Podophyllotoxin

Podophyllotoxin (PTOX) is a natural aryltetralin lignan isolated from the Podophyllum species, which has been developed as an antineoplastic drug. Its derivatives, including etoposide, teniposide and etopophos, have been approved as anticancer drugs and are widely used in clinical chemotherapy. PTOX analogs generally exert cytotoxic effects mainly through the inhibition of topoisomerase II or tubulin polymerization, resulting in DNA damage, cell cycle arrest, and apoptosis in various cancers, including lung cancer, breast cancer, liver cancer, gastric cancer, colorectal cancer, bladder cancer, and leukemia.
Optimization of the structure of the Podophyllotoxin rings has improved its efficacy, increased water solubility, and decreased side effects. In addition, it has been proven in many studies that PTOX derivatives inhibit tumor growth, metastasis, and angiogenesis by regulating signaling pathways such as PI3K/AKT/mTOR, ERK, STAT3, and NF-κB. Podophyllotoxin and its derivatives have strong potential for future cancer treatments. However, additional clinical trials and pharmacokinetic studies are required to further confirm their efficacy and safety in humans.

Fig. 1 The inhibitory effects of Podophyllotoxin on cell cancer cycle. (Motyka S.; et al. 2023)

Podophyllotoxin (PPT), a highly potent but toxic antitumor lignan, has been developed into several organic nanocarrier systems, such as polymer conjugates, micelles, and liposomes, to address its poor solubility, low selectivity, and severe side effects. They can improve drug solubility, optimize pharmacokinetics, and allow targeted and stimuli-responsive release. The typical synthetic strategies include covalent conjugation using C7-OH group and then self-assembly or nanoprecipitation or ionic gelation.
Representative nanoconjugates include H2O2-responsive PEG-Podophyllotoxin micelles, pH-sensitive chitosan NPs, redox-sensitive PEG-SS-Podophyllotoxin micelles, folate-receptor-targeted dual-drug micelles. The nanoconjugates demonstrate better tumor accumulation, prolonged circulation, and enhanced cytotoxicity against multiple cancer cell lines, with reduced toxicity to normal cells. Liposomal systems and transfersomes also enable further routes of delivery, such as topical application.

Fig. 2 Preparation methods of Podophyllotoxin nanoparticles. (Miranda-Vera C.; et al. 2025)