Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?

Abstract

Nanotechnology offers several attractive design features that have prompted its exploration for cancer diagnosis and treatment. Nanosized drugs have a large loading capacity, the ability to protect the payload from degradation, a large surface on which to conjugate targeting ligands, and controlled or sustained release. Nanosized drugs also leak preferentially into tumor tissue through permeable tumor vessels and are then retained in the tumor bed due to reduced lymphatic drainage. This process is known as the enhanced permeability and retention (EPR) effect. However, while the EPR effect is widely held to improve delivery of nanodrugs to tumors, it in fact offers less than a 2-fold increase in nanodrug delivery compared with critical normal organs, resulting in drug concentrations that are not sufficient for curing most cancers. In this Review, we first overview various barriers for nanosized drug delivery with an emphasis on the capillary wall's resistance, the main obstacle to delivering drugs. Then, we discuss current regulatory issues facing nanomedicine. Finally, we discuss how to make the delivery of nanosized drugs to tumors more effective by building on the EPR effect.

Figure 1.

Barriers for the delivery of nano-sized drugs into tumors

Figure 2.

Methods for improving cancer nano-sized drug delivery based on EPR effects by manipulating intrinsic physiological barriers.

Figure 3.

A. 800 nm fluorescence image. NIR-PIT induced SUPR effects delivered PEGylated quantum dots (800 nm emission; 50 nm in diameter) into a NIR-PIT treated tumor at a 24-fold higher concentration than in nontreated tumor with conventional EPR effects at 1 hour after injection. Yellow arrow indicates the NIR-PIT treated tumor and the white arrow indicates the nontreated tumor. B. DIC (left) and IR700 fluorescence microscopic image (right) of N87 tumor. IR700 injected after NIR-PIT accumulated in the deeper area of NIR-PIT treated tumor. C. Super enhanced delivery of antibody-drug conjugate (ADC, trastuzumab-CA4) into NIR-PIT treated tumor (arrow indicates NIR-PIT treated tumor). ADC accumulated in NIR-PIT treated tumor only 1 hour after injection and accumulation area increased gradually, indicating the retention of ADC due to the SUPR effect. D. SUPR delivery of gadofosveset, a protein-binding MRI contrast agent. Gadofosveset greatly and homogeneously enhances only post NIR-PIT treated tumor 30 in after injection. Arrow indicates tumor. E. Intratumoral leakage of large nanoparticles (~200 nm) following NIR-PIT. NIR-PIT treated tumor showed low signal intensity on T2* weighted MR images after administration of super paramagnetic iron oxide (SPIO; mean diameter ~200 nm), indicating the selective uptake of SPIO (green arrow). Blue arrow indicates non-treated tumor.