Algae: A Robust Living Material Against Cancer

Abstract

Cancer is the second leading cause of death worldwide. Its incidence has been increasing in recent years, and it is becoming a major threat to human health. Conventional cancer treatment strategies, including surgery, chemotherapy, and radiotherapy, have faced problems such as drug resistance, toxic side effects and unsatisfactory therapeutic efficacy. Therefore, better development and utilization of biomaterials can improve the specificity and efficacy of tumor therapy. Algae, as a novel living material, possesses good biocompatibility. Although some reviews have elucidated several algae-based biomaterials for cancer treatment, the majority of the literature has focused on a limited number of algae. As a result, there is currently a lack of comprehensive reviews on the subject of anticancer algae. This review aims to address this gap by conducting a thorough examination of algal species that show potential for anticancer activity. Furthermore, our review will also elucidate the engineering strategies of algae and discuss the challenges and prospects associated with their implementation.

Keywords: algae; anticancer mechanism; biomaterials; engineering strategies; neoplasms.

Figure 1

Mechanistic illustration of algae against tumors. The illustration mainly consists of different categories of algae, engineering strategies, and anticancer mechanisms. Three engineering strategies, cell membrane coating, hydrogel loading and material modification, were adopted to realize sustained release, increased stability and enhanced biological properties for better anticancer activities. The anticancer mechanisms of algae include (1) direct cytotoxic effects, (2) drug delivery systems, and (3) relief of hypoxia and photodynamic therapy. Created with BioRender.com with enkaryotes and prokaryotes in the middle circle drawn by Adobe illulstrator.

Figure 2

Engineered algae could ameliorate hypoxia to improve radiotherapy and PDT. (A) Illustrative description of the process and treatment of algae engineering. (B) Algal photograph. (C) SEM images of algae. (D) Engineered algae can effectively reach tumor sites and improve oxyhemoglobin after intravenous injection. (E) CD31 staining of cancer microvessels. (F) Engineered algae can increase oxygen, enhance radiation therapy, release chlorophyll, and induce PDT. (G) Confocal fluorescence images show elevated intracellular oxygen levels after treatment with engineered algae under hypoxic incubation conditions of the hypoxic probe. Reprinted from Qiao Y, Yang F, Xie T, et al. Engineered algae: A novel oxygen-generating system for effective treatment of hypoxic cancer. Science Advances. 2020;6(21):eaba5996. Creative Commons.

Figure 3

Observations of the anticancer mechanism of algal extracts and their efficacy after treatment. (A) Molecular mechanism of the anticancer activity of algal extracts. Reprinted from Lin Y, Qi X, Liu H, et al. The anticancer effects of fucoidan: a review of both in vivo and in vitro investigations. Cancer Cell Int. 2020;20:154. Creative Commons. (B) Detection of apoptosis using live-dead cell cytostaining and flow cytometry. (a, AuNCs/HA upon NIR irradiation; b, DOX/AuNCs/HA; c, DOX/AuNCs/HA upon NIR irradiation; d, Reproduced with permission; doxorubicin (DOX); Gold nanorods (AuNRs); hyaluronic acid (HA)). Reprinted from Sun R, Chen H, Sutrisno L, et al. Nanomaterials and their composite scaffolds for photothermal therapy and tissue engineering applications. Sci Technol Adv Mater. 2021;22(1):404–428. Creative Commons. (C) Representative images of tumor immunohistochemical staining. (near-infra-red (NIR), photosynthesis microcapsule (PMC)). Reprinted from Wang W, Zheng H, Jiang J, et al. Engineering micro oxygen factories to slow tumor progression via hyperoxic microenvironments. Nature communications. 2022;13(1):4495. Creative Commons.

Figure 4

Ideas and possible mechanisms of algae in tumor therapy. (A) Algae-based composite nanoparticles loaded with photodynamic chemotherapeutic immunomodulation to enhance tumor oxygenation and stimulate anticancer immune responses for cancer therapy. Aggregates specifically at the tumor site and penetrates flexibly into the tumor mass, thereby increasing the oxygenation state of the tumor. Adapted with permission from American Chemical Society: ACS Nano, Oxygen-delivering polyfluorocarbon nanovehicles improve tumor oxygenation and potentiate photodynamic-mediated anticancer immunity. Wang Z, Gong X, Li J, et al. Copyright© 2021 ACS Nano. (B) Possible mechanism of engineered algae-mediated combination therapy: Reduced HIF1 and VEGF protein levels promote apoptosis and necrosis. Reprinted from Qiao Y, Yang F, Xie T, et al. Engineered algae: A novel oxygen-generating system for effective treatment of hypoxic cancer. Science Advances. 2020;6(21):eaba5996. Creative Commons. (C) Engineered algae-mediated RT and PDT can effectively inhibit tumor growth after intravenous injection. Average cancer growth curve. (1, control; 2, laser alone; 3, RBCM-Algae alone; 4, x-ray irradiation (RT) alone; 5, RT + laser; 6, RBCM-Algae + laser; 7, RBCM-Algae + RT; and 8, RBCM-Algae + RT + laser. Student’s two-tailed t test, not significant P ≥ 0.05; *P < 0.05; ***P < 0.001; photodynamic therapy (PDT); red blood cell membrane (RBCM)). Reprinted from Qiao Y, Yang F, Xie T, et al. Engineered algae: A novel oxygen-generating system for effective treatment of hypoxic cancer. Science Advances. 2020;6(21):eaba5996. Creative Commons. (D) Kaplan‒Meier curve showing the survival rate of the indicated rabbits at 140 days. (near-infra-red (NIR), photosynthesis microcapsule (PMC), the data are presented as *p < 0.05). Nat Commun. 2022 Aug 2;13(1):4495. Open Access. (E) A regimen in which engineered algae-mediated RT and PDT can effectively inhibit tumor growth after intravenous injection. Reprinted from Qiao Y, Yang F, Xie T, et al. Engineered algae: A novel oxygen-generating system for effective treatment of hypoxic cancer. Science Advances. 2020;6(21):eaba5996. Creative Commons. (F) Effect of algae in a hyperoxic microenvironment on cancer. Representative axial CT images of tumor growth. (near-infra-red (NIR), photosynthesis microcapsule (PMC)). Reprinted from Wang W, Zheng H, Jiang J, et al. Engineering micro oxygen factories to slow tumor progression via hyperoxic microenvironments. Nature communications. 2022;13(1):4495. Creative Commons.

