Background: The acidic microenvironment of cancer can promote tumor metastasis and drug resistance. Acidic tumor microenvironment-targeted therapy is currently an important means for treating tumors, inhibiting metastasis, and overcoming drug resistance. In this study, a dual pH-responsive DOX-encapsulated liposome ([email protected]) was designed and fabricated for targeting the acidic tumor microenvironment. On the one hand, the response of acid-sensitive peptide (DVar7) to the acidic tumor microenvironment increased the uptake of liposomes in tumors and prolonged the retention time; on the other hand, the response of acid-sensitive phospholipid (DOPE) to the acidic tumor microenvironment improved the controlled release of DOX in tumors. Methods: The acid-sensitive peptide DVar7 modified liposomes can be obtained by simple incubation of DSPE-DVar7 with DOX-loaded DOPE liposomes ([email protected]). The tumor targeting of the dual pH-responsive liposome was investigated in vitro and in vivo by near-infrared fluorescence imaging. The tumor therapeutic efficacy of [email protected] was evaluated in breast cancer mouse model using the traditional liposome as a control. Moreover, we regulated the tumor microenvironment acidity by injecting glucose to further enhance the therapeutic efficacy of cancer. Results: DVar7 can allosterically insert into the tumor cell membrane in the acidic tumor microenvironment to enhance the tumor uptake of liposomes and prolong the retention time of liposomes in tumor. In addition, the therapeutic efficacy of pH-responsive liposomes can be further enhanced by glucose injection regulating the acidity of tumor microenvironment. Discussion: DVar7 modified acid-sensitive nanocarriers combined with acidity regulation have great potential to improve drug resistance in clinical practice, thus improving the response rate and therapeutic effect of chemotherapy.

Objectives: Strategies to improve the responsiveness of programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade therapy remain an essential topic in cancer immunotherapy. In this study, we developed a new radiolabeled nanobody-based imaging probe ^99mTc-MY1523 targeting PD-L1 for the enhanced therapeutic efficacy of PD-L1 blockade immunotherapy by the guidance of ^99mTc-MY1523 SPECT/CT imaging. Methods: The binding affinity and specificity of nanobody MY1523 were measured in vitro. MY1523 was radiolabeled with ^99mTc by a site-specific transpeptidation of Sortase-A, and the biodistribution and single photon emission CT (SPECT)/CT were performed in mice bearing different tumors. We used interferon-γ (IFN-γ) as an intervention means to establish animal models with different levels of PD-L1 expression, then investigated the ability of ^99mTc-MY1523 SPECT/CT for the in vivo non-invasive measurement of PD-L1 expression in tumors. Finally, the PD-L1 blockade immunotherapies guided by ^99mTc-MY1523 SPECT/CT were carried out in MC-38, A20, and 4T1 tumor-bearing mouse models, followed by the testing of tumor infiltration T cells. Results: MY1523 exhibited a high binding affinity and specificity to PD-L1 and had no competitive binding with the therapeutic antibody. ^99mTc-MY1523 was prepared with high specific activity and radiochemical purity. It was found that tumor PD-L1 expression was dynamically upregulated by IFN-γ intervention in MC-38, A20, and 4T1 tumor-bearing mouse models, as indicated by ^99mTc-MY1523 SPECT/CT. The PD-L1 blockade therapy initiated during the therapeutic time window determined by ^99mTc-MY1523 SPECT/CT imaging significantly enhanced the therapeutic efficacy in all animal models, while the tumor growth was effectively suppressed, and the survival time of mice was evidently prolonged. A correlation between dynamically upregulated PD-L1 expression and improved PD-L1 blockade therapy effectiveness was revealed, and the markedly increased infiltration of effector T cells into tumors was verified after the imaging-guided therapy. Conclusion: Our results demonstrated that ^99mTc-MY1523 SPECT/CT allowed a real-time, quantitative and dynamic mapping of PD-L1 expression in vivo, and the imaging-guided PD-L1 blockade immunotherapy significantly enhanced the therapeutic efficacy. This strategy merits translation into clinical practice for the better management of combination therapies with radiotherapy or chemotherapy.

