Recently, Professor Zhang Jianxiang's team of the Army Medical University and the Yuyue Pathological Science Research Center and Professor Guo Jiawei's team of the Army Medical University jointly published a research paper titled "Self-illuminating liposome-derived in situ triggerable photodynamic therapy combining radionuclide therapy for synergistic treatment of lung cancer" in the international journal Acta Pharmaceutica Sinica B.

As a malignant tumor with high incidence and mortality worldwide, lung cancer is constantly developing, although traditional treatment methods such as surgery, chemotherapy, radiotherapy, etc., the patient's response rate is limited and the survival prognosis is poor, so innovative treatment methods are urgently needed. The research team developed a bifunctional liposome nanoplatform called CLL-¹⁷⁷Lu, which uses "self-luminescence" and radionuclides to bring new hope to the treatment of lung cancer.

Traditional PDT requires external laser activation of photosensitizers, and the "photosensitizer" in the new therapy is a CL (Lumino-dihydroprophene e6 conjugate) specially designed by scientists. Lumino is a substance that can be activated by high concentrations of reactive oxygen species (ROS) in the tumor microenvironment. After activation, it releases energy. ； Dihydroporphine e6 (Ce6) is a photosensitizer that can receive the energy of luminol, produce "single-stack oxygen" with strong killing, and accurately destroy tumor cells. This "chemiluminescence resonance energy transfer (CRET)" mechanism allows PDT to get rid of its dependence on external light sources. Like "with its own flashlight", it automatically activates the killing mode inside the tumor, perfectly solving the problem of deep tumor treatment.

Based on the self-luminescent PDT, the research team also equipped the liposome with a commonly used radionuclide in clinical practice -¹⁷⁷Lu. ¹⁷⁷Lu can release beta rays, directly destroying tumor cell DNA and inhibiting its proliferation ； More importantly, its half-life (6.65 days) and tissue penetration distance (about 670μm) are moderate, which can cause less damage to surrounding normal tissue and higher safety. Through the "encapsulation" of liposomes, ¹⁷⁷Lu can gather more accurately in the tumor site, reducing the distribution in normal organs, which not only enhances the efficacy but also reduces side effects.

The anti-cancer effect of CLL-¹⁷⁷Lu is far more than a simple superposition of two therapies. Research has found that it can "encircle and suppress" tumors through triple mechanisms: First, strong lethality: dual attacks on tumor cells: singlet oxygen produced by photodynamic therapy, directly destroying tumor cell membranes and organelles. ； ¹⁷⁷Lu's beta rays break tumor cell DNA and prevent it from dividing and proliferating. The combination of the two can rapidly induce tumor cell apoptosis. In in vitro experiments, the killing rate of lung cancer cells (A549) and breast cancer lung metastatic cells (4T1) is significantly higher than that of monotherapy. The second is to reshape the tumor microenvironment: activate the immune system. The "crawling" of tumors is that they can induce the immune system to "dormant", while CLL-¹⁷⁷Lu can "awaken" immune cells: the ROS and tumor cell fragments produced by the therapy will stimulate the transformation of macrophages to "M1" (M1 macrophages are the "main force" in anti-cancer, which can swallow tumor cells and release inflammatory factors) ； At the same time, it can promote T cell infiltration, enhance systemic anti-tumor immune response, and reduce the risk of metastasis. The third is to inhibit metastasis: cut off the tumor "supply line". Tumor metastasis depends on neovascularization to provide nutrition, while CLL-¹⁷⁷Lu can significantly inhibit tumor angiogenesis (by reducing CD31 protein expression), just like "cutting off the enemy's food and grass", preventing the tumor from spreading from the source.

In mouse models, the performance of CLL-¹⁷⁷Lu is exciting: lung cancer xenograft model: tumor volume shrinks by more than 70% after treatment, and tumor weight is significantly lower than that of the monotherapy group； Breast cancer lung metastasis model: the number of lung metastasis foci decreased, and the colonization rate of 4T1 tumor cells in the lung decreased by more than 50% ； Safety: There is no obvious damage to the normal organs of mice (heart, liver, spleen, lungs, and kidneys). Blood indicators (such as liver and kidney function and blood routine) are all within the normal range, proving that they are low toxicity.

▲Schematic diagram of bifunctional liposome engineering of in situ-triggered photodynamic therapy (PDT) and radiation therapy

Acta Pharmaceutica Sinica B is an international pharmacy journal co-organized by the Institute of Pharmaceuticals of the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Society. It was founded in 2011 and published by Elsevier. The latest impact factor of the journal is 14.6, and it is listed as Top journals in the Medical District 1 of the Chinese Academy of Sciences and the JCR Q1 section. The journal mainly publishes original research in pharmaceutical-related fields such as drug chemistry, pharmacy, and pharmacology, covering basic research and clinical applications. It is an authoritative platform for scientific researchers in this field to publish cutting-edge results.

Click on the lower left to read the original text and access the original text link.

https://pubs.acs.org/doi/10.1021/acsnano.5c02492