Nano Today
Volume 11, Issue 2, April 2016, Pages 133-144
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Surface charge critically affects tumor penetration and therapeutic efficacy of cancer nanomedicines

https://doi.org/10.1016/j.nantod.2016.04.008Get rights and content

Highlights

  • Positively charged PEGylated nanomedicines exhibit shorter blood circulation and lower tumor accumulation than their neutral and anionic counterparts.

  • Positively charged PEGylated nanomedicines exhibit superior extravasation and penetration in tumors.

  • Positively charged PEGylated nanomedicines show higher cellular uptake in disaggregated tumors.

  • Positively charged PEGylated nanomedicines exhibit enhanced antitumour efficacy in a variety of tumor models.

Summary

Physiochemical properties of nanomedicines determine their in vivo fate and ultimate therapeutic efficacy. Establishing correlations between nanoparticle properties and their physiological response is vitally important for nanomedicine design and optimization. To date, the correlation between surface charge, a fundamental property of a nanomedicine, and its therapeutic efficacy remains poorly understood. Here, we systematically investigated the influence of surface charge on the pharmacokinetics, tumor accumulation, penetration, and antitumor efficacy of nanoparticles constructed from PEG-b-PLA, loaded with docetaxel, and tuned by various lipids to yield three groups of ∼100 nm nanoparticles with positive, neutral or negative charge. Our results indicate that cationic PEGylated nanoparticles, although slightly inferior in blood circulation time and tumor accumulation, outperform their anionic or neutral counterparts in inhibiting tumor growth in five different tumor models. Docetaxel-loaded cationic nanoparticles significantly suppressed tumor growth with an inhibition ratio of ∼90%, compared with the ∼60% achieved by their anionic or neutral counterparts. Further studies reveal that better tumor penetration and 2.5-fold higher cellular uptake of cationic PEGylated nanoparticles is responsible for their superior treatment efficacy. This fundamental study provides a foundation for engineering the next generation of nano-delivery systems for in vivo applications.

Introduction

Physiochemical properties of cancer nanomedicines such as size, shape, and surface chemistry play a critical role in their behavior in complex in vivo physiological environments, which ultimately determine their antitumor effect [1], [2], [3]. Establishing defined correlations between the basic physiochemical properties of nanomedicines and their in vivo fate, especially the therapeutic effect, is particularly instructive for improving the therapeutic outcomes and guiding the design of nano-delivery systems. In the past decade, numerous studies have investigated the influence of particle size on the interactions of nanoparticles (NPs) with biological systems [4], [5], [6]. In contrast, the influence of surface charge remains poorly understood. In vitro, surface charge decides the extent of cellular uptake, distribution in subcellular compartments, and permeability in multicellular spheroids [7], [8], [9], [10], [11], [12]. In vivo, NPs with neutral and negative surface charges reduce the adsorption of serum proteins, resulting in longer circulation half-lives [13]. McDonald and colleagues have showed that positively charged liposomes exhibited higher binding and internalization by angiogenic endothelial cells in tumors than in normal vasculature [14]. Despite these advances, how surface charge affects polymeric nanoparticle transport in the tumor interstitium in vivo, along with how it correlates with the ultimate antitumor activity has not been elucidated.

In this study, we prepared a series of PEGylated lipid-associated polymeric NPs with variable surface charges and examined their in vivo performance. The NPs were prepared by assembling poly(ethylene glycol)-block-poly(d,l-lactide) (PEG-b-PLA) copolymers with varying lipid components to modulate surface charge (Fig. 1A). We systematically investigated the influence of surface charge on the pharmacokinetics, tumor accumulation, penetration, and therapeutic effect of these PEGylated NPs. Our results reveal that cationic PEGylated nanoparticles, although slightly inferior in blood circulation and tumor accumulation, are more effective in inhibiting tumor growth than their anionic or neutral counterparts in a variety of tumor models. Further studies demonstrate that cationic PEGylated NPs have improved penetration in the tumor interstitium, which ultimately enhances the intratumor drug availability and leads to the superior treatment efficacy.

Section snippets

Materials

PEG-b-PLA (poly(ethylene glycol)-block-poly(d,l-lactide)) and BHEM-Chol (N,N-Bis(2-hydroxyethyl)-N-methyl-N-(2-cholesteryloxycarbonyl aminoethyl) ammonium bromide) were synthesized according to the literature [15]. DOTAP (1,2-dioleoyl-3-trimethylammonium-propane chloride), EPC (1,2-dioleoyl-sn-glycero-3-ethylphosphocholine chloride), DSPG (1,2-distearoyl-sn-glycero-3-phospho-(1′-rac-glycerol) sodium), and DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) were purchased from Avanti Polar

Surface charge modulation of docetaxel-loaded lipid-associated NPs

Before preparing the lipid-associated polymeric NPs, we first carried out a combinatorial screening to identify one PEG-b-PLA particle suitable for comparison. Size, size distribution, and drug loading level of a nanomedicine are all sensitive to the composition of the carrier. We systematically varied the length of the PEG and the PLA segments of the diblock copolymer. After screening a library of 18 PEG-b-PLA nanoparticles, we selected four NPs with size of approximately 50 or 100 nm, narrow

Discussion

Physiochemical characteristics of NPs such as size and surface charge are crucial parameters dictating their in vivo performance. Among the physiological responses, tumor penetration could have a profound effect on the ultimate antitumor efficacy [5]. This is because the tumor microenvironment develops an elevated interstitial fluid pressure and dense extracellular matrix, which could dramatically restrict the interstitial transport of nanoscaled particles [1], [25], [26]. Numerous studies have

Competing interests

The authors declare no competing interests.

