Abstract
Combinations of conventional chemotherapeutics with unconventional anticancer agents such as reactive oxygen and nitrogen species may offer treatment benefits for cancer therapies. Here we report a novel polymeric platform combining the delivery of Doxorubicin (DOXO) with the light-regulated release of nitric oxide (NO). An amphiphilic block-copolymer (P1) was designed and synthesized as the drug carrier, with pendant amine groups to attach DOXO via a urea linkage and a NO photodonor (NOPD) activable by visible light. The two grafted-copolymers (P1-DOXO and P1-NOPD) self-assembled via solvent displacement methods into nanoparticles (NPs), containing both therapeutic components (NP1) and, for comparison, the individual NOPD (NP2) and DOXO (NP3). All the NPs were fully characterized in terms of physicochemical, photochemical and photophysical properties. These experiments demonstrated that integration of the NOPD within the polymeric scaffold enhanced the NO photoreleasing efficiency when compared with the free NOPD, and that the proximity to DOXO on the polymer chains did not significantly affect the enhanced photochemical performance. Internalization of the NPs into lung, intestine, and skin cancer cell lines was investigated after co-formulation with Cy5 fluorescent tagged polymers, and cytotoxicity of the NPs against the same panel of cell lines was assessed under dark and light conditions. The overall results demonstrate effective cell internalization of the NPs and a notable enhancement in killing activity of the dual-action therapeutic NP1 when compared with NP2, NP3 and the free DOXO, respectively. This suggests that the combination of DOXO with photoregulated NO release, achieved through the mixed formulation strategy of tailored polymer conjugate NPs, may open new treatment modalities based on the use of NO to improve cancer therapies.
Highlights
Multimodal cancer therapy involves the use of two or more treatment modalities with the aim to attack tumors by acting either on a single oncogenic pathway through different mechanisms or across parallel pathways without amplification of side effects.[1,2,3,4,5,6,7] In this regard, the combination of conventional chemotherapeutics with light-activated release of oxidizing agents such as reactive oxygen and nitrogen species (ROS and RNS) may open new routes to better therapies.[8]
We have recently demonstrated the successful combination of NO photodonor (NOPD) with DOXO as a suitable strategy to fight multi-drug resistance (MDR), increasing the intracellular accumulation of DOXO, enhancing its activity and significantly reducing its active concentration.[30]
We hypothesized that the anticancer performance of DOXO might be enhanced by exploiting the photoregulated release of nitric oxide (NO), and describe a multicomponent (NOPD-DOXO) polymeric platform which can be assembled by a simple formulation strategy
Summary
Pearce,b‡ Loretta Lazzarato,a Barbara Rolando,a Aurore Fraix,c Thais F. Vasey,b Cameron Alexander,b Vincenzo Taresco*b and Salvatore Sortino*c aDepartment of Drug Science and Technology, University of Turin, 10125, Turin, Italy. BSchool of Pharmacy, University of Nottingham, NG7 2RD United Kingdom. CLaboratory of Photochemistry, Department of Drug Sciences, University of Catania, I-95125 Catania, Italy. Supporting Information Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. ORCID Federica Sodano: 0000-0003-2013-4893 Amanda Pearce: 0000-0003-3372-7380 Loretta Lazzarato: 0000-0001-7100-8593 Barbara Rolando: 0000-0001-6138-1503 Aurore Fraix: 0000-0002-8328-3290 Cameron Alexander: 0000-0001-8337-1875 Vincenzo Taresco: 0000-0003-4476-8233 Salvatore Sortino: 0000-0002-2086-1276
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