www.acsnano.org
New Insights into “Permeability” as in the Enhanced Permeability and Retention Effect of Cancer Nanotherapeutics gaps contribute to nanoparticle uptake at the cancer site.8,9 It is often suggested that the size (100−500 nm) of these gaps is a determining factor of a preferred or optimal nanocarrier size for drug delivery, often quoted to be in the size range of 50−200 nm.1 However, this size range also fits the dimensions of endocytic compartments (e.g., caveolae, clathrin-coated pits, and macropinocytotic vesicles), which may play a role in vascular transcytosis. 10 We also know that there are considerable differences in the tumor matrix and microenvironment that contribute to differences between different cancer types.
T
here has been significant debate about the nature of the enhanced permeability retention effect (EPR) for promoting drug delivery by therapeutic nanoparticles at sites of rapid cancer growth.1,2 While the usual explanation of EPR centers on tumor blood vessel leakiness as a result of structural and architectural abnormalities,1 the reality is that the basis for “enhanced permeability” is incompletely understood. Although vascular abnormalities such as abnormal fenestrations, structural disorganization, irregular branching, serpentine structure, uneven distribution density, and irregular perfusion have been reported at the site of growing cancers,1,2 we also know that for tumors with a dysplastic stroma (e.g., pancreatic cancer), the vasculature may be poorly perfused and even collapsed or obstructed by tumor-associated fibroblasts or pericytes that adhere tightly to the vascular wall.3,4 It is therefore of interest that in addition to structural or architectural vascular abnormalities, impairment of lymphatic drainage and permeability enhancing factors (e.g., nitric oxide, bradykinin, vascular endothelial growth factors, angiotensin II, prostaglandins, cytokines) contribute to the EPR effect.1,2,5 Surprisingly, there is infrequent mention of the role of nutritional pathways that constitute the basis for increased blood flow to the tumor site, including vascular transport mechanisms that could potentially be useful for uptake of macromolecules and nanoparticles.
In addition to structural or architectural vascular abnormalities, impairment of lymphatic drainage and permeability enhancing factors (e.g., nitric oxide, bradykinin, vascular endothelial growth factors, angiotensin II, prostaglandins, and cytokines) contribute to the EPR effect. Against this background, it is interesting that a transcytosis pathway, comprised of an extensive network of grouped and interlinked cytoplasmic vesicles and vacuoles (also known as the vesiculo-vascular organelle or VVO), has been described in normal endothelial cells.11 This endocytic pathway also constitutes an important mechanism for nutrient supply to growing tumors under the control of vascular endothelial growth factors (VEGF). In this regard, it has been shown that growth factors, such as VEGF-A, VEGF-A165, TGF-β, and semaphorin 3A display a C-terminal peptide motif that binds to neuropilin-1 (NRP-1), a receptor expressed on tumor blood vessels.12 Neuropilin-1 triggers an endocytic transcytosis process, where the vesicles resemble macropinocytotic vesicles or take on the appearance of the VVO pathway.13 The pathway can be therapeutically controlled by a cyclic 9-amino acid (iRGD) peptide that contains the NRP-1 binding motif on the vascular growth factors in a cryptic form.13 iRGD exhibits the sequence CRGDKGPDC, in which the lysine can be an arginine and the aspartic acid a glutamic acid. Upon binding to αvβ3 and αvβ5 integrins, overexpressed at the cancer site, proteolytic cleavage of iRGD releases a C-terminal (CendR) motif to trigger NRP-1-mediated transcytosis.12,14 Through the use of iRGD and electron-dense therapeutic nanoparticles, it was possible to obtain ultrastructural evidence for the transcytosis pathway in an orthotopic pancreatic tumor model
