Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities.
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We thank N. Watson (W. M. Kreck Microscopy Facility at the Whitehead Institute, Massachusetts Institute of Technology) for providing ionized carbon coated grids; E. Oliva (Department of Pathology at Massachusetts General Hospital) for expert histopathologic review of tissue sections; G. Orbaid for a critical reading; and, A. Villanueva for assistance in preparing a 3D render of a PMIL cryo-EM tomogram. This work was supported by National Institutes of Health Grants R01 CA156177 (to T.H.), R01-CA160998 (to T.H.), and P01-CA084203 (to B.W.P., S.P.P. and T.H.) and F32-CA144210 (to B.Q.S.).
The authors declare no competing financial interests.
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Spring, B., Bryan Sears, R., Zheng, L. et al. A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways. Nature Nanotech 11, 378–387 (2016). https://doi.org/10.1038/nnano.2015.311
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