Acknowledgments

The authors are grateful to the support of Core Facility Center for Life Sciences, University of Science and Technology of China. This study was supported by the National Basic Research Program of China (973 Programs, 2012CB932500, 2015CB932100 and 2013CB933900) and the National Natural Science Foundation of China (51125012, 51390482). Support from NIH (HL109442 and AI096305) is also acknowledged.

Hong-Xia Wang obtained her Ph.D. at University of Science and Technology of China under the guidance of Prof. Jun Wang. She is currently a postdoctoral researcher in Prof. Kam Leong's lab at Columbia University. Her research focuses on the development of nanocarriers for siRNA and drug therapy, and in understanding the critical barriers to the systemic administration of these nanomedicines.

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    Hong-Xia Wang obtained her Ph.D. at University of Science and Technology of China under the guidance of Prof. Jun Wang. She is currently a postdoctoral researcher in Prof. Kam Leong's lab at Columbia University. Her research focuses on the development of nanocarriers for siRNA and drug therapy, and in understanding the critical barriers to the systemic administration of these nanomedicines.

    Zu-Qi Zuo is currently a Ph.D. candidate of biomaterials in University of Science and Technology of China. His research interests include nanoparticle-mediated cancer cell or cancer stem cell therapy and immunotherapy. Some of his achievements are promoting tumor penetration of nanoparticles for cancer stem cell therapy.

    Jin-Zhi Du received his B.S. and Ph.D. degree at University of Science and Technology of China in 2006. He is currently a postdoctoral associate in the research group of Prof. Shuming Nie at Emory University and Georgia Institute of Technology. His research interest focuses on the design and development of stimuli-responsive materials/nanoparticles for cancer detection and therapy.

    Yu-Cai Wang is a Professor in School of Life Sciences, with a joint appointment in Medical Center of University of Science and Technology of China. His current research interests are developing functional polymeric and nano-materials and exploring their bioapplications.

    Rong Sun recently received her Ph.D. in Prof. Jun Wang's group at University of Science and Technology of China. She is involved in the study of co-delivery of drugs with nanoparticle for cancer stem cell therapy.

    Zhi-Ting Cao received her B.S. in Sichuan University. After graduation, she participated in Hefei National Laboratory for Physical Sciences at the Microscale and is currently a Ph.D. candidate in University of Science and Technology of China. Her research areas include studying drug-resistant cancer and the protein corona on nanoparticles.

    Xiao-Dong Ye is an Associated Professor of Chemical Physics at University of Science and Technology of China. His area of expertise is in the field of macromolecular folding kinetics and laser light scattering.

    Ji-Long Wang received his B.S. in Tianjin Medical University and is currently a Ph.D. candidate of Biomaterials at University of Science and Technology of China. His research topics are the effects of surface PEG on the in vivo fate of nanoparticles and the oral drug delivery system for treatment of chronic ulcerative colitis.

    Kam W. Leong is the Samuel Y. Sheng Professor of Biomedical Engineering at Columbia University, with a joint appointment in the Department of Systems Biology at the Columbia University Medical Center. His research focuses on nanoparticle-mediated drug-, gene- and immuno-therapy, from design and synthesis of new carriers to applications for cancer, hemophilia, infectious diseases, and cellular reprogramming. He is the Editor-in-Chief of Biomaterials, and a member of the National Academy of Inventors and the USA National Academy of Engineering.

    Jun Wang is a Professor in School of Life Sciences of University of Science and Technology of China (USTC), with joint appointments in Medical Center of USTC, Hefei National Laboratory for Physical Sciences at Microscale, and High Magnetic Field Laboratory of Chinese Academy of Science. He has been elected Fellows of American Society of Gene and Cell Therapy (ASGCT), Chinese Society for Biomaterials, Chinese Chemical Society Division of Chemical Biology and Chinese Micro/Nano Technology Society Division of Nanomedicine. He is on the editorial boards of Biomaterials Science, Acta Biomaterialia, and ChemNanoMat. His current research interests are developing biodegradable nanomaterial-based drug delivery systems for targeted therapies of malignant, infectious and immune-related diseases, with a particular focus on RNAi-based cancer therapy, cancer stem cell-targeted therapy, anti-infective therapy, and immunotherapy.

    1

    These two authors contributed equally to this work.

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