•Conjugating a photosensitive platinum(IV) prodrug onto a biodegradable polyester MPEG-b-P(LA-co-MCC-OH).•Utilizing nanoparticles for circumventing the cisplatin cellular pathway via delivering of photosensitive Pt(IV) prodrugs for the first time.•Nanoparticles showed photo and pH dually sensitive drug release profiles.•Nanoparticles expressed higher platinum intracellular uptake than cisplatin.•Nanoparticles displayed lower systemic toxicity compared to cisplatin and a targeting drug distribution.A photosensitive platinum(IV) prodrug (UVA-Pt2) was attached to a biodegradable polymer (PE, methoxyl-poly(ethylene glycol)-block-poly(lactide-co-2-methyl-2-carboxyl-propylene carbonate-ethanol amine)) and then the conjugate was self-assembled to micelles (NP-UVA-Pt2). In vitro MTT assay of NP-UVA-Pt2 demonstrated an improved cytotoxicity against SKOV-3 cells than that of cisplatin. Confocal laser scanning microscopy (CLSM) indicated that NP-UVA-Pt2 were endocytosed rather than internalized by passive diffusion, and thus, this process has nothing to do with copper transporter protein (Ctr1) as reported for cisplatin, which is closely related to drug resistance of Pt based drugs. Intracellular platinum content measured by ICP-MS result suggested that NP-UVA-Pt2 expressed higher platinum intracellular uptake than cisplatin. NP-UVA-Pt2 demonstrated fast and robust response to photo irradiation while the nanoparticles were stable in PBS at PH7.4 in the dark. The great drug efficacy of NP-UVA-Pt2 under UVA irradiation and the ineffectiveness in the dark makes NP-UVA-Pt2 an ideal light responsive on-demand drug delivery system. Hence, NP-UVA-Pt2 will be a promising platinum based drug in the near future.

Ethnopharmacological relevanceArmillaria mellea (Vahl. ex. Fr.) Karst is an important traditional Chinese medicine used in dispelling wind and removing obstruction in the meridians, and strengthening tendons and bones. Armillaria mellea has been recorded in the book Caobenshiyi which was written by ancestor for the function of suppressing hyderactive liver for calming endogenous wind medicine. The aim of this study is to investigate the cytotoxic activity for liver cell lines (normal and cancerous) of protoilludane sesquiterpene aryl esters from the mycelium of A. mellea.Materials and methodsA systemic fractionation of the mycelium extracts of A. mellea and relative activity mechanisms were studied.ResultsTwo new protoilludane sesquiterpene aryl esters named 5′-methoxy-armillasin (1) and 5-hydroxyl-armillarivin (2) were isolated. In addition, eight known protoilludane sesquiterpene aryl esters armillaridin (3), armillartin (4), armillarin (5), melleolide B (6), armillarilin (7), armillasin (8), armillarigin (9) and melleolide (10) were also isolated from the mycelium of A. mellea. The relative configurations of the two new compounds were confirmed by NOESY spectra. Among ten protoilludane sesquiterpene aryl esters, compounds 2, 3, 4, 7, 8, 9 and 10 were active constituents with highly cytotoxic activity against HepG2 cells (4.95–37.65 μg/mL). We reported here for the time, that compound 10 (melleolide) showed anti-tumor ability on hepatoma cell. The relative mechanism was assessed on HepG2 cells.ConclusionsAmong all the ten protoilludane sesquiterpene aryl esters, melleolide (10) showed the best cytotoxic activity for HepG2 cells (4.95 μg/mL) and lower activity for L02 cells (16.05 μg/mL). Mechanism study showed that melleolide decreased the viability of the cancer cells with varying levels of cleaved-caspase 3, caspase 8, caspase 9, Bax and Ki67 expression. On the other hand, melleolide induced HepG2 cell cycle arrest at the G2/M phase.Two new (1–2) and eight known (3–10) protoilludane sesquiterpene aryl esters were separated from the mycelium of Armillaria mellea. Their high cytotoxic activity and the relative mechanism were covered.Download high-res image (222KB)Download full-size image