Enhanced permeability and retention effect based nanomedicine, a solution for cancer

Tumor-targeting is becoming more and more important for cancer chemotherapy. Though many molecular-target drugs have been developed in the past two decades which shed some light on targeted tumor therapy,clinical results of those molecular-target drugs are not so encouraging especially for solid tumors, problems mostly relating to the heterogeneity and mutations of target molecules in human solid tumors. More general tumor-targeting strategy is thus anticipated. In this regard, the enhanced permeability and retention(EPR) effect which is a unique phenomenon of solid tumors based on the anatomical and pathophysiological nature of tumor blood vessels, is receiving more and more attentions. This EPR effect now served as a standard for tumor-targeted macromolecular anticancer therapy, namely nanomedicine. Many nanoplatforms have been developed as targeted drug delivery systems, including liposome, polymeric micelles, polymer conjugate, nanoparticles. Ample macromolecular drugs are now approved for clinical use or in clinical stage development, all of which by taking advantage of EPR effect, show superior in vivo pharmacokinetics and remarkable tumor selectivity, resulting in improved antitumor effects with less adverse effects. We thus believe EPR-based nanomedicine will be a solution for cancer in the future, whereas further consideration of factors involved in EPR effect and strategies to augment/improve EPR effect are warranted.

Research advances in enhanced coal seam gas extraction by controllable shock wave fracturing

With the continuous increase of mining in depth,the gas extraction faces the challenges of low permeability,great ground stress,high temperature and large gas pressure in coal seam.The controllable shock wave(CSW),as a new method for enhancing permeability of coal seam to improve gas extraction,features in the advantages of high efficiency,eco-friendly,and low cost.In order to better utilize the CSW into gas extraction in coal mine,the mechanism and feasibility of CSW enhanced extraction need to be studied.In this paper,the basic principles,the experimental tests,the mathematical models,and the on-site tests of CSW fracturing coal seams are reviewed,thereby its future research directions are provided.Based on the different media between electrodes,the CSW can be divided into three categories:hydraulic effect,wire explosion and excitation of energetic materials by detonating wire.During the process of