Fig. 1 Engineered microalgae in tumors (green)
Microalgae is a single-celled microorganism that can photosynthesize in nature and is widely used in biofuels, food, health care products and other fields. Recently, zhou Min's team from the Second Affiliated Hospital of Medicine of Zhejiang University/Institute of Translational Medicine collaborated with Sun Yi's team to make new progress in the application of engineered active microalgae in vivo cancer treatment, and published online in Science Advances, a comprehensive journal under Science Advances, entitled "Engineered algae: a novel oxygen-generating system for effective treatment of." hypoxic cancer" research paper. The article was selected by the editorial board of the journal as the rottate highlight image focus promotion.
Fig. 2 Engineered microalgae under light improve the tumor hypoxia microenvironment
The engineered active microalgae in this study can be delivered to hypoxic tumor areas to increase local oxygen levels and restore sensitivity of cancer-resistant cells to radiation therapy and photodynamic therapy. Producing oxygen in situ in the tumor by microalgae-mediated photosynthesis significantly improves the hypoxic environment of the tumor, thereby improving the efficacy of radiation therapy. At the same time, the chlorophyll released by microalgae produces reactive oxygen species under laser excitation, which further imparts photosensitivity and enhances the apoptosis of tumor cells. Therefore, combining oxygen-producing microalgae biological systems with radiation therapy and photodynamic therapy has the potential to create a new cancer treatment strategy. Taken together, this study reveals a new approach to the treatment of tumors using photosynthesis and provides a new concept for the future development of algae-enhanced radiation therapy and photodynamic therapy.
Fig. 3 Schematic diagram of the programmed treatment of engineered microalgae and morphology of microalgae
Due to the rapid growth of cancer cell clumps around the microvascular area, solid tumors will inevitably form a hypoxic state [1]. Local hypoxia in tumors seriously hinders the effectiveness of cancer treatment, particularly radiation therapy (RT) involving intratumoral oxygen[2] and photodynamic therapy (PDT)[3]. Improving oxygenation concentrations in hypoxic tumor areas and overcoming hypoxia can greatly enhance the efficacy of PDT/RT. Therefore, re-oxygenation of hypoxic tumors is an effective way to overcome hypoxic-based resistant cancer treatments [4]. In response to this problem, a number of studies have tried to use nanocarriers to generate oxygen in the tumor in situ to increase local oxygen in hypoxic areas to enhance therapeutic efficacy. However, the clinical translational value of this method is limited, mainly because most delivery vectors are captured by the mononuclear phagocyte system (MPS) in the liver and spleen, resulting in only about 0.7% of the doses administered to reach the tumor [5]. The high uptake of nanocarriers in major organs increases the risk of systemic toxicity of the drug and hinders its transition to clinical applications.
Fig. 4 In vitro experiments for the programmed treatment of engineered microalgae
(Under light, microalgae produce oxygen rapidly to improve the hypoxia state of cancer cells; under X-ray irradiation, it efficiently destroys the DNA of cancer cells and achieves the sensitization effect of radiation therapy; and the subsequent release of chlorophyll can realize cascade photodynamic therapy.) ）
In nature, microalgae have evolved over hundreds of millions of years to obtain complex photosynthetic systems that enable efficient photocatalytic oxygen production [6]. Microalgae have been used in a variety of applications due to their photosynthetic effects, including biofuels, nutraceuticals, food, animal feed, organic fertilizers, air purification, biodegradation and bioactive compounds. Chlorella (C. chlorella) vulgaris) is a single-celled chlorella belonging to the order Chlorella of the phylum Tetracytophyllum elegans, which produces oxygen through photosynthesis processes. Due to the abundance of algae resources, low cost and homogeneity, algae has traditionally been used as a research model for novel food sources. Notably, chlorella is able to reduce endotoxemia in digestive disorders [8] and enhance host defenses against peritonitis [9] without toxic side effects. In addition, C. vulgaris contains large amounts of chlorophyll, which can be photosynthesized in a wide wave range. This function can be used for PDT [10] due to reactive oxygen species (ROS) generated under 650 nm wavelength laser irradiation. Chlorophyll, the main decomposition product of algae, has no genetic side effects on mammalian cells, including chromosomal breaks, and can limit the bioavailability of carcinogens without a significant immune response-inducing effect.
