All‐In‐One Biomimetic Nanoplatform Based on Hollow Polydopamine Nanoparticles for Synergistically Enhanced Radiotherapy of Colon Cancer

Photodynamic therapy (PDT) has been applied to treat a wide range of medical conditions, including wet age-related macular degeneration psoriasis, atherosclerosis, viral infection and malignant cancers. However, the tissue penetration limitation of excitation light hinders the widespread clinical use of PDT. To overcome this "Achilles' heel", deep PDT, a novel type of phototherapy, has been developed for the efficient treatment of deep-seated diseases. Based on the different excitation sources, including near-infrared (NIR) light, X-ray radiation, and internal self-luminescence, a series of deep PDT techniques have been explored to demonstrate the advantages of deep cancer therapy over conventional PDT excited by ultraviolet-visible (UV-Vis) light. In particular, the featured applications of deep PDT, such as organelle-targeted deep PDT, hypoxic deep PDT and deep PDT-involved multimodal synergistic therapy are discussed. Finally, the future development and potential challenges of deep PDT are also elucidated for clinical translation. It is highly expected that deep PDT will be developed as a versatile, depth/oxygen-independent and minimally invasive strategy for treating a variety of malignant tumours at deep locations.

Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs), including those helping cells recover from radiation injuries, such as the activation of DNA damage sensing and early transduction pathways, cell cycle arrest, and DNA repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance, and some important advances and breakthroughs have already been achieved in recent years. On the basis of comprehensively reviewing the DDR signal pathways, we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization. We further discuss recent advances identified from preclinical studies, current clinical trials, and clinical application of chemical inhibitors targeting key DDR proteins, including DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia–telangiectasia mutated and Rad3-related), the MRN (MRE11-RAD50-NBS1) complex, the PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, and HIF-1 (hypoxia-inducible factor-1). Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy.

The metabolome, the small molecule chemical entities involved in metabolism, has traditionally been studied with the aim of identifying biomarkers in the diagnosis and prediction of disease. However, the value of metabolomics has been redefined from a simple biomarker identification tool to a technology for the discovery of active drivers of biological processes. In this review, we describe the molecular mechanisms by which the active cell metabolome affects cellular physiology through modulation of other ‘omic’ levels, including the genome, epi-genome, transcriptome and proteome. This concept of activity screening guided by metabolomics to identify biologically active metabolites, or “activity metabolomics”, is having broad impact on biology.