation have the potential for improving retention and inducing cell apoptosis in tumour therapy.

An activated excretion-retarded tumor imaging strategy towards metabolic organs.

Intraoperative fluorescence-based tumor imaging plays a crucial role in performing the oncological safe tumor resection with the advantage of differentiating tumor from normal tissues. However, the application of these fluorescence contrast agents in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) was dramatically hammered as a result of lacking active targeting and poor retention time in tumor, which limited the Signal to Noise Ratio (SNR) and narrowed the imaging window for complicated surgery. Herein, we reported an activated excretion-retarded tumor imaging (AERTI) strategy, which could be in situ activated with MMP-2 and self-assembled on the surface of tumor cells, thereby resulting in a promoted excretion-retarded effect with an extended tumor retention time and enhanced SNR. Briefly, the AERTI strategy could selectively recognize the Integrin αvß3. Afterwards, the AERTI strategy would be activated and in situ assembled into nanofibrillar structure after specifically cleaved by MMP-2 upregulated in a variety of human tumors. We demonstrated that the AERTI strategy was successfully accumulated at the tumor sites in the 786-O and HepG2 xenograft models. More importantly, the modified modular design strategy obviously enhanced the SNR of AERTI strategy in the imaging of orthotopic RCC and HCC. Taken together, the results presented here undoubtedly confirmed the design and advantage of this AERTI strategy for the imaging of tumors in metabolic organs.

In Situ Constructed Nano-Drug Depots through Intracellular Hydrolytic Condensation for Chemotherapy of Bladder Cancer.

Intravesical administration of first-line drugs has shown failure in the treatment of bladder cancer owing to the poor tumor retention time of chemotherapeutics. Herein, we report an intracellular hydrolytic condensation (IHC) system to construct long-term retentive nano-drug depots in situ, wherein sustained drug release results in highly efficient suppression of bladder cancer. Briefly, the designed doxorubicin (Dox)-silane conjugates self-assemble into silane-based prodrug nanoparticles, which condense into silicon particle-based nano-drug depots inside tumor cells. Significantly, we demonstrate that the IHC system possesses highly potent antitumor efficacy, which leads to the regression and eradication of large established tumors and simultaneously extends the overall survival of air pouch bladder cancer mice compared with that of mice treated with Dox. The concept of intracellular hydrolytic condensation can be extended via conjugating other chemotherapeutic drugs, which may facilitate rational design of novel nanomedicines for augmentation of chemotherapy.

The Harbin Medical University nephrectomy score: a quantitative system for evaluating the complexity of laparoscopic retroperitoneal simple nephrectomy.

BACKGROUND: Laparoscopic retroperitoneal simple nephrectomy (LRSN) has been widely accepted as a mainstay option for benign non-functioning kidney. The complexity of the procedure, however, differs and remains a subject of controversy. OBJECTIVE: To develop a standardised Harbin Medical University nephrectomy score (HMUNS) system for evaluating LRSN complexity. SUBJECTS AND METHODS: A total of 6 variables with different factors comprising primary diseases, history of upper urinary tract surgery, body mass index (BMI), surgeon's learning curve, kidney volume, and Mayo Adhesive Probability (MAP) scores were included in the HMUN score. 95 consecutive patients who underwent LRSN at our institution were divided into low (2 to 6 points) and high (7 to 17 points) complexity groups with HMUNS and investigated the differences of operative time (OT), estimated blood loss (EBL), postoperative hospitalisation time (PHT), rate of intraoperative conversion to open surgery, and the Clavien-Dindo classifi cation (CDC) between both groups. RESULTS: Longer mean operative times (193.2±69.3 min vs. 151.9±46.3 min, p <0.05), more median estimated blood loss (100.0mL vs. 50.0mL, p <0.05), and higher rates of conversion to open surgery (1.2% vs. 25%, p <0.05) were observed in the high-complexity group (n=12) than in the low-complexity group (n=83). However, there were no remarkable differences between the two groups related to the baseline characteristics, post-surgical hospitalisation times, and postoperative complications. CONCLUSIONS: The HMUNS can effectively reflect LRSN complexity, thus providing a quantitative system for risk estimation and treatment decisions. Because of some limitations, further well-designed studies are necessary to confirm our fi ndings. Patient summary: The HMUNS, including primary diseases, history of upper urinary tract surgery, BMI, surgeon's learning curve, kidney volume, and MAP score, can provide an effective quantitative tool to evaluate the complexity of LRSN.

The Harbin Medical University nephrectomy score: a quantitative system for evaluating the complexity of laparoscopic retroperitoneal simple nephrectomy

ABSTRACT Background: Laparoscopic retroperitoneal simple nephrectomy (LRSN) has been widely accepted as a mainstay option for benign non-functioning kidney. The complexity of the procedure, however, differs and remains a subject of controversy. Objective: To develop a standardised Harbin Medical University nephrectomy score (HMUNS) system for evaluating LRSN complexity. Subjects and methods: A total of 6 variables with different factors comprising primary diseases, history of upper urinary tract surgery, body mass index (BMI), surgeon's learning curve, kidney volume, and Mayo Adhesive Probability (MAP) scores were included in the HMUN score. 95 consecutive patients who underwent LRSN at our institution were divided into low (2 to 6 points) and high (7 to 17 points) complexity groups with HMUNS and investigated the differences of operative time (OT), estimated blood loss (EBL), postoperative hospitalisation time (PHT), rate of intraoperative conversion to open surgery, and the Clavien-Dindo classification (CDC) between both groups. Results: Longer mean operative times (193.2±69.3 min vs. 151.9±46.3 min, p <0.05), more median estimated blood loss (100.0mL vs. 50.0mL, p <0.05), and higher rates of conversion to open surgery (1.2% vs. 25%, p <0.05) were observed in the high-complexity group (n=12) than in the low-complexity group (n=83). However, there were no remarkable differences between the two groups related to the baseline characteristics, post-surgical hospitalisation times, and postoperative complications. Conclusions: The HMUNS can effectively reflect LRSN complexity, thus providing a quantitative system for risk estimation and treatment decisions. Because of some limitations, further well-designed studies are necessary to confirm our findings. Patient summary: The HMUNS, including primary diseases, history of upper urinary tract surgery, BMI, surgeon's learning curve, kidney volume, and MAP score, can provide an effective quantitative tool to evaluate the complexity of LRSN.