Editorial pubs.acs.org/molecularpharmaceutics
Emerging Technology in Evaluation of Nanomedicine he field of nanomedicine has seen significant progress in recent decades, both in design and in scope of the applications. Nanomedicines can be created with everincreasing control over the size, shape, surface properties, and material platforms. Their applications range from delivery of therapeutic agents to diagnostic or prognostic imaging of tissues and organs. We read reports of new nanoparticulate drug carriers, which demonstrate great biological activities in cells and animal models, in nearly every issue of Molecular Pharmaceutics. However, their clinical translation has been slow, and the number of products on the market has not much increased since the early history of nanomedicine. This imbalance between technical advances and product development has puzzled readers of this field, often raising questions regarding the effectiveness of current strategies to develop new nanomedicines. While multiple reasons may account for the tedious progress, one of the most critical (yet often neglected) challenges is the lack of methodologies to characterize and evaluate nanomedicines in conditions that reflect physiological complexity. Under the current experimental settings, the knowledge obtained from in vitro and preclinical studies has little value in predicting clinical outcomes of new nanomedicines. For example, a new nanoparticle system is routinely characterized with respect to its surface charge and ligand density, which are then correlated with its behaviors and biological effects in cell models. On the other hand, the surface property of a nanoparticle drastically changes in blood or other physiological fluids, where the nanoparticle is readily covered with protein corona. Given the disparity between in vitro properties and in vivo outcomes, many groups have migrated to a research model that involves early in vivo proof of concept studies. However, this strategy is not widely applicable due to the high cost, nor is it readily justified from the ethical perspective. It also remains a question how much predictive value an animal model can provide. With the increasing recognition of the gap between technical advances and product development, it is high time to initiate an open discussion of current challenges in evaluating properties of nanomedicines and predicting their therapeutic and diagnostic/prognostic values in human with greater reliability than currently possible. This special issue has been organized with this goal in mind, featuring articles focusing on nanomedicine evaluation. It begins with three review articles that provide an overview of the state of the art and emerging techniques. In the first of these articles, Nanoparticle Characterization: State of the Art, Challenges, and Emerging Technologies, Yoon Yeo and colleagues present a critical review of in vitro and in vivo techniques currently used in the evaluation of a new nanomedicine. This review is followed by Multifaceted Transport Characteristics of Nanomedicine: Needs for Characterization in Dynamic Environment, by Bumsoo Han and colleagues, where they discuss spatiotemporal transport barriers of nanoparticle delivery to solid tumors from the engineering perspective. The authors present case studies based on two theoretical tumor models with different length scales to illustrate the complexity and
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multifaceted nature of nanoparticle−tumor interactions. In the third review article, Microdevices for Nanomedicine, Daniel Kohane and coauthors discuss miniaturized devices with a variety of applications ranging from organ mimicry to nanomaterial synthesis, which have gained significant interest as a way of facilitating high-throughput evaluation of new therapeutic agents and controlled production of drug delivery systems. Subsequently, several original articles describe unique methodologies to investigate biological fates of nanomedicines. Suzie Pun et al. describe the use of subcellular fractionation methods for quantitative analysis of intracellular trafficking of nonviral vectors in Investigation of Polyethylenimine/DNA Polyplex Transfection to Cultured Cells Using Radiolabeling and Subcellular Fractionation Methods. By differential radiolabeling of plasmid DNA and a polymeric carrier, they observe that cellular uptake and intracellular trafficking of the two components are quite different, which indicates early dissociation of the complex in the transfection process. In the next article, In Vitro Evaluation of Dendrimer−Polymer Hybrid Nanoparticles on Their Controlled Cellular Targeting Kinetics, Seungpyo Hong and colleagues describe a new nanoparticle system called nanohybrid, where folate-targeted polyamidoamine dendrimers were encapsulated in PEGylated biodegradable nanoparticles