Mediating Tumor Targeting Efficiency of Nanoparticles Through Design (original) (raw)
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Tailoring nanoparticle designs to target cancer based on tumor pathophysiology
Proceedings of the National Academy of Sciences of the United States of America, 2016
Nanoparticles can provide significant improvements in the diagnosis and treatment of cancer. How nanoparticle size, shape, and surface chemistry can affect their accumulation, retention, and penetration in tumors remains heavily investigated, because such findings provide guiding principles for engineering optimal nanosystems for tumor targeting. Currently, the experimental focus has been on particle design and not the biological system. Here, we varied tumor volume to determine whether cancer pathophysiology can influence tumor accumulation and penetration of different sized nanoparticles. Monte Carlo simulations were also used to model the process of nanoparticle accumulation. We discovered that changes in pathophysiology associated with tumor volume can selectively change tumor uptake of nanoparticles of varying size. We further determine that nanoparticle retention within tumors depends on the frequency of interaction of particles with the perivascular extracellular matrix for s...
Multifunctional Polymeric Nanosystems for Tumor-Targeted Delivery
Cancer is the second leading cause of morbidity and mortality in the United States, with occurrences portraying an upward trend for the future. In 2007, approximately 10 million cases of cancer will occur globally, with a total of around 1.5 million new cancer cases and over 560,000 deaths expected in the United States (U.S. National Institute of Health, 2006). Strikingly, remarkable advances in diagnosis and therapy of cancer have been made over the past few decades resulting from significant advances in fundamental cancer biology. What lacks in this case is clinical translation of these advances into effective therapies. A major hurdle in cancer diagnosis and therapy is the targeted and efficacious delivery of agents to the tumor site, while avoiding adverse damage resulting from systemic administration. While systemic drug delivery already hinges largely on physicochemical properties of the drug, such as size, diffusivity, and plasma protein binding affinity, tumors possess a dense, heterogeneous vasculature and an outward net convective flow that act as hurdles to efficient drug deposition at the target site (Jang et al., 2003). Nanocarriermediated delivery has emerged as a successful strategy to enhance delivery of therapeutics and imaging agents to tumors, thereby increasing the potential for diagnosis at an earlier stage or for therapeutic success (or both). Based on the initial observation by Maeda and Matsumura that tumors possess a fenestrated vasculature, with pores on average ranging between 200 and 800 nm, and a lack of lymphatic drainage, together termed the enhanced permeability and retention (EPR) effect, it was found that colloidal carriers in the nanometer size range could target tumors passively, by specific extravasation through these fenestrations, and are retained at the site for prolonged time because of lack of lymphatic drainage (Matsumura and Meada, 1986). This physiological advantage has been used successfully to enhance delivery of diagnostic and therapeutic agents, leading to the U.S. Food and Drug Administration (FDA) approval of nanoparticle formulations such as Feridex® for diagnostic applications and Doxil® and Abraxane® for cancer therapy (U.S. Food and Drug Administration, 2006).
Design considerations for tumour-targeted nanoparticles
Nature Nanotechnology, 2010
Inorganic/organic hybrid nanoparticles are potentially useful in biomedicine, but to avoid non-specific background fluorescence and long-term toxicity, they need to be cleared from the body within a reasonable timescale 1 . Previously, we have shown that rigid spherical nanoparticles such as quantum dots can be cleared by the kidneys if they have a hydrodynamic diameter of approximately 5.5 nm and a zwitterionic surface charge 2 . Here, we show that quantum dots functionalized with highaffinity small-molecule ligands that target tumours can also be cleared by the kidneys if their hydrodynamic diameter is less than this value, which sets an upper limit of 5-10 ligands per quantum dot for renal clearance. Animal models of prostate cancer and melanoma show receptor-specific imaging and renal clearance within 4 h post-injection. This study suggests a set of design rules for the clinical translation of targeted nanoparticles that can be eliminated through the kidneys.
