Cancer drug delivery: considerations in the rational design of nanosized bioconjugates.
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.
Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
Hisataka
H
Kobayashi
Baris
B
Turkbey
Rira
R
Watanabe
Peter L
PL
Choyke
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry*; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy
D000970:Antineoplastic Agents