Strategies for advancing cancer nanomedicine

Abstract

Cancer nanomedicines approved so far minimize toxicity, but their efficacy is often limited by physiological barriers posed by the tumour microenvironment. Here, we discuss how these barriers can be overcome through innovative nanomedicine design and through creative manipulation of the tumour microenvironment.

Figure 1

The transport barriers to drug delivery in tumours. a, Drugs enter a tumour through its blood supply. These drugs — ranging in size from a few ångströms to roughly 100 nm — must then cross the blood vessel walls (that is, extravasate) to penetrate into tissues. As convection is negligible in large regions of tumours, these drugs must then diffuse through the extravascular space. As the drugs distribute through the extravascular space they may eventually reach their target cancer cells. b, In tumours, the pores of blood vessel walls range from roughly 1 nm up to hundreds of nanometres in diameter. As a consequence of this spatially non-uniform permeability, nanoparticles extravasate only from some regions of tumour vessels, and when they do, they penetrate only a few cell layers into tumours. c, Matrix molecules such as collagen can form a barrier that limits nanomedicine distribution through the interstitial space. These matrix molecules create pores of roughly 10 nm to hundreds of nanometres and can sterically block particles from regions of tumours or can impede these particles through hydrodynamic and electrostatic interactions. d, The blood supply to tumours is spatially and temporally heterogeneous. Blood flow in some regions of tumours is quite brisk, while impaired in other regions because of vascular compression and excessive leakiness. As few as 20% of the blood vessels in a tumour may actually carry blood flow, making the distances a drug must travel to reach cancer cells up to hundreds of micrometres. Figure reproduced with permission from: b, ref. , © 1994 AACR; c, ref. , © 2006 AACR; d, ref. , © 2013 NPG.

Figure 2

The complex structure of the tumour microenvironment. a, Tumours may be ‘desmoplastic’ (rich in stromal cells and extracellular matrix) or ‘cellular’ (largely composed of cancer cells). Targeted nanomedicines or their drug cargo can bind, specifically or non-specifically, to components of both tumour classes including cells and matrix molecules, which can retard their movement into tumours. The nature of this binding-site barrier therefore varies by cancer type. b, The properties of the microenvironment change with increasing depth away from functional blood vessels. Oxygen levels decrease with depth, and this problem is exacerbated by low perfusion, resulting in hypoxia. Excessive carbon dioxide and lactic acid production lead to low pH away from blood vessels. As a consequence of increasing cancer-cell density and hypoxia, the concentrations of various enzymes also vary with depth away from vessels. These factors can be exploited to trigger targeted drug release deep in tumours.

Figure 3

Normalizing the tumour microenvironment to improve drug delivery and efficacy. Drug-delivery barriers resulting from tumour pathophysiology cannot all be overcome by nanomedicine design. Nanomedicines can be combined with therapies that normalize these physiological abnormalities for enhanced anti-tumour efficacy. a, Vascular normalization repairs blood vessels, making them more mature, more homogenous and less leaky. This lowers interstitial fluid pressure which restores a transvascular fluid pressure difference that results in improved blood flow and convective nanoparticle penetration in tumours. b, Stress normalization reduces solid stress, the mechanical stress that compresses tumour blood vessels, to restore perfusion throughout tumours. This increases the supply of drugs, such as nanomedicines, throughout tumours. c, Matrix normalization modulates the structure of matrix molecules such as collagen, reducing their hindrance to nanomedicine distribution. This results in a more uniform distribution of nanomedicines in tumours. Depending on the extent of matrix depletion and reorganization, matrix normalization can potentially also normalize solid stress and lead to increased perfusion in addition to improved matrix penetration.