Size‐Dependent EPR Effect of Polymeric Nanoparticles on Tumor Targeting
Advanced Healthcare Materials, 2019
Passive targeting of large nanoparticles by the enhanced permeability and retention (EPR) effect is a crucial concept for solid tumor targeting in cancer nanomedicine. There is, however, a trade‐off between the long‐term blood circulation of nanoparticles and their nonspecific background tissue uptake. To define this size‐dependent EPR effect, near‐infrared fluorophore‐conjugated polyethylene glycols (PEG‐ZW800s; 1–60 kDa) are designed and their biodistribution, pharmacokinetics, and renal clearance are evaluated in tumor‐bearing mice. The targeting efficiency of size‐variant PEG‐ZW800s is investigated in terms of tumor‐to‐background ratio (TBR). Interestingly, smaller sized PEGs (≤20 kDa, 12 nm) exhibit significant tumor targeting with minimum to no nonspecific uptakes, while larger sized PEGs (>20 kDa, 13 nm) accumulate highly in major organs, including the lungs, liver, and pancreas. Among those tested, 20 kDa PEG‐ZW800 exhibits the highest TBR, while excreting unbound molecul...
A robust approach to enhance tumor-selective accumulation of nanoparticles
Oncotarget
While nanoparticles have shown great promise as drug carriers in cancer therapy, their effectiveness is critically dependent on the structural characteristics of the tumor vasculature. Here we demonstrate that several agents capable of inducing vascular responses akin to those observed in inflammatory processes enhance the accumulation of nanoparticles in tumors. The vascular-active agents tested in this study included a bacterium, a pro-inflammatory cytokine, and microtubule-destabilizing drugs. Using radiolabeled nanoparticles, we show that such agents can increase the tumor to blood ratio of radioactivity by more than 20-fold compared to nanoparticles alone. Moreover, vascular-active agents dramatically improved the therapeutic effect of nanoparticles containing radioactive isotopes or chemotherapeutic agents. This resulted in cures of animals with subcutaneous tumors and significantly prolonged the survival of animals with orthotopic brain tumors. In principle, a variety of vasc...
Scientific Reports, 2016
Nanoparticles are useful tools in oncology because of their capacity to passively accumulate in tumors in particular via the enhanced permeability and retention (EPR) effect. However, the importance and reliability of this effect remains controversial and quite often unpredictable. In this preclinical study, we used optical imaging to detect the accumulation of three types of fluorescent nanoparticles in eight different subcutaneous and orthotopic tumor models, and dynamic contrast-enhanced and vessel size index Magnetic Resonance Imaging (MRI) to measure the functional parameters of these tumors. The results demonstrate that the permeability and blood volume fraction determined by MRI are useful parameters for predicting the capacity of a tumor to accumulate nanoparticles. Translated to a clinical situation, this strategy could help anticipate the EPR effect of a particular tumor and thus its accessibility to nanomedicines. Low-molecular-weight targeted anticancer drugs administered intravenously are usually homogeneously distributed in most tissues but are expected to eventually perform their (specific) function in cancer cells only. Depending on the importance and quality of this specific therapeutic activity, these drugs often provide insufficient therapeutic benefits and cause severe systemic toxicity. In such cases, it is expected that their entrapment in a nanoparticle (NP) will reduce their accumulation in healthy tissues while improving it in tumors via the so-called "enhanced permeability and retention (EPR) effect 1,2 ". Indeed, molecules less than 40-45 kDa can leak out of the tumor vascular bed by diffusion, depending on the difference in concentration between the therapeutic solution and tumor. They are also rapidly cleared as they are evacuated by the lymph and blood circulation. By contrast, larger molecules and NPs (up to 500 nm in size) have greater difficulties extravasating from the vascular bed. They benefit from the augmented permeability of tumor blood vessels to leak out of the vascular bed more efficiently than in normal tissues under a convection flow, which can be represented by the difference in pressure between the therapeutic solution and tumor. Large molecules are then captured in the tumor's interstitial space. The quantitative importance of the EPR effect is thus related to the tumor biology (i.e., systolic blood pressure that pushes blood into the tumor tissue, blood and lymphatic vessel architecture and functions, interstitial fluid and extracellular matrix composition and pressure 3-5 , and the presence of tumor-associated cells and necrotic areas 6), as well as to the physico-chemical properties of the NP's (i.e., stealth, circulation times, size, electrostatic charge, shape, and density 7-11). The EPR effect is expected to increase the NP's therapeutic index while reducing its toxicity. However, the number of clinical applications derived from this concept and number of nanovectors approved for human use remains limited 12-14 .
