Functionalized Nanomaterials for Inhibiting ATP-Dependent Heat Shock Proteins in Cancer Photothermal/Photodynamic Therapy and Combination Therapy

Abstract

Phototherapies induced by photoactive nanomaterials have inspired and accentuated the importance of nanomedicine in cancer therapy in recent years. During these light-activated cancer therapies, a nanoagent can produce heat and cytotoxic reactive oxygen species by absorption of light energy for photothermal therapy (PTT) and photodynamic therapy (PDT). However, PTT is limited by the self-protective nature of cells, with upregulated production of heat shock proteins (HSP) under mild hyperthermia, which also influences PDT. To reduce HSP production in cancer cells and to enhance PTT/PDT, small HSP inhibitors that can competitively bind at the ATP-binding site of an HSP could be employed. Alternatively, reducing intracellular glucose concentration can also decrease ATP production from the metabolic pathways and downregulate HSP production from glucose deprivation. Other than reversing the thermal resistance of cancer cells for mild-temperature PTT, an HSP inhibitor can also be integrated into functionalized nanomaterials to alleviate tumor hypoxia and enhance the efficacy of PDT. Furthermore, the co-delivery of a small-molecule drug for direct HSP inhibition and a chemotherapeutic drug can integrate enhanced PTT/PDT with chemotherapy (CT). On the other hand, delivering a glucose-deprivation agent like glucose oxidase (GOx) can indirectly inhibit HSP and boost the efficacy of PTT/PDT while combining these therapies with cancer starvation therapy (ST). In this review, we intend to discuss different nanomaterial-based approaches that can inhibit HSP production via ATP regulation and their uses in PTT/PDT and cancer combination therapy such as CT and ST.

Keywords: cancer combination therapy; heat shock protein; nanomedicine; photodynamic therapy; photothermal therapy.

Figure 1

A schematic illustration of the type I and type II photochemical reaction mechanisms of photodynamic therapy (PDT). PS, photosensitizer; ¹PS*, photosensitizer in a singlet excited state; ³PS*, photosensitizer in a triplet excited state.

Figure 2

A schematic diagram of HSP70 and the inhibition of HSP70 via the N-terminal and C-terminal inhibitors. The HSP70 has an N-terminal nucleotide-binding domain (NBD) responsible for ATPase activity and a C-terminal substrate-binding domain (SBD) required for peptide binding. A linker connects two domains. The N-terminal NBD provides ATP/ADP pockets for ATP binding. The SBD is further divided into two subdomains, SBDα and SBDβ, which function as the lid and core, respectively, during substrate binding. (a) The N-terminal inhibitor binds to NBD by competing with ATP, thus hindering its interaction with the NBD of HSP70. (b) The C-terminal inhibitor binds to SBDβ by restricting the interaction of HSP70 with its client proteins.

Figure 3

A schematic diagram of HSP90 and the inhibition of HSP90 via the N-terminal and C-terminal inhibitors. The N, M, and C stand for the N-terminal domain (NTD), middle domain (MD), and C-terminal domain (CTD) in HSP90, respectively. The NTD and MD are connected by the charged linker (CL). (a) The N-terminal inhibitor binds to the NTD of HSP90 and halts its interaction with ATP. (b) The C-terminal inhibitor binds to the CTD of HSP90 and blocks its interaction with the co-chaperones.

Figure 4

The chemical structure of small-molecule inhibitors of HSP90 and HSP70.

Figure 5

Dually enhanced phototherapy by gambogic acid and hyperthermia-activated chemotherapy for synergistic breast cancer treatment. Reprinted with permission from [118]. Copyright 2023, Elsevier B.V.

Figure 6

Functionalized boron nanosheets as an intelligent nanoplatform for synergistic low-temperature photothermal therapy and chemotherapy. Reproduced with permission from [127]. Copyright 2020 Royal Society of Chemistry.

Figure 7

A nanoagent based on supramolecular glyco-assembly for eradicating tumors in vivo. Reproduced with permission from [139]. Copyright 2022 American Chemical Society.

Figure 8

Pifithrin-μ incorporated in gold nanoparticles amplifies pro-apoptotic unfolded protein response cascades to potentiate synergistic glioblastoma therapy. Reprinted with permission from [149]. Copyright 2020, Elsevier Ltd.

Figure 9

A multimodal imaging-guided nanosystem for the cooperative combination of tumor starvation and enhanced mild-temperature photothermal therapy (PTT) and photodynamic therapy (PDT). Reproduced with permission from [174]. (A) Procedure for preparing the nanosystem. (B) Schematic illustration showing the multilevel mechanism of the nanosystem. Copyright 2020 Royal Society of Chemistry.