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Over the past three decades, the enhanced permeability and retention (EPR) effect has been considered the basis of tumor-targeted drug delivery. Various cancer nanomedicines, ...including macromolecular drugs, have been designed to utilize this mechanism for preferential extravasation and accumulation in solid tumors. However, such nanomedicines have not yet achieved convincing therapeutic benefits in clinics. Increasing evidence suggests that the EPR effect is over-represented in human tumors, especially in metastatic tumors. This review covers the evolution of the concept, the heterogeneity and limitation of the EPR effect in clinical realities, and prospects for alternative strategies independent of the EPR effect.
The enhanced permeability and retention (EPR) effect of solid tumors as seen with nanomedicines and macromolecular drugs is well known. However, many researchers appear to lack a full understanding ...of this effect. The effect varies depending on a patient's pathological and physiological characteristics and clinical condition. When a patient's systolic blood pressure is low side of about 90mmHg instead of 120–130mmHg, the hydrodynamic force pushing blood from the luminal side of a vessel into tumor tissue becomes significantly low, which results in a low EPR. Also, a vascular embolism in a tumor may impede blood flow and the EPR. Here, I describe the background of the EPR effect, heterogeneity of this effect, physiological and pathological factors affecting the effect, the EPR effect in metastatic tumors, artifacts of the EPR effect with micellar and liposomal drugs, problems of macromolecular drug stability and drug release, and access to target sites.
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In this review, I have discussed various issues of the cancer drug targeting primarily related to the EPR (enhanced permeability and retention) effect, which utilized nanomedicine or macromolecular ...drugs. The content goes back to the development of the first polymer–protein conjugate anticancer agent SMANCS and development of the arterial infusion in Lipiodol formulation into the tumor feeding artery (hepatic artery for hepatoma). The brief account on the EPR effect and its definition, factors involved, heterogeneity, and various methods of augmentation of the EPR effect, which showed remarkably improved clinical outcomes are also discussed. Various obstacles involved in drug developments and commercialization are also discussed through my personal experience and recollections.
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•Modular semi-digital EPR imaging system was developed.•Digital automatic frequency control minimizes RF reflection.•Digital automatic scan control stabilizes field scans.•Surface ...loop resonator for RS EPR was developed.•In vivo RS EPR imaging at 800 MHz was demonstrated.
An electron paramagnetic resonance (EPR) imaging system has been custom built for use in pre-clinical and, potentially, clinical studies. Commercial standalone modules have been used in the design that are MATLAB-controlled. The imaging system combines digital and analog technologies. It was designed to achieve maximum flexibility and versatility and to perform standard and novel user-defined experiments. This design goal is achieved by frequency mixing of an arbitrary waveform generator (AWG) output at the intermediate frequency (IF) with a constant source frequency (SF). Low noise SF at 250, 750, and 1000 MHz are available in the system. A wide range of frequencies from near-baseband to L-band can be generated as a result. Two-stage downconversion at the signal detection side is implemented that enables multi-frequency EPR capability. In the first stage, the signal frequency is converted to IF. A novel AWG-enabled digital auto-frequency control method that operates at IF is described that is used for automatic resonator tuning. Quadrature baseband EPR signal is generated in the second downconversion step. The semi-digital approach of mixing low-noise frequency sources with an AWG permits generation of arbitrary excitation patterns that include but are not limited to frequency sweeps for resonator tuning and matching, continuous-wave, and pulse sequences. Presented in this paper is the demonstration of rapid scan (RS) EPR imaging implemented at 800 MHz. Generation of stable magnetic scan waveforms is critical for the RS method. A digital automatic scan control (DASC) system was developed for sinusoidal magnetic field scans. DASC permits tight control of both amplitude and phase of the scans. A surface loop resonator was developed using 3D printing technology. RS EPR imaging system was validated using sample phantoms. In vivo imaging of a breast cancer mouse model is demonstrated.