Interface Focus, 2015
Through nanomedicine, game-changing methods are emerging to deliver drug molecules directly to diseased areas. One of the most promising of these is the targeted delivery of drugs and imaging agents via drug carrier-based platforms. Such drug delivery systems can now be synthesized from a wide range of different materials, made in a number of different shapes, and coated with an array of different organic molecules, including ligands. If optimized, these systems can enhance the efficacy and specificity of delivery compared with those of non-targeted systems. Emerging integrated multiscale experiments, models and simulations have opened the door for endless medical applications. Current bottlenecks in design of the drug-carrying particles are the lack of knowledge about the dispersion of these particles in the microvasculature and of their subsequent internalization by diseased cells (Bao et al . 2014 J. R. Soc. Interface 11 , 20140301 ( doi:10.1098/rsif.2014.0301 )). We describe mul...
Tumor targeting of functionalized lipid nanoparticles: Assessment by in vivo fluorescence imaging
European Journal of Pharmaceutics and Biopharmaceutics, 2010
Lipid nanoparticles (LNP) coated by a poly(oxyethylene) polymer have been manufactured from low cost and human use-approved materials, by an easy, robust, and up-scalable process. The incorporation in the formulation of maleimide-grafted surfactants allows the functionalization of the lipid cargos by targeting ligands such as the cRGD peptide binding to a v b 3 integrin, a well-known angiogenesis biomarker. LNP are able to encapsulate efficiently lipophilic molecules such as a fluorescent dye, allowing their in vivo tracking using fluorescence imaging. In vitro study on HEK293(b3) cells over-expressing the a v b 3 integrins demonstrates the functionalization, specific targeting, and internalization of cRGD-functionalized LNP in comparison with LNP-cRAD or LNP-OH used as negative controls. Following their intravenous injection in Nude mice, LNP-cRGD can accumulate actively in slow-growing HEK293(b3) cancer xenografts, leading to tumor over skin fluorescence ratio of 1.53 ± 0.07 (n = 3) 24 h after injection. In another fast-growing tumor model (TS/A-pc), tumor over skin fluorescence ratio is improved (2.60 ± 0.48, n = 3), but specificity between the different LNP functionalizations is no more observed. The different results obtained for the two tumor models are discussed in terms of active cRGD targeting and/or passive nanoparticle accumulation due to the Enhanced Permeability and Retention effect.
Cancers
Optimizing the interface between nanoparticles (NPs) and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through the blood vessels. In this study, accumulation of Polyethylene Glycol (PEG) functionalized gold nanoparticles (GNPs) was first tested using in vitro monolayer cells and multilayer cell models prior to in vivo models. A diameter of 10 nm sized GNP was selected for this study for sufficient penetration through tumor tissue. The surfaces of the GNPs were modified with PEG molecules, to improve circulation time by reducing non-specific uptake by the reticuloendothelial system (RES) in animal models, and with a peptide containing integrin binding domain, RGD (arginyl-glycyl-aspartic acid), to improve internalization at the cellular level. A 10-12% accumulation of the injected GNP dose within the tumor was observed in vivo and the GNPs remained within the tumor tissue up to 72 h. This study suggests an in vitro platform for optimizing the accumulation of NP complexes in cells and tissue structures before testing them in animal models. Higher accumulation within the tumor in vivo upon surface modification is a promising outcome for future applications where GNPs can be used for drug delivery and radiation therapy.
Clearance Pathways and Tumor Targeting of Imaging Nanoparticles
ACS nano, 2015
A basic understanding of how imaging nanoparticles are removed from the normal organs/tissues but retained in the tumors is important for their future clinical applications in early cancer diagnosis and therapy. In this review, we discuss current understandings of clearance pathways and tumor targeting of small-molecule- and inorganic-nanoparticle-based imaging probes with an emphasis on molecular nanoprobes, a class of inorganic nanoprobes that can escape reticuloendothelial system (RES) uptake and be rapidly eliminated from the normal tissues/organs via kidneys but can still passively target the tumor with high efficiency through the enhanced permeability permeability and retention (EPR) effect. The impact of nanoparticle design (size, shape, and surface chemistry) on their excretion, pharmacokinetics, and passive tumor targeting were quantitatively discussed. Synergetic integration of effective renal clearance and EPR effect offers a promising pathway to design low-toxicity and h...