Smart Targeting To Improve Cancer Therapeutics

Abstract

Cancer is the second largest cause of death worldwide with the number of new cancer cases predicted to grow significantly in the next decades. Biotechnology and medicine can and should work hand-in-hand to improve cancer diagnosis and treatment efficacy. However, success has been frequently limited, in particular when treating late-stage solid tumors. There still is the need to develop smart and synergistic therapeutic approaches to achieve the synthesis of strong and effective drugs and delivery systems. Much interest has been paid to the development of smart drug delivery systems (drug-loaded particles) that utilize passive targeting, active targeting, and/or stimulus responsiveness strategies. This review will summarize some main ideas about the effect of each strategy and how the combination of some or all of them has shown to be effective. After a brief introduction of current cancer therapies and their limitations, we describe the biological barriers that nanoparticles need to overcome, followed by presenting different types of drug delivery systems to improve drug accumulation in tumors. Then, we describe cancer cell membrane targets that increase cellular drug uptake through active targeting mechanisms. Stimulus-responsive targeting is also discussed by looking at the intra- and extracellular conditions for specific drug release. We include a significant amount of information summarized in tables and figures on nanoparticle-based therapeutics, PEGylated drugs, different ligands for the design of active-targeted systems, and targeting of different organs. We also discuss some still prevailing fundamental limitations of these approaches, eg, by occlusion of targeting ligands.

Keywords: EPR effect; active targeting; drug delivery systems; nanoparticles; passive targeting; stimulus-responsive targeting.

Figure 1

Scheme of (A) a free drug (eg, chemotherapy) versus encapsulated drug in a DDS for tumor delivery by passive targeting via the EPR effect and (B) active targeting using a ligand-mediated cellular internalization of the encapsulated drug via receptor-mediated endocytosis. The nanosize of well-designed DDS allows the drug to circulate for a longer period of time in the bloodstream to eventually extravasate and accumulate in the tumor tissue through “leaky” tumor vasculature. Decorating the nanocarriers with targeting ligands allows the specific binding to receptors overexpressed on tumor cells.

Figure 2

From passive to active targeting by the attachment of steering molecules to the surface of the NPs for molecular recognition by cancer cell membrane. Abbreviations: FA, folic acid; HA, hyaluronic acid; Tf, transferrin; EGF, epidermal growth factor.

Figure 3

Scheme of the types of stimuli-responsive strategies utilized in the development of DDS. Drug release can in principle occur in the extracellular microenvironment or directly in the cell cytoplasm.