Opinion
Frontiers in cancer nanomedicine: directing mass transport through biological barriers

https://doi.org/10.1016/j.tibtech.2009.12.007Get rights and content

The physics of mass transport within body compartments and across biological barriers differentiates cancers from healthy tissues. Variants of nanoparticles can be manufactured in combinatorially large sets, varying by only one transport-affecting design parameter at a time. Nanoparticles can also be used as building blocks for systems that perform sequences of coordinated actions, in accordance with a prescribed logic. We refer to these as Logic-Embedded Vectors (LEVs). Nanoparticles and LEVs are ideal probes for the determination of mass transport laws in tumors, acting as imaging contrast enhancers, and can be employed for lesion-selective delivery of therapy. Their size, shape, density and surface chemistry dominate convective transport in the bloodstream, margination, cell adhesion, selective cellular uptake, as well as sub-cellular trafficking and localization. As argued here, the understanding of transport differentials in cancer, termed ‘transport oncophysics’, reveals a promising new frontier in oncology: the development of lesion-specific delivery particulates that exploit mass transport differentials to deploy treatment of greater efficacy and reduced side effects.

Introduction

In a seminal paper, Hanahan and Weinberg [1] identified six fundamental acquired capabilities as the shared-trait identifiers of the very diverse family of heterogeneous diseases collectively termed ‘cancer’. These are: tissue invasion and metastasis; sustained angiogenesis; self-sufficiency in growth signals; limitless replicative potential; evasion of apoptosis; and insensitivity to anti-growth signals. Tissue invasion and metastasis are exquisitely cancer-defining transport phenomena at the cellular level (Box 1). All cancer hallmark mechanisms are based on a complex set of defects in the regulatory circuitry that governs normal cell homeostasis and proliferation. Regulatory circuitries at the cell level, in turn, are based on information flow pathways that involve mass transport at the molecular level, because their effectors are cascades of interaction among molecules endowed with a coordinated set of mutual recognition specificities. For instance, extra-cellular transport properties crucially impact cell proliferation through signals received by the cell via trans-membrane receptors that bind diffusible growth factor, cell adhesion molecules, and extra-cellular matrix components. The hallmark of acquired self-sufficiency in growth signals is known to be related to over-expression of growth factor receptors (e.g. EGF, HER2/neu) or receptor type switching (integrins), and might be impacted by disruptions in the signal transport chain, such as by independent or enhanced signaling resulting from receptor over-expression, or other causes. Dys-regulation of the downstream receiving and processing of signals emitted by ligand-activated growth factor receptors and integrins [1] is a transport-based type of mechanism for the induction of self-sufficiency in growth signals (e.g. SOS-Ras-Raf-MAPK pathway). The acquisition of insensitivity to antigrowth signals, which characterizes a large majority of cancers, comprises molecular processing components, which are interrelated to transport properties and the emergence of dys-regulated transport barriers to signaling molecules. Apoptosis controls are largely embedded in cell-to-cell contact signals that mandate the preservation of ‘health’ architectural configurations, and are therefore impacted by transport differentials in cells and molecules.

Collectively, these observations suggest a novel framework for the understanding of cancer, based on aberrations of mass transport at all levels, from molecules to the full organism. This paper is dedicated to identifying fundamental elements of this framework, and proposing novel, transport oncophysics-based diagnostic and therapeutic strategies. Nanotechnologies naturally emerge as the fundamental enabling platforms for this approach – that is, the novel frontier of cancer nanomedicine.

Section snippets

Cancer as a multi-scale mass-transport pathology

Cancer is a disease of the cell, which is inextricably linked to its surrounding biological milieu through a complexity of interactions with its microenvironment and distant sites within the host organism 1, 2. Both the proximal contact and the remote interactions centrally involve mass transport-based information transfer, in the form of molecular signals, the directed movement of cells, and the dynamic elaboration of tissue. The higher-scale portrait of cancer that emerges is that of a

Conclusions

Mass transport differentials are defining characteristics of cancer. Biological barriers are determinants of sufficient relevance in mass transport differentials that a new operational (“oncophysics”) classification of individual lesions might be envisioned based on the characteristics of transport through biobarriers. Nano- and micro-particulates are ideal probes for the study of mass transport differentials in cancer, and, as an immediate corollary, are perfectly suited to the preferential

Acknowledgments

Biana Godin, Paolo Decuzzi, Rita Serda and Tong Sun are gratefully acknowledged for their insightful discussion of the manuscript, and assistance in its preparation. Matt Landry is gratefully recognized for his artistry in the preparation of Figure 1. The author acknowledges financial support from the following sources: DODW81XWH-09-1-0212, DODW81XWH-07-2-0101; NASA NNJ06HE06A; NIH RO1CA128797, NIH – R33 CA122864, NIH U54CA143837 and State of Texas, Emerging Technology Fund.

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