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:

• active targeting
• drug delivery systems
• EPR effect
• nanoparticles
• passive targeting
• stimulus-responsive targeting

Acknowledgments

This publication was made possible by the support of the University of Puerto Rico Rio Piedras Campus and San Juan Bautista School of Medicine. The authors thank Dr. Estela Estapé for her outstanding dedication and support in the writing process of this review. Moraima Morales-Cruz and Yamixa Delgado are co-first authors.

Abbreviations

ABC phenomenon, accelerated blood clearance; BBB, blood–brain barrier; CPP, cell-penetrating peptide; Cyt C, cytochrome c; MDRS, multidrug resistance syndrome; DDS, drug delivery system; DNR, daunorubicin; EGF, epidermal growth factor; EPR, enhanced permeation and retention effect; FA, folic acid; FAR, folic acid receptor; GHS, glutathione; HA, hyaluronic acid; HRG, heregulins; IL, interleukin; LHRH, luteinizing hormone-releasing hormone; MMP, membrane-type matrix metalloproteinase; NP, nanoparticle; PDC, peptide–drug conjugate; PDT, photodynamic therapy; PEG, poly(ethylene glycol); PLGA, poly(lactic-co-glycolic) acid; PLL, poly-L-lysine; PS, photosensitizing agent; PTX, paclitaxel; RES, reticuloendothelial system; RGD peptide, Arg-Gly-Asp peptide; RT, radiation therapy; ROS, reactive oxygen species; TGF, transforming growth factor; Tf, transferrin; TfR, transferrin receptor; SA, serum albumin; VEGF, vascular endothelial growth factor.

Author Contributions

MMC and YD contributed equally in the design and selection of the topics for this article. All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work. KG and YD coordinated and conceived the review article.

Disclosure

The authors report no conflict of interest in this work.