Black Phosphorus, an Emerging Versatile Nanoplatform for Cancer Immunotherapy

Abstract

Black phosphorus (BP) is one of the emerging versatile nanomaterials with outstanding biocompatibility and biodegradability, exhibiting great potential as a promising inorganic nanomaterial in the biomedical field. BP nanomaterials possess excellent ability for valid bio-conjugation and molecular loading in anticancer therapy. Generally, BP nanomaterials can be classified into BP nanosheets (BPNSs) and BP quantum dots (BPQDs), both of which can be synthesized through various preparation routes. In addition, BP nanomaterials can be applied as photothermal agents (PTA) for the photothermal therapy (PTT) due to their high photothermal conversion efficiency and larger extinction coefficients. The generated local hyperpyrexia leads to thermal elimination of tumor. Besides, BP nanomaterials are capable of producing singlet oxygen, which enable its application as a photosensitizer for photodynamic therapy (PDT). Moreover, BP nanomaterials can be oxidized and degraded to nontoxic phosphonates and phosphate under physiological conditions, improving their safety as a nano drug carrier in cancer therapy. Recently, it has been reported that BP-based PTT is capable of activating immune responses and alleviating the immunosuppressive tumor microenvironment by detection of T lymphocytes and various immunocytokines, indicating that BP-based nanocomposites not only serve as effective PTAs to ablate large solid tumors but also function as an immunomodulation agent to eliminate discrete tumorlets. Therefore, BP-mediated immunotherapy would provide more possibilities for synergistic cancer treatment.

Keywords: black phosphorus nanomaterial; cancer immunotherapy; immune stimulation; photodynamic therapy; photothermal therapy; synergistic therapeutic modality.

Figure 1

Schematic illustration of the outstanding properties of BP nanomaterials and their applications in anticancer therapy. (A) BP nanomaterials are ideal nano drug carriers with excellent agent-loading ability in drug delivery due to their puckered structure, electronegative surface, and excellent biodegradability. (B) BP nanomaterials exhibit an outstanding photothermal effect under 808 nm laser irradiation due to their broad visible absorption, leading to hyperthermia and the subsequent tumoricidal effect. (C) Due to the unique electronic structure, BP nanomaterials show excellent photodynamic effect under 660 nm laser irradiation, producing large amount of singlet oxygen in local tumor, and eventually leading to tumor destruction. (D) Both PTT and PDT can induce immunogenic cell death (ICD) when irradiating the tumor in situ at specific wavelength. Antigens are released in large quantities from the destroyed tumor tissue, which can strongly activate tumor immunity for further producing tumoricidal effect and inhibiting tumor metastasis.

Figure 2

Synthesis routes of BPNSs based on (A) tape exfoliation method, (B) wet ball milling exfoliation method, and (C) ultrasonic-assisted liquid-phase exfoliation method (Reproduced with permission from [48], WILEY, 2015).

Figure 3

Synthesis routes of BPQDs based on (A) ultrasonic exfoliation method (Reproduced with permission from [57], WILEY, 2015), (B) the solvothermal method, and (C) blender breaking method (Reproduced with permission from [61], WILEY, 2016).

Figure 4

Schematic illustration of the surface modification of BP nanomaterials. BP nanomaterials can be functionalized non-covalently or covalently for property improvement. Non-covalent functionalization can be further classified into polymer modification, inorganic nanomaterial modification, and lipid-based nanocarrier modification. Furthermore, covalent functionalization can be further classified into small molecule modification, polymer modification, and metallic nanomaterial modification.

Figure 5

Schematic illustration of the delivery of immunotherapeutic agents through BP nanomaterials in cancer immunotherapy. The checkpoint inhibitor, antigen, and immunoadjuvant are three main types of immunotherapeutic agents which can be loaded on BP nanomaterials to elicit distinct effects for cancer immunotherapy.

Figure 6

Schematic illustration of the synergistic cancer photoimmunotherapy based on BP nanomaterials. When exposed to specific laser irradiation during anticancer treatment, BP nanomaterials exhibit excellent phototherapy effect, which can not only destroy the tumor in situ, but activate tumor immunity as well. As a result, both subsequent tumor destruction and tumor metastasis inhibition can be acquired through this synergistic anticancer therapy.