The basis for “enhanced permeability” is incompletely understood. There is generally good agreement that nanocarriers (such as liposomes and polymeric nanoparticles) can be used to enhance the delivery and concentration of chemotherapeutics at the tumor site over free drug in animal as well as in human studies.1,6 In fact, compelling evidence has recently been provided that imaging of superparamagnetic iron oxide nanoparticles (SPIONs) or other traceable nanoparticles can serve as useful imaging guides to predict which patients are likely to respond to nanomedicine therapies.7 A key question, therefore, becomes the understanding of the biophysicochemical basis for nanoparticle extravasation at the cancer site. Is extravasation primarily a process of nanoparticles slipping through abnormal fenestrations or gaps between adjacent endothelial cells or is the major access route transendothelial transport pathways that assist tumor growth and nutrition? Alternatively, is transcytosis a combination of both processes? While it is known that nanoparticles can be successfully delivered to organs with a portal vascular system, which include endothelial cells with vascular fenestrations (e.g., the liver and bone marrow), it has been difficult to determine to what extent passive nanoparticle transport through interendothelial cell © 2017 American Chemical Society
Published: October 24, 2017 9567
DOI: 10.1021/acsnano.7b07214 ACS Nano 2017, 11, 9567−9569
Editorial
Cite This: ACS Nano 2017, 11, 9567-9569
ACS Nano
Editorial
blood vessels, that there is a difference in iRGD responsiveness.15 The tumor of a subject with high vascular NRP-1 expression had improved iRGD-mediated drug delivery and therapeutic effect compared to a tumor with low expression levels. This effect opens up the possibility that development of additional biomarkers that reflect responsiveness to vascular growth factors or related treatment modalities may complement the use of nanoparticle imaging for predicting the tumor response to therapeutic nanoparticles.15
Andre Nel, Associate Editor
Erkki Ruoslahti Sanford Burnham Medical Research Institute Figure 1. A representative electron micrograph highlights the presence of intravenously injected nanocarrier (lipid-coated mesoporous silica nanoparticle or silicasome; top left insert) in a Kras-mutated orthotopic pancreatic tumor, including the vesicular transport in endothelial cells via an iRGD-induced transcytosis process. For ease of visualization, the vessel lumen, endothelial cell, and tumor interstitium were pseudocolored in pink, orange, and cyan, respectively. The particles were green pseudostained.
Huan Meng
■
University of California Los Angeles
AUTHOR INFORMATION
ORCID
15
in mice (Figure 1). This observation demonstrated that transcytosis of therapeutic mesoporous silica nanoparticles could be significantly increased from the luminal to the abluminal side of the endothelial cell, including trafficking of the particles through the tumor matrix to a perinuclear deposition site in dying cancer cells.15 While the particles can be chemically conjugated to iRGD, this coordination does not have to be the case because the CendR pathway functions as a bulk transport system. Thus, any drug, macromolecule, or nanoparticle present in the blood can be swept into the transcytosis pathway, thereby providing a bystander effect.12 Interestingly, the activity of the NRP-1 pathway is increased by nutrient deprivation, suggesting this pathway may be physiologically controlled to support the survival of the tumor at times of poor nutrient availability.13 In addition to controlling transcytosis of nutritional compounds, the receptors that are engaged by vascular growth factors impact signaling pathways that control vascular permeability. Consequently, it is possible that the NRP-1 pathway may coexist with other mechanisms that may enhance the EPR effect, but with different time kinetics. While the response to the CendR motif commences within minutes, enhanced nanocarrier uptake through the co-delivery of vasodilators, blood pressure elevators, stromal depletion, or physical methods (such as heat or cavitation) may be of slower onset. Nonetheless, the improved understanding of extravasation mechanisms enables new therapeutic modalities to be introduced to enhance nanoparticle accumulation in tumors. The effect may differ from tumor to tumor and from patient to patient, enabling personalized use of nanotherapeutics.15 For instance, we have demonstrated in patient-derived pancreas cancer xenografts, phenotyped for NRP-1 expression on tumor