to achieve advantages of both small targeted particles (targeting and tissue penetration) and large stealth particles (long-term circulation). To obtain a proof of concept, the authors employed a series of in vitro characterization methods including classic cell culture studies for the investigation of cellular uptake and 3-dimensional (3D) multicellular tumor spheroids for the evaluation of dendrimer penetration into tumors. The 3D tumor model is the focus of the next article, Development of an in Vitro 3D Tumor Model to Study Therapeutic Ef f iciency of an Anticancer Drug, written by Kinam Park and colleagues. They describe a new method for creating uniformly sized spheroids as a 3D tumor model using the hydrogel template, which are then combined with a microfluidic device that simulates a dynamic in vivo environment. The next series of articles focus on studies with specimen of living animals or animal models. Justin Hanes and colleagues, in their article, Ex Vivo Characterization of Particle Transport in Mucus Secretions Coating Freshly Excised Mucosal Tissues, present evaluation of nanoparticle transport through mucus barrier ex vivo. For this purpose, they use mucosal tissues freshly obtained from mouse gastrointestinal, vaginal, and respiratory tracts, instead of mucosal secretions, and observe locational and cyclical variations in the mucus mesh, reflected in the rates of nanoparticle transport. In the next article, Quantitative Detection of PLGA Nanoparticle Degradation in Tissues following Intravenous Administration, Joshua Reineke and Abdul Mohammad determine degradation kinetics of poly(lactic-co-glycolic) acid Special Issue: Emerging Technology in Evaluation of Nanomedicine Published: June 3, 2013 2091
dx.doi.org/10.1021/mp400264n | Mol. Pharmaceutics 2013, 10, 2091−2092
Molecular Pharmaceutics
Editorial
(PLGA) nanoparticles distributed in the livers, spleens, and lungs in mice. They observe that in vivo biodegradation of PLGA nanoparticles does not necessarily match in vitro prediction and varies with the size and anatomical locations where they are distributed. The authors comment that in vivo biodistribution and degradation of polymers need to be considered in design of new carriers and may be determined with the method described in their study. While Reineke and Mohammad use tissue sampling and gel permeation chromatography for detection of polymers, Kwangmeyung Kim and coauthors rely on radiolabeling of nanoparticles for noninvasive biodistribution study. In their article, Facile Method To Radiolabel Glycol Chitosan Nanoparticles with 64Cu via Copper-Free Click Chemistry for MicroPET Imaging, the authors use copper-free click chemistry for radiolabeling chitosan-based nanoparticles and examine their biodistribution in tumorbearing mice with microPET. They highlight several advantages of this labeling method, including a mild reaction condition, no need for purification, high labeling efficiency, and stability of the labeling in serum, which makes it attractive for radiolabeling of various nanoparticles. The issue concludes with an article by Ayyappan Rajasekaran and colleagues, Dexamethasone-Loaded Block Copolymer Nanoparticles Induce Leukemia Cell Death and Enhance Therapeutic Eff icacy: A Novel Application in Pediatric Nanomedicine, where they employ a mouse model of acute lymphoblastic leukemia in the evaluation of antileukemic potential of nanoencapsulated dexamethasone. Using this model, the authors demonstrate that sustained systemic delivery of low dose dexamethasone by polymeric nanoparticles is effective in delaying the onset of disease symptoms and increasing the survival time. A significant aspect of this study is that the nanoparticles are evaluated in an animal model with circulating leukemic cells, which closely mimics hematological malignancies; hence, the preclinical results likely have a good predictive value. As the editor of this special issue, I hope that these articles will stimulate more discussions on reliable and predictive methods of nanomedicine characterization and help accelerate clinical development of new products. Finally, I would like to thank all the authors, who contributed their time and effort for this special issue. I also thank Drs. Gordon Amidon and Carston Wagner for the opportunity and Kimberly Barrett for the administrative support.
Yoon Yeo,* Guest Editor
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Department of Industrial and Physical Pharmacy, Weldon School of Biomedical Engineering (by Courtesy), Purdue University, West Lafayette, Indiana 47907, United States
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Corresponding Author
*E-mail:
[email protected]. Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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dx.doi.org/10.1021/mp400264n | Mol. Pharmaceutics 2013, 10, 2091−2092
