Combinational Antitumor Strategies Based on the Active Ingredients of Toad Skin and Toad Venom

Abstract

A multidrug combination strategy is an important mean to improve the treatment of cancer and is the mainstream scheme of clinical cancer treatment. The active ingredients of traditional Chinese medicine, represented by toad skin and toad venom, have the advantages of high efficiency, low toxicity, wide action and multiple targets and have become ideal targets in combined treatment strategies for tumors in recent years. Toad skin and toad venom are traditional Chinese animal medicines derived from Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider that have shown excellent therapeutic effects on the treatment of various cancers and cancer pain as adjuvant antitumor drugs in clinical practice. The involved mechanisms include inducing apoptosis, arresting the cell cycle, inhibiting cell proliferation, migration and invasion, inhibiting tumor angiogenesis, reversing the multidrug resistance of tumor cells, and regulating multiple signaling pathways and targets. Moreover, a multidrug combination strategy based on a nanodelivery system can realize the precise loading of the active ingredients of toad skin or toad venom and other antitumor drugs and carry drugs to overcome physiological and pathological barriers, complete efficient enrichment in tumor tissues, and achieve targeted delivery to tumor cells and the controlled release of drugs, thus enhancing antitumor efficacy and reducing toxicity and side effects. This article reviewed the clinical efficacy and safety of the combination of toad skin and toad venom with chemotherapeutic drugs, targeted drugs, analgesics and other drugs; evaluated the effects and mechanisms of the combination of toad skin and toad venom with chemotherapy, targeted therapy, radiotherapy or hyperthermia, traditional Chinese medicine, signaling pathway inhibitors and other therapies in cell and animal models; and summarized the codelivery strategies for the active ingredients of toad skin and toad venom with chemotherapeutic drugs, small-molecule targeted drugs, monoclonal antibodies, active ingredients of traditional Chinese medicine, and photodynamic and photothermal therapeutic drugs to provide a basis for the rational drug use of toad skin and toad venom in the clinic and the development of novel drug delivery systems.

Keywords: cancer; cancer pain; codelivery strategies; combinational antitumor strategies; toad skin; toad venom.

Figure 1

The source of toad skin and toad venom and the structure of their related active ingredients.

Figure 2

The mechanism of action of the active ingredients of toad skin and toad venom combined with chemotherapy and targeted therapy.

Figure 3

Schematic diagram of the classification of co-delivery systems based on active ingredients of toad skin and toad venom.

Figure 4

(a) Preparation scheme of RGD-modified erythrocyte membrane camouflaged GOQDs-PEG-TAT@DOX@CS-6 nanosystem (GTDC@M-R NPs). (b) Proposed mechanism of GTDC@M-R NPs mediated tumor ablation and metastasis inhibition, and GTDC@M-R NPs-mediated transfection of DOX and CS-6 in MDA-MB-231 cells. Reprinted from Acta Biomaterialia, Volume 113, Fan J, Liu B, Long Y, et al, Sequentially-targeted biomimetic nano drug system for triple-negative breast cancer ablation and lung metastasis inhibition, Pages 554–569, Copyright 2020, with permission from Elsevier.

Figure 5

The synthesis process of Le/Bu@mSiO₂-FA. Reproduced with permission from Ning Z, Zhao Y, Yan X, Hua Y, Meng Z. Flower-like composite material delivery of co-packaged lenvatinib and bufalin prevents the migration and invasion of cholangiocarcinoma. Nanomaterials-Basel. 2022;12(12):2048. Copyright 2022, MDPI AG. (https://creativecommons.org/licenses/by/4.0/).

Figure 6

Schematic diagram of the designed strategy for the combined therapy of CPCCM NPs. Reproduced with permission from Zeng Z, Wang Z, Chen S, et al. Bio-nanocomplexes with autonomous O(2) generation efficiently inhibit triple negative breast cancer through enhanced chemo-PDT. J Nanobiotechnol. 2022;20(1):500. Copyright 2022, BioMed Central.

Figure 7

Schematic depiction of preparation (A) and in vivo application (B) of PC@M NPs. Reproduced with permission from Luo M, Tan C, Cao R, et al. Hybrid membrane camouflaged prussian blue nanoparticles with cinobufagin loading for chemo/photothermal therapy of colorectal cancer. Mater Design. 2023;232:112088. Copyright 2023, Elsevier Ltd.