Cancer drug delivery: considerations in the rational design of nanosized bioconjugates

Abstract

In order to efficiently deliver anticancer agents to tumors, biocompatible nanoparticles or bioconjugates, including antibody-drug conjugates (ADCs), have recently been designed, synthesized, and tested, some even in clinical trials. Controlled delivery can be enhanced by changing specific design characteristics of the bioconjugate such as its size, the nature of the payload, and the surface features. The delivery of macromolecular drugs to cancers largely relies on the leaky nature of the tumor vasculature compared with healthy vessels in normal organs. When administered intravenously, macromolecular bioconjugates and nanosized agents tend to circulate for prolonged times, unless they are small enough to be excreted by the kidney or stealthy enough to evade the macrophage phagocytic system (MPS), formerly the reticulo-endothelial system (RES). Therefore, macromolecular bioconjugates and nanosized agents with long circulation times 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, success of cancer drug delivery only relying on the EPR effect is still limited. To cure cancer patients, further improvement of drug delivery is required by both designing superior agents and enhancing EPR effects. In this Review, we describe the basis of macromolecular or nanosized bioconjugate delivery into cancer tissue and discuss current diagnostic methods for evaluating leakiness of the tumor vasculature. Then, we discuss methods to augment conventional "permeability and retention" effects for macromolecular or nanosized bioconjugates in cancer tissue.

Figure 1

General pharmacokinetics of macromolecular and nanosized bioconjugates when injected intravenously. EPR effects operate only with sufficiently long circulation of bioconjugates.

Figure 2

Images of a patient with high serum PSA (17.8 ng/mL) are shown. Axial T2W MRI (A) and ADC maps of diffusion weighted MRI (B) show a midline to the left anterior transition zone lesion in the mid prostate level (arrows). K_trans (C) and k_ep (D) maps generated from the DCE MRI data using a two-compartment model quantitative technique show an area of leaky vasculature that highly suggests cancer (arrows). Targeted biopsy revealed that highly malignant prostate cancer grew within the suggested lesion.

Figure 3

Strategies for further improving cancer delivery of macromolecular and nanosized bioconjugates over conventional EPR effects.

Figure 4

Photoimmunotherapy induced super-enhanced permeability and retention (SUPR) effects delivered PEGylated quantum dots (800 nm emission; 50 nm in diameter) into PIT-treated tumor 24-fold higher concentration than in nontreated tumor with conventional EFR effects at 1 h after injection. (A: white light image, B: 800 nm fluorescence image.)