Gadolinium (Gd³⁺)-coordinated texaphyrin (Gd-Tex) is a promising radiosensitizer that entered clinical trials, but temporarily fails largely due to insufficient radiosensitization efficacy. Little attention has been given to using nanovesicles to improve its efficacy. Herein, Gd-Tex is transformed into building blocks “Gd-Tex-lipids” to self-assemble nanovesicles called Gd-nanotexaphyrins (Gd-NTs), realizing high density packing of Gd-Tex in a single nanovesicle and achieving high Gd-Tex accumulation in tumors. To elucidate the impact of O₂ concentration on Gd-Tex radiosensitization, myoglobin (Mb) is loaded into Gd-NTs (Mb@Gd-NTs), resulting in efficient relief of tumor hypoxia and significant enhancement of Gd-Tex radiosensitization, eventually inducing the obvious long-term antitumor immune memory to inhibit tumor recurrence. In addition to Gd³⁺, the versatile Mb@Gd-NTs can also chelate ¹⁷⁷Lu³⁺ (Mb@¹⁷⁷Lu/Gd-NTs), enabling SPECT/MRI dual-modality imaging for accurately monitoring drug delivery in real-time. This “one-for-all” nanoplatform with the capability of chelating various trivalent metal ions exhibits broad clinical application prospects in imaging-guided radiosensitization therapy.

BACKGROUND: Considering that trophoblast cell-surface antigen 2 (Trop2) is overexpressed in a wide range of human epithelial cancers, it presents an attractive target for diagnosis and treatment of multiple types of cancer. Herein, we have developed a Trop2-specific radiotracer, ⁶⁸ Ga-MY6349, and present a prospective, investigator-initiated trial to explore the clinical value of ⁶⁸ Ga-MY6349 PET/CT. METHODS: In this translational study, 90 patients with 15 types of cancer who underwent ⁶⁸ Ga-MY6349 PET/CT were enrolled prospectively. Among them, 78 patients underwent paired ⁶⁸ Ga-MY6349 and ¹⁸ F-FDG PET/CT, and 12 patients with prostate cancer underwent paired ⁶⁸ Ga-MY6349 and ⁶⁸ Ga-PSMA-11 PET/CT. RESULTS: Among the 90 patients across 15 types of cancer, ⁶⁸ Ga-MY6349 uptake in tumors was generally high but heterogeneous, varying among lesions, patients, and cancer types. Trop2 expression level determined by immunohistochemistry was highly correlated with ⁶⁸ Ga-MY6349 uptake at primary and metastatic tumor sites. ⁶⁸ Ga-MY6349 PET/CT showed higher tumor uptake (quantified by maximum standardized uptake value) than ¹⁸ F-FDG PET/CT in certain types of cancer, including breast (7.2 vs. 5.4, P < 0.001), prostate (9.2 vs. 3.0, P < 0.001), and thyroid cancers (8.5 vs. 3.7, P < 0.001). Compared with ⁶⁸ Ga-PSMA-11, ⁶⁸ Ga-MY6349 PET/CT exhibited comparable lesion uptake (12.2 vs. 12.5, P = 0.223) but a better tumor-to-background contrast (15.8 vs. 12.2, P < 0.001) for primary and metastatic prostate cancer, allowing visualization of more metastatic lesions. CONCLUSION: ⁶⁸ Ga-MY6349 PET/CT is a noninvasive method for comprehensively assessing Trop2 expression in tumors, which can improve diagnosis and staging for cancer patients and aid in decision making for Trop2-targeted therapies and advancing of personalized treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT06188468. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Nuclear Energy R&D project, Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare, Key Scientific Research Program for Young Scholars in Fujian, and Fujian Natural Science Foundation for Distinguished Young Scholars.