Key Points
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The development of the next generation of nanoparticle therapeutics — based on polymeric nanoparticles that combine the pre-eminent features of traditional delivery vectors such as liposomes and polymer-drug conjugates, but offer new flexibility to overcome some of the key barriers in the field — is gaining momentum.
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To achieve intracellular drug delivery, strategies for overcoming various biological barriers — from the system level, to the organ level and to the cellular level — are needed. For intravenously injected engineered nanoparticles, the avoidance of multiple organ-level clearance mechanisms, such as those operating in the spleen and in the liver, must be compensated for if the carrier is to reach its intended destination. Ultimately, the effectiveness of any engineered nanoparticle will depend on the efficiency of the carrier to deliver its cargo to the intracellular site of action, which in many cases requires organelle-specific targeting.
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The size, the surface characteristics and the shape of a nanoparticle have a key role in its biodistribution in vivo. The effects of size have been studied extensively with spherically shaped particles and some general trends have been noted. Particle size is also known to influence the mechanism of cellular internalization. However, current findings indicate that particle shape is just as important, if not more so, than size in controlling key aspects of both biodistribution and nanoparticle internalization.
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Achieving tailored activated release of therapeutic cargo still represents a key barrier in the field of engineered nanoparticles. The predominant strategies so far incorporate materials that are enzymatically degradable, pH sensitive or reductively labile, which facilitate bond breaking between the drug and the carrier, or destabilization of the carrier on reaching the intended site of action.
Abstract
Engineered nanoparticles have the potential to revolutionize the diagnosis and treatment of many diseases; for example, by allowing the targeted delivery of a drug to particular subsets of cells. However, so far, such nanoparticles have not proved capable of surmounting all of the biological barriers required to achieve this goal. Nevertheless, advances in nanoparticle engineering, as well as advances in understanding the importance of nanoparticle characteristics such as size, shape and surface properties for biological interactions, are creating new opportunities for the development of nanoparticles for therapeutic applications. This Review focuses on recent progress important for the rational design of such nanoparticles and discusses the challenges to realizing the potential of nanoparticles.
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Acknowledgements
We thank S. Gratton, K. Herlihy, J. Kelly, T. Merkle, M. Napier and J. Wang for help with figures. R.A.P. is supported by the National Science Foundation under CHE-1004878 and CHE-0840518. J.M.D. is supported by the Science and Technology Centers program of the National Science Foundation under CHE-9876674; the National Institutes of Health (NIH) Program Project Grant PO1-GM059299; NIH Grant U54-CA119343 (the Carolina Center for Cancer Nanotechnology Excellence); DARPA 07-4627; Liquidia Technologies; the Office of Naval Research N00014-08-1-0978; the William R. Kenan Jr, Distinguished Professorship; and the Chancellor's Eminent Professorship at the University of North Carolina at Chapel Hill, USA.
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Joseph M. DeSimone is co-founder of a company called Liquidia Technologies which has licensed the PRINT technology. As such, J.M.D. is a member of the Board of Directors and is a consultant at Liquidia. He also has an equity position in the company.
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- Therapeutic index
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In the case of the anticancer drug doxorubicin, which displays dose-limiting cardiotoxicity, the therapeutic index is the amount of drug in the tumour compared with the amount of drug in the heart.
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Petros, R., DeSimone, J. Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov 9, 615–627 (2010). https://doi.org/10.1038/nrd2591
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DOI: https://doi.org/10.1038/nrd2591
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