Design considerations for nanotherapeutics in oncology - PubMed (original) (raw)

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Design considerations for nanotherapeutics in oncology

Triantafyllos Stylianopoulos et al. Nanomedicine. 2015 Nov.

Abstract

Nanotherapeutics have improved the quality of life of cancer patients, primarily by reducing the adverse effects of chemotherapeutic agents, but improvements in overall survival are modest. This is in large part due to the fact that the enhanced permeability and retention effect, which is the basis for the use of nanoparticles in cancer, can be also a barrier to the delivery of nanomedicines. A careful design of nanoparticle formulations can overcome barriers posed by the tumor microenvironment and result in better treatments. In this review, we first discuss strengths and limitations of clinically-approved nanoparticles. Then, we evaluate design parameters that can be modulated to optimize delivery. The benefits of active tumor targeting and drug release rate on intratumoral delivery and treatment efficacy are also discussed. Finally, we suggest specific design strategies that should optimize delivery to most solid tumors and discuss under what conditions active targeting would be beneficial.

From the clinical editor: Advances in nanotechnology have seen the introduction of new treatment modalities for cancer. The principle of action using nanocarriers for drug delivery is based mostly on the Enhanced Permeability and Retention effect. This phenomenon however, can also be a hindrance. In this article, the authors performed an in-depth review on various nanoparticle platforms in cancer therapeutics. They also suggested options to improve drug delivery, in terms of carrier design.

Keywords: Cancer therapy; Controlled drug release; EPR effect; Nanomedicine; Nanoparticle targeting.

Copyright © 2015 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Conflict of interests: R.K.J. received research grants from Dyax, Med Immune and Roche; consultaning fees from Enlight, Ophthotech, SPARC and SynDevRx; owns equity in Enlight, Ophthotech, SynDevRx and XTuit, serves on the Board of Directors of XTuit and Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. No reagents or funding from these companies was used in these studies. Therefore, there is no significant financial or other competing interest in the work.

Figures

Figure 1

Figure 1

Chronology of first clinical approvals of nanomedicines after the introduction of the EPR effect. Myocet is approved only in Europe and Canada, Lipusu in China, Genexol-PM in South Korea and PICN in India. The size of nanoparticles given in parenthesis is approximate. *Abraxane becomes ~10 nm in size from ~130 nm following disintegration in the blood . The size of Lipusu is not available.

Figure 2

Figure 2

Effect of particle physicochemical properties on transvascular transport. A.) Interstitial fluid pressure, Pi, in solid tumors is elevated and is approximately equal to microvascular pressure, Pv, which eliminates transvascular pressure gradients and renders diffusion the dominant mechanism of transport. Spherical particles move with the flow, while elongated particles rotate as they move and interact with the vessel wall. Cationic particles are concentrated near the vessel wall owing to electrostatic attractions. B.) Transvascular transport of nanoparticles is size-dependent, with small nanoparticles, less than 60 nm in diameter, able to effectively extravasate (adapted with permission from ). C.) Cationic nanoparticles have superior transvascular flux in solid tumors, with q [Coulomb/m2] being the surface charge density (simulation results obtained with permission from ) and D. and E.) Rods can more effectively extravasate into the tumor compared with spherical particles of the same hydrodynamic diameter. Asterisk denotes a statistically significant difference (obtained with permission from ).

Figure 3

Figure 3

Effect of particle physicochemical properties on interstitial transport. A.) Interstitial fluid pressure is often uniformly elevated rendering diffusion the main mechanism of interstitial transport within the pores of the collagen network in the tumor interstitial space (adapted with permission from ). B.) Size-dependent interstitial diffusivity as a function of the hydrodynamic radius for diffusion in PBS, the dorsal skin and the brain (with permission from ). C.) Simulation results for the effect of electrostatic repulsion on interstitial diffusivity. Normalized diffusion is the ratio of the diffusion coefficient in the tissue over the diffusion coefficient in water and λ is the ratio of particle radius divided by the fiber radius (with permission from ). D.) Effect of particle shape on the interstitial transport of nanoparticles. Intratumor distribution refers to the area of tumor sections occupied by the particles and the distribution of the spherical and rod-like particles in a tumor section (Bottom). Asterisk denotes a statistically significant difference (with permission from ).

Figure 4

Figure 4

Effect of binding affinity and drug release rate on the efficacy of two-stage and multistage drug delivery systems. A.) Conventional, two-stage delivery systems are composed of the nano-carrier and the drug. The drug is released by the nano-carrier in a controlled fashion. B.) Optimization contour plot of the fraction of killed cells as a function of the binding affinity of the drug and the drug release rate. C.) Multi-stage drug delivery systems consist of an extra step in the delivery of nanomedicines to solid tumors including a primary nanoparticle, a secondary nanoparticle and the drug. D.) Optimization contour plot for a multi-stage delivery system (Adapted with permission from ).

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References

    1. Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol. 2010;7:653–64. - PMC - PubMed
    1. Prabhakar U, Maeda H, Jain RK, Sevick-Muraca EM, Zamboni W, Farokhzad OC, et al. Challenges and Key Considerations of the Enhanced Permeability and Retention Effect for Nanomedicine Drug Delivery in Oncology. Cancer Res. 2013;73:2412–7. - PMC - PubMed
    1. Chauhan VP, Jain RK. Strategies for advancing cancer nanomedicine. Nat Mater. 2013;12:958–62. - PMC - PubMed
    1. Gerlowski LE, Jain RK. Microvascular permeability of normal and neoplastic tissues. Microvasc Res. 1986;31:288–305. - PubMed
    1. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent Smancs. Cancer Res. 1986;46:6387–92. - PubMed

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