Andre Nel: 0000-0002-5232-4686 Erkki Ruoslahti: 0000-0003-2496-3445 Huan Meng: 0000-0001-8844-3938 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
■
REFERENCES
(1) Fang, J.; Nakamura, H.; Maeda, H. The EPR Effect: Unique Features of Tumor Blood Vessels for Drug Delivery, Factors Involved, and Limitations and Augmentation of the Effect. Adv. Drug Delivery Rev. 2011, 63, 136−151. (2) Bae, Y. H.; Park, K. Targeted Drug Delivery to Tumors: Myths, Reality, Possibility. J. Controlled Release 2011, 153, 198−205. (3) Cabral, H.; Matsumoto, Y.; Mizuno, K.; Chen, Q.; Murakami, M.; Kimura, M.; Terada, Y.; Kano, M. R.; Miyazono, K.; Uesaka, M.; Nishiyama, N.; Kataoka, K. Accumulation of Sub-100 nm Polymeric Micelles in Poorly Permeable Tumours Depends on Size. Nat. Nanotechnol. 2011, 6, 815−823. (4) Meng, H.; Zhao, Y.; Dong, J.; Xue, M.; Lin, Y.-S.; Ji, Z.; Mai, W. X.; Zhang, H.; Chang, C. H.; Brinker, C. J.; Zink, J. I.; Nel, A. E. TwoWave Nanotherapy To Target the Stroma, Optimize Gemcitabine Delivery To a Human Pancreatic Cancer Model in Mice. ACS Nano 2013, 7, 10048−10065. (5) Prabhakar, U.; Maeda, H.; Jain, R. K.; Sevick-Muraca, E. M.; Zamboni, W.; Farokhzad, O. C.; Barry, S. T.; Gabizon, A.; Grodzinski, P.; Blakey, D. C. Challenges, Key Considerations of the Enhanced Permeability, Retention (EPR) Effect for Nanomedicine Drug Delivery in Oncology. Cancer Res. 2013, 73, 2412−2417. (6) Clark, A. J.; Wiley, D. T.; Zuckerman, J. E.; Webster, P.; Chao, J.; Lin, J.; Yen, Y.; Davis, M. E. CRLX101 Nanoparticles Localize in Human Tumors, Not in Adjacent, Nonneoplastic Tissue after
9568
DOI: 10.1021/acsnano.7b07214 ACS Nano 2017, 11, 9567−9569
ACS Nano
Editorial
Intravenous Dosing. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 3850− 3854. (7) Miller, M. A.; Arlauckas, S.; Weissleder, R. Prediction of AntiCancer Nanotherapy Efficacy by Imaging. Nanotheranostics 2017, 1, 296−312. (8) Li, S.-D.; Huang, L. Pharmacokinetics, Biodistribution of Nanoparticles. Mol. Pharmaceutics 2008, 5, 496−504. (9) Zhao, F.; Meng, H.; Yan, L.; Wang, B.; Zhao, Y. Nanosurface Chemistry, Dose Govern the Bioaccumulation, Toxicity of Carbon Nanotubes, Metal Nanomaterials, Quantum Dots. in Vivo. Sci. Bull. 2015, 60, 3−20. (10) Tuma, P. L.; Hubbard, A. L. Transcytosis: Crossing Cellular Barriers. Physiol. Rev. 2003, 83, 871−932. (11) Feng, D.; Nagy, J. A.; Hipp, J.; Dvorak, H. F.; Dvorak, A. M. Vesiculo-Vacuolar Organelles, the Regulation of Venule Permeability to Macromolecules by Vascular Permeability Factor, Histamine, and Serotonin. J. Exp. Med. 1996, 183, 1981−1986. (12) Sugahara, K. N.; Teesalu, T.; Karmali, P. P.; Kotamraju, V. R.; Agemy, L.; Greenwald, D. R.; Ruoslahti, E. Coadministration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs. Science 2010, 328, 1031−1035. (13) Pang, H.-B.; Braun, G. B.; Friman, T.; Aza-Blanc, P.; Ruidiaz, M. E.; Sugahara, K. N.; Teesalu, T.; Ruoslahti, E. An Endocytosis Pathway Initiated through Neuropilin-1, Regulated by Nutrient Availability. Nat. Commun. 2014, 5, 4904−4904. (14) Teesalu, T.; Sugahara, K. N.; Kotamraju, V. R.; Ruoslahti, E. CEnd Rule Peptides Mediate Neuropilin-1-Dependent Cell, Vascular, and Tissue Penetration. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 16157−16162. (15) Liu, X.; Lin, P.; Perrett, I.; Lin, J.; Liao, Y.-P.; Chang, C. H.; Jiang, J.; Wu, N.; Donahue, T.; Wainberg, Z.; Nel, A. E.; Meng, H. Tumor-Penetrating Peptide Enhances Transcytosis of SilicasomeBased Chemotherapy for Pancreatic Cancer. J. Clin. Invest. 2017, 127, 2007−2018.
9569
DOI: 10.1021/acsnano.7b07214 ACS Nano 2017, 11, 9567−9569
