Nanoparticle delivery of photosensitive Pt(IV) drugs for circumventing cisplatin cellular pathway and on-demand drug release

• 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.

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