Figure 5

Algae combined with photodynamic anticancer experiments and cell validation experiments. (A) Schematic diagram of algae-based PDT to enhance anticancer effects. Reprinted from Wang H, Liu H, Guo Y, et al. Photosynthetic microorganisms coupled photodynamic therapy for enhanced antitumor immune effect. Bioact Mater. 2022;12:97–106. Creative Commons. (B) Photograph of the tumor at the end point. (PBS, PBS plus laser irradiation (PBS+L), nanoparticles (PDG), PBS plus laser irradiation (PDG+L), gemcitabine (Gem), sensitive prodrug of chemo-immunomodulatory gemcitabine (PF11DG), the treatment of PF11DG plus laser irradiation (PF11DG+L). Adapted with permission from American Chemical Society: ACS Nano, Oxygen-delivering polyfluorocarbon nanovehicles improve tumor oxygenation and potentiate photodynamic-mediated anticancer immunity. Wang Z, Gong X, Li J, et al. Copyright© 2021 ACS Nano. (C) Scratch experiments were used to demonstrate the cellular effects of infrared light irradiation signaling pathways. (near-infra-red (NIR), photosynthesis microcapsule (PMC). Reprinted from Wang W, Zheng H, Jiang J, et al. Engineering micro oxygen factories to slow tumor progression via hyperoxic microenvironments. Nature communications. 2022;13(1):4495. Creative Commons. (D) To demonstrate in vivo tumor targeting, permeability, etc. In vivo tumor accumulation of photodynamic agents in mice under an in vivo imaging system. Adapted with permission from American Chemical Society: ACS Nano, Oxygen-delivering polyfluorocarbon nanovehicles improve tumor oxygenation and potentiate photodynamic-mediated anticancer immunity. Reprinted from Wang W, Zheng H, Jiang J, et al. Engineering micro oxygen factories to slow tumor progression via hyperoxic microenvironments. Nature communications. 2022;13(1):4495. Creative Commons. (E) Staining of new daughter cells, confocal visualization. (near-infra-red (NIR), photosynthesis microcapsule (PMC)). Reprinted from Wang W, Zheng H, Jiang J, et al. Engineering micro oxygen factories to slow tumor progression via hyperoxic microenvironments. Nature communications. 2022;13(1):4495. Creative Commons. (F) Cell proliferation assessment Photosynthetic microcapsules prepared from algae are less cytotoxic and can inhibit cancer cells in the presence of infrared light. (near-infra-red (NIR), photosynthesis microcapsule (PMC), the data are presented as mean ± SD. ***p < 0.001 compared to control cells according to two-tailed Student’s t-test). Reprinted from Wang W, Zheng H, Jiang J, et al. Engineering micro oxygen factories to slow tumor progression via hyperoxic microenvironments. Nature communications. 2022;13(1):4495. Creative Commons.

Figure 6

In addition to anticancer activity, algae exhibit hemostatic, antibacterial and prorepair-oriented anticancer effects postoperatively, and other issues need to be studied in depth. (A) Schematic representation of the main mechanism of action of antimicrobial compounds derived from macroalgae. Reprinted from Silva A, Silva SA, Carpena M, et al. Macroalgae as a Source of Valuable Antimicrobial Compounds: Extraction and Applications. Antibiotics (Basel). 2020;9(10). Creative Commons. (B) Schematic diagram of the combination of algae and hydrogel for wound hemostasis. Reprinted from Zou CY, Lei XX, Hu JJ, et al. Multicrosslinking hydrogels with robust bioadhesion and pro-coagulant activity for first-aid hemostasis and infected wound healing. Bioact Mater. 2022;16:388–402. Creative Commons. (C) Schematic diagram of algae promoting chronic wound repair. Reprinted from Chen H, Cheng Y, Tian J, et al. Dissolved oxygen from microalgae-gel patch promotes chronic wound healing in diabetes. Science advances. 2020;6(20):eaba4311. Creative Commons. (D) The shallower wounds are covered by algae, thus maintaining a good moist environment and promoting wound repair and healing. Reprinted from Chen H, Cheng Y, Tian J, et al. Dissolved oxygen from microalgae-gel patch promotes chronic wound healing in diabetes. Science advances. 2020;6(20):eaba4311. Creative Commons.