Fig. 5 Tumor targeting delivery of engineered microalgae and improvement of intratumoral hypoxia
In this study, chlorella modified by the engineered red blood cell membrane can effectively reduce the immune phagocytosis of immune cells, significantly reducing the scavenging effect of macrophages, thereby more effectively delivering nanodrugs to tumor tissues. Using fluorescence imaging, the uptake of engineered chlorella in the tumor site can be dynamically observed, and the optimal radiotherapy time can be selected; the dynamic change of the blood oxygen content of engineered microalgae in the tumor tissue can be observed by photoacoustic imaging, which realizes the real-time and dynamic monitoring of tumor hypoxia; at the same time, the chlorophyll contained in microalgae also has fluorescence characteristics, which can realize the dynamic fluorescence imaging function. Engineered chlorella delivered to tumor tissue produces oxygen in situ inside the tumor through photosynthesis, which can significantly alleviate the anaerobic state of the tumor and have a better radiotherapy effect under X-ray irradiation. At the same time, it was found that chlorella itself contains chlorophyll that can be used as a photosensitizer to produce reactive oxygen species, which is applied to photodynamic therapy. In the early radiotherapy process, a large amount of chlorophyll is released from the chlorella into the tumor tissue, and then after 650 nm of laser irradiation, cascade photodynamic therapy can be realized, which significantly inhibits the growth of the tumor. Therefore, this study combines two molecular imaging modes of photoacoustic imaging/fluorescence imaging to provide a precise treatment plan for further radiotherapy and photodynamic cascade therapy of tumors.
Fig. 6 Molecular pathways for the programmed treatment of hypoxic tumors by engineered microalgae
At present, biomaterials with macromolecules, inorganic nanos and hybrid nanoparticles as the main carriers are widely used in the diagnosis and treatment of tumors, and remarkable technological achievements have been made. However, the medical transformation of materials has put forward very strict requirements for large-scale production and biosecurity, which has undoubtedly become the main obstacle to the transformation of various biomaterials from basic research to clinical. Therefore, how to design and prepare a drug-loading system with mass production feasibility, ideal therapeutic effect and high biosecurity is an important problem to be solved in this field. The results of this paper show that natural active microalgae have good biosafety and the prospect of large-scale production. Therefore, around the integrated drug delivery system of diagnosis and treatment based on natural active microalgae, with good biosecurity and image monitoring feasibility, through rational design and targeted application strategies, a synthetic efficient and safe active microalgae drug carrier system is designed for tumor diagnosis and treatment under medical image guidance. On this basis, a new treatment scheme for malignant tumors based on natural biologically active microalgae is established, and the feasibility of clinical translation is explored, and a new type of tumor treatment material research and development technology is provided. It is expected to obtain new technologies and new products for tumor diagnosis and treatment with clinical application prospects, good druggability and independent intellectual property rights.
Qiao Yue, ph.D. student of Zhou Min's team at the Institute of Translational Medicine of Zhejiang University/ Assistant Researcher of the Ophthalmology Center of the Second Affiliated Hospital of Zhejiang University, Yang Fei, doctoral student of Sun Yi's team of the Institute of Translational Medicine of Zhejiang University, and Xie Tingting, master student of Zhou Min's team, are the co-first authors of the paper. Zhou Min, researcher at the Institute of Translational Medicine of Zhejiang University/Second Affiliated Hospital of Zhejiang University, and Professor Sun Yi of the Institute of Translational Medicine of Zhejiang University are the co-corresponding authors of the paper. Professor Lu Zhimin of the Institute of Translational Medicine of Zhejiang University is one of the co-authors of the paper.
The research work has been strongly supported by the Ophthalmology Center of Zhejiang University, the Key Laboratory of Malignant Tumor Early Warning and Intervention of the Ministry of Education, and the State Key Laboratory of Modern Optical Instruments, and the research has also been funded by the National Key Research and Development Program, the National Natural Science Foundation of China, the China Postdoctoral Science Foundation, and the Zhejiang Provincial Key Research and Development Program.
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[4] Rummer JL, McKenzie DJ, Innocenti A, Supuran CT, Brauner CJ. Root Effect hemoglobin may have evolved to enhance general tissue oxygen delivery. Science 340, 1327-1329 (2013).
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[6] Georgianna DR, Mayfield SP. Exploiting diversity and synthetic biology for the production of algal biofuels. Nature 488, 329-335 (2012).
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