I am honored to undertake the work for Guest Editor for this Special Issue of EPR Effect-Based Tumor Targeted Nanomedicine for the Journal of Personalized Medicine. It has already been 35 years since ...we published the concept of the EPR effect for the first time. The discovery of the new concept of EPR effect gave an impetus effect of growth momentum in nanomedicine, and numerous works are focused on tumor delivery, although the initial idea was based on vascular permeability in infection-induced inflamed tissue, where we discovered bradykinin in the key mediator of vascular permeability.I know, however, there are pros and cons to EPR effect. Cons stem either from a poor understanding of EPR effect, or somehow a biased view of the EPR effect, or from the tumor models being used, particularly in the clinical settings where vascular blood flow is so frequently obstructed. I hope scientists in the clinic, or basic researchers working on the tumor drug delivery, will join the forum of this Special Issue and express their data and opinions.The scope of this issue includes an in-depth understanding of the EPR effect, and issues associated with tumor microenvironment and also further exploitation of EPR effect in human cancer. In addition, new strategies for enhancement of the EPR effect using nanomedicine will be welcome, which is as important as the EPR effect itself. These papers cover not only cancer therapy, but also imaging techniques using nanofluorescent agents, including photodynamic therapy for inflammation, and boron neutron capture therapy.
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•Analytic methods to study the charge carrier dynamics are introduced.•The fates of charge carrier trapping and recombination are understood.•Various interfacial charge transfer ...processes are discussed case-by-case.
Heterogeneous photocatalysis mediated by semiconducting TiO2 has attracted continuous interest during the past decades and has shown great potentials in environmental remediation and solar energy conversion. Basically, photocatalysis is initiated by the TiO2 excitation. The generated charge carriers undergo trapping, recombination, and interfacial transfer before proceeding the redox reaction at TiO2 surface. Monitoring the charge carrier dynamics is of particulate importance for understanding the underlying mechanism and designing efficient photocatalysts. This review overviews the recent progress in characterization of charge carrier dynamics. We will present the analytic techniques for monitoring the fate of charge carriers at each elementary photocatalytic step, including charge carrier generation, trapping and recombination inside the photocatalyst, as well as the interfacial charge transfer. The charge carrier dynamics at TiO2/H2O interface, hole transfer reactions for O2 production, and photocatalytic oxidation of organic compounds and nitric oxides, and electron transfer reactions for photocatalytic reduction of viologens and metal ions are addressed, aiming at a deeper understanding of photocatalytic process.
KCNE3 is a single transmembrane protein of the KCNE family that modulates the function and trafficking of several voltage-gated potassium channels, including KCNQ1. Structural studies of KCNE3 have ...been previously conducted in a wide range of model membrane mimics. However, it is important to assess the impact of the membrane mimics used on the observed conformation and dynamics. In this study, we have optimized a method for the reconstitution of the KCNE3 into POPC/POPG lipid bilayer vesicles for electron paramagnetic resonance (EPR) spectroscopy. Our CD spectroscopic data suggested that the degree of regular secondary structure for KCNE3 protein reconstituted into lipid bilayered vesicle is significantly higher than in DPC detergent micelles. Electron paramagnetic resonance (EPR) spectroscopy in combination with site-directed spin labeling (SDSL) was used to probe the structural dynamics of S49C, M59C, L67C, V85C, and S101C mutations of KCNE3 in both DPC micelles and in POPC/POPG lipid bilayered vesicles. Our CW-EPR power saturation data suggested that the site S74C is buried inside the lipid bilayered membrane while the site V85C is located outside the membrane, in contrast to DPC micelle results. These results suggest that the KCNE3 micelle structures need to be refined using data obtained in the lipid bilayered vesicles in order to ascertain the native structure of KCNE3. This work will provide guidelines for detailed structural studies of KCNE3 in a more native membrane environment and comparing the lipid bilayer results to the isotropic bicelle structure and to the KCNQ1-bound cryo-EM structure.
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•A method for the reconstitution of KCNE3 into lipid bilayered vesicles was optimized for EPR spectroscopic study.•The secondary structure for KCNE3 in lipid bilayered vesicles is significantly higher than in detergent micelles.•Site-directed spin labeling EPR is used to probe structural dynamics of KCNE3 in micelles and lipid bilayered vesicles.•KCNE3 micelle structures need to be refined using lipid bilayered vesicles data to ascertain its native structure.
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•Three novel low-cost optimization approaches of a commercial MW resonator for three experimental purposes (CW, transient and pulse EPR) are proposed.•The simulated enhanced B1 ...homogeneity could be experimentally verified by the perturbing sphere method and by CW EPR measurements on BDPA.•Application of time-resolved EPR spectroscopy on light-induced triplet states in pentacene revealed an enhanced MW conversion for all proposed resonator optimizations.•The resonator characterization by CW and pulse EPR measurements show improved volume sensitivity.
Microwave (MW) resonators in Electron Paramagnetic Resonance (EPR) spectroscopy concentrate the MW magnetic field (B1) at the sample and separate the MW electric field from the sample. There are numerous experimental methods in EPR spectroscopy which all impose different requirements on MW resonators (e.g. high or low quality factor, MW conversion, and B1-field homogeneity). Although commercial spectrometers offer standardized MW resonators for a broad application range, newly emerging and highly-specialized research fields push these spectrometers to or beyond their sensitivity limits. Optimizing the MW resonator offers one direct approach to improve the sensitivity. Here we present three low-cost optimization approaches for a commercially available X-band (9–10 GHz) MW resonator for three experimental purposes (continuous-wave (CW), transient and pulse EPR). We obtain enhanced MW conversion factors for all three optimized resonators and higher quality factors for two optimized resonators. The latter is important for CW and transient EPR. Furthermore, we fabricated a resonator which features an extended area of homogeneous B1-field and, hence, improved pulse EPR performance. Our results demonstrate that small changes to a commercial MW resonator can enhance its performance in general or for specific applications.
We investigate and model a method for producing entanglement between two spatially separated Bose-Einstein condensates (BECs). In our approach, a spin-polarized BEC is squeezed using a (Sz)2 ...interaction, then are split into two separate clouds. After the split, we consider that the particle number in each cloud collapses to a fixed number. We show that this procedure is equivalent to applying an interaction corresponding to squeezing each cloud individually plus an entangling operation. We analyze the system's inter-well entanglement properties and show that it can be detected using correlation-based entanglement criteria. The nature of the states is illustrated by Wigner functions and have the form of a correlated squeezed state. The conditional Wigner function shows high degrees of non-classicality for dimensionless squeezing times beyond 1 N , where N is the number of particles per BEC.
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The Enhanced Permeability and Retention (EPR) effect has been recognized as the central paradigm in tumor-targeted delivery in the last decades. In the wake of this concept, ...nanotechnologies have reached phenomenal levels in research. However, clinical tumors display a poor manifestation of EPR effect. Factors including tumor heterogeneity, complicating tumor microenvironment, and discrepancies between laboratory models and human tumors largely contribute to poor efficiency in tumor-targeted delivery and therapeutic failure in clinical translation. In this article, approaches for evaluation of EPR effect in human tumor were overviewed as guidance to employ EPR effect for cancer treatment. Strategies to augment EPR-mediated tumoral delivery are discussed in different dimensions including enhancement of vascular permeability, depletion of tumor extracellular matrix and optimization of nanoparticle design. Besides, the recent development in alternative tumor-targeted delivery mechanisms are highlighted including transendothelial pathway, endogenous cell carriers and non-immunogenic bacteria-mediated delivery. In addition, the emerging preclinical models better reflect human tumors are introduced. Finally, more rational applications of EPR effect in other disease and field are proposed. This article elaborates on fundamental reasons for the gaps between theoretical expectation and clinical outcomes, attempting to provide some perspective directions for future development of cancer nanomedicines in this still evolving landscape.
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