Augmentation of the Enhanced Permeability and Retention Effect with Nitric Oxide-Generating Agents Improves the Therapeutic Effects of Nanomedicines (original) (raw)
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International Journal of Pharmaceutics, 2019
The modulation of blood flow to tumors is a prominent strategy for improving the tumor accumulation of nanomedicines, resulting from the enhanced permeability and retention (EPR) effect. We previously reported a promising EPR enhancer-a nitric oxide (NO) donor-containing liposome (NO-LP)which showed enhanced accumulation in tumor tissue. Herein, we study NO-LP in greater detail to clarify its practical use as an EPR enhancer. NO-LP was found to have advantages as a NO donor, including the ability to maintain NO donation over long periods of time, and a constant rate of NOrelease irrespective of the environmental pH. NO-LP showed rapid accumulation in tumor tissue after injection (1 h), and then accumulation was continuously enhanced until 48 h. Enhanced NO-LP accumulation was observed specifically in tumor, while the accumulation in other organs remained relatively unchanged. The results obtained show the promising features of NO-LP as an EPR enhancer.
Advances in Enzyme Regulation, 2001
Effective cancer therapy remains one of the most challenging tasks to the scientific community, with little advancement on overall cancer survival landscape during the last two decades. A major limitation inherent to most conventional anticancer chemotherapeutic agents is their lack of tumor selectivity. One way to achieve selective drug targeting to solid tumors is to exploit abnormalities of tumor vasculature, namely hypervascularization, aberrant vascular architecture, extensive production of vascular permeability factors stimulating extravasation within tumor tissues, and lack of lymphatic drainage. Due to their large size, nano-sized macromolecular anticancer drugs administered intravenously (i.v.) escape renal clearance. Being unable to penetrate through tight endothelial junctions of normal blood vessels, their concentration builds up in the plasma rendering them long plasma half-life. More importantly, they can selectively extravasate in tumor tissues due to its abnormal vascular nature. Overtime the tumor concentration will build up reaching several folds higher than that of the plasma due to lack of efficient lymphatic drainage in solid tumor, an ideal application for EPR-based selective anticancer nanotherapy. Indeed, this selective high local concentration of nano-sized anticancer drugs in tumor tissues has proven superior in therapeutic effect with minimal side effects in both preclinical and clinical settings.
Enhanced delivery of macromolecular antitumor drugs to tumors by nitroglycerin application
Cancer Science, 2009
Dose regimens of anticancer agents are usually designed on the basis of the maximum tolerable drug doses, and toxicity prevents drug usage at higher doses, even though the drugs may be more effective at the higher doses. We previously studied macromolecular anticancer drugs, i.e. those larger than 40 kDa, and observed their accelerated accumulation in tumors. Their concentration in tumors was more than 5-100-fold their blood concentration because of the enhanced permeability and retention (EPR) effect. Here, we report that the EPR effect was enhanced by applying nitroglycerin (NG) ointment on the skin of tumor-bearing animals. Tumors studied included breast cancer, which was induced in Sprague-Dawley rats by the chemical carcinogen 7,12-dimethylbenz[a]anthracene, and three different transplanted tumor models in mice. NG was applied on tumor or nontumorous normal skin as well. Two to three times more putative macromolecular drug (an Evans blue/albumin complex) was delivered to solid tumors with NG than without NG. We also demonstrated that NG enhanced tumor delivery with another macromolecular drug candidate, PZP, i.e. polyethylene glycol-conjugated zinc protoporphyrin IX, which inhibits heme oxygenase-1. In addition, we investigated the therapeutic effect of NG using a combination with low molecular weight anthracycline or high molecular weight PZP in mouse tumor models. NG had no apparent toxicity at the doses used, and showed significantly increased therapeutic effects in both cases. Regardless of its site of application, NG thus enhanced the delivery of the drug to tumors, and enhanced therapeutic effects. (Cancer Sci
Nanomedicine for drug targeting: strategies beyond the enhanced permeability and retention effect
International Journal of Nanomedicine, 2014
The growing research interest in nanomedicine for the treatment of cancer and inflammatory-related pathologies is yielding encouraging results. Unfortunately, enthusiasm is tempered by the limited specificity of the enhanced permeability and retention effect. Factors such as lack of cellular specificity, low vascular density, and early release of active agents prior to reaching their target contribute to the limitations of the enhanced permeability and retention effect. However, improved nanomedicine designs are creating opportunities to overcome these problems. In this review, we present examples of the advances made in this field and endeavor to highlight the potential of these emerging technologies to improve targeting of nanomedicine to specific pathological cells and tissues.
Nanoparticle Delivery and Tumor Vascular Normalization: The Chicken or The Egg?
Frontiers in Oncology
Tumor-induced angiogenesis has been a significant focus of anti-cancer therapies for several decades. The immature and "leaky" tumor vasculature leads to significant cancer cell intravasation, increasing the metastatic potential, while the disoriented and hypo-perfused tumor vessels hamper the anti-tumor efficacy of immune cells and prevent the efficient diffusion of chemotherapeutic drugs. Therefore, tumor vascular normalization has emerged as a new treatment goal, aiming to provide a mature tumor vasculature, with higher perfusion, decreased cancer cell extravasation, and higher efficacy for anti-cancer therapies. Here we propose an overview of the nanodelivery approaches that target tumor vasculature, aiming to achieve vascular normalization. At the same time, abnormal vascular architecture and leaky tumor vessels have been the cornerstone for nanodelivery approaches through the enhanced permeability and retention (EPR) effect. Vascular normalization presents new opportunities and requirements for efficient nanoparticle delivery against the tumor cells and overall improved anti-cancer therapies.
Polymers
Passive targeting is the foremost mechanism by which nanocarriers and drug-bearing macromolecules deliver their payload selectively to solid tumors. An important driver of passive targeting is the enhanced permeability and retention (EPR) effect, which is the cornerstone of most carrier-based tumor-targeted drug delivery efforts. Despite the huge number of publications showcasing successes in preclinical animal models, translation to the clinic has been poor, with only a few nano-based drugs currently being used for the treatment of cancers. Several barriers and factors have been adduced for the low delivery efficiency to solid tumors and poor clinical translation, including the characteristics of the nanocarriers and macromolecules, vascular and physiological barriers, the heterogeneity of tumor blood supply which affects the homogenous distribution of nanocarriers within tumors, and the transport and penetration depth of macromolecules and nanoparticles in the tumor matrix. To add...
MedChemComm, 2017
We propose a method to improve the enhanced permeability and retention (EPR) effect of nanomedicines based on tumor-specific vasodilation using a nitric oxide (NO) donor-containing liposome. NONOate, a typical NO donor, was incorporated into a PEGylated liposome to retard the protonation-induced release of NO from NONOate by the protecting lipid bilayer membrane. The NONOate-containing liposome (NONOate-LP) showed similar blood retention to an empty PEGylated liposome but almost twice the amount accumulated within the tumor. This improvement in the EPR effect is thought to have been caused by specific vasodilation in the tumor tissue by NO released from the NONOate-LP accumulated in the tumor. The improved EPR effect by NONOate-LP will be useful for the accumulation of co-administered nanomedicines.
Exploiting the enhanced permeability and retention effect for tumor targeting
Drug Discovery Today, 2006
Of the tumor targeting strategies, the enhanced permeability and retention (EPR) effect of macromolecules is a key mechanism for solid tumor targeting, and considered a gold standard for novel drug design. In this review, we discuss various endogenous factors that can positively impact the EPR effect in tumor tissues. Further, we discuss ways to augment the EPR effect by use of exogenous agents, as well as practical methods available in the clinical setting. Some innovative examples developed by researchers to combat cancer by the EPR mechanism are also discussed.
Vascular Permeability and Drug Delivery in Cancers
Frontiers in Oncology, 2013
The endothelial barrier strictly maintains vascular and tissue homeostasis, and therefore modulates many physiological processes such as angiogenesis, immune responses, and dynamic exchanges throughout organs. Consequently, alteration of this finely tuned function may have devastating consequences for the organism. This is particularly obvious in cancers, where a disorganized and leaky blood vessel network irrigates solid tumors. In this context, vascular permeability drives tumor-induced angiogenesis, blood flow disturbances, inflammatory cell infiltration, and tumor cell extravasation.This can directly restrain the efficacy of conventional therapies by limiting intravenous drug delivery. Indeed, for more effective anti-angiogenic therapies, it is now accepted that not only should excessive angiogenesis be alleviated, but also that the tumor vasculature needs to be normalized. Recovery of normal state vasculature requires diminishing hyperpermeability, increasing pericyte coverage, and restoring the basement membrane, to subsequently reduce hypoxia, and interstitial fluid pressure. In this review, we will introduce how vascular permeability accompanies tumor progression and, as a collateral damage, impacts on efficient drug delivery. The molecular mechanisms involved in tumor-driven vascular permeability will next be detailed, with a particular focus on the main factors produced by tumor cells, especially the emblematic vascular endothelial growth factor. Finally, new perspectives in cancer therapy will be presented, centered on the use of anti-permeability factors and normalization agents.
International Journal of Pharmaceutics, 2015
Paclitaxel (PTX)-loaded polymeric micelles (M-PTX) have been shown to enhance the blood flow and oxygenation of tumors 24 h after treatment. We hypothesized that these changes in the tumor microenvironment could lead to an enhancement of the EPR (enhanced permeability and retention) effect. M-PTX, administered 24 h before analysis, increased the accumulation of macromolecules, nanoparticles and polymeric micelles in tumors. This increased EPR effect could be linked to normalization of the tumor vasculature and decreased interstitial fluid pressure. M-PTX used as a pretreatment allowed a more effective delivery of three nanomedicines into tumors: polymeric micelles, liposomes and nanoparticles. These experiments demonstrate an enhanced EPR effect after M-PTX treatment, which lead to better availability and enhanced efficacy of a subsequent treatment with nanomedicines.