PerspectiveTargeted drug delivery to tumors: Myths, reality and possibility
Introduction
The ultimate goal of drug delivery research is to help patients by developing clinically useful formulations. During the last several decades controlled drug delivery technology has advanced significantly, leading to the development of various clinical formulations improving patient compliance and convenience [1]. Current technologies allow delivery of drugs at desired release kinetics for extended periods of time ranging from days to years. Oral and transdermal drug delivery systems routinely deliver drugs for 24 h, substantially improving drug efficacy and minimizing side effects. Implantable systems can locally deliver drugs for months, even years. While significant advances have been made, there are still areas where substantial improvements need to be made to reach the next level of clinical relevance. One such area is targeted drug delivery to solid tumors. The clinically significant impact of targeted drug delivery lies in the ability to specifically target a drug or drug carrier to minimize drug-originated systemic toxic effects.
Successful translation (from bench to bedside) of potential cancer and gene therapies, particularly small interfering RNA (siRNA) delivery, will largely depend on targeted drug delivery strategies. Overcoming the many challenges of identifying a successful targeted drug delivery strategy requires an understanding of events involving transport of drug or drug carrier to a target site after intravenous (i.v.) administration as well as issues relevant for specific target diseases and the body's response toward a drug delivery system. The current lack of clear recognition of problems facing the drug delivery field can be anticipated to result in only marginal advances in targeted drug delivery technologies in the coming years. The current unmet needs and challenges in this area were summarized by Professor Alexander T. Florence who is one of the few who raised awareness on the exaggerated claims of the nanoparticle-based drug targeting [2], [3]. They need to be better appreciated and understood for achieving greater success in drug targeting to tumors. Thus, it would be profitable to address a variety of issues and factors that could affect the development of improved targeted drug delivery systems. Many terms have been used to describe nano-sized drug delivery systems, and here the term “nanoparticle” is used to represent a spectrum of systems, including nanocarrier, nanovehicle, nanosystem, nanostructure, and other terms used in the literature.
Section snippets
A few observations on anticancer treatment
A typical in vitro study of targeted anticancer drug delivery is based on cultured human cancer cells which express a unique surface marker specifically selected to test the targeted delivery strategy being examined. Cytotoxicity is commonly examined by the addition of a drug delivery system directly to cells grown as a monolayer or in suspension. Such studies produce a dose–response curve with an IC50 (the concentration needed to inhibit 50% cell growth) of an anticancer agent under these in
Targeted drug delivery
The term “targeted drug delivery” (or “drug targeting”) used in drug delivery is distinct from “targeted therapy” (or “targeting therapy”) that is frequently used in drug discovery. Targeted drug delivery refers to predominant drug accumulation within a target zone that is independent of the method and route of drug administration [9]. On the other hand, targeted therapy or targeted medicine means specific interaction between a drug and its receptor at the molecular level [10], [11], [12].
Current understanding on drug targeting of i.v. administered systems
Our current understanding of drug targeting to tumors is based on a combination of several independent concepts, involving events associated with the EPR effect, nanoparticle properties and design, increased retention in the circulation due to PEGylation, and ligand–receptor type interactions, as shown in Fig. 1. Each of these concepts is briefly discussed below to clarify the potential confusion associated with each concept.
Reality of tumor targeting
The concept of combining the EPR effect of nanoparticles with the longer systemic circulation properties that can be achieved following PEGylation has been explored. Frequently, antibodies or ligands intended to bind specific receptor molecules on tumor target cells have been PEGylated. Ligand-modified PEGylated nanoparticles showed increased drug accumulation at the target tumor site, but the actual percentage of PEGylated nanoparticles accumulating at the tumor site was only a few percent (at
Clinical EPR effect
Chemotherapy is used after debulking surgery, aiming at unseen residual or metastasized malignant cancer cells. Targeted drug delivery using nanoparticles may provide an opportunity for treating tumors, particularly those which are large enough to develop vasculature or for patients who are not surgical candidates for debulking. In experimental animal models, the EPR effect has been shown to differ from tumor to tumor xenografts implanted at the same site [67], and from site to site following
Future
True targeted drug delivery is still beyond our grasp, but it is probably the single most important property that drug delivery systems should acquire for treating cancers and certain other diseases where it will be important to place a drug selective at specific site of the body. The information necessary to achieve effective drug targeting may already exist, and we simply are not able to extract the answers from all information currently available. By understanding our current
Acknowledgments
This study was supported in part by these grants: NIHCA101850, CA122356, and CA140348 (YHB), and NIH CA129287 and Showalter Research Trust Fund (KP). The authors greatly appreciate careful reading and invaluable comments by Professors Randy Mrsny and Alexander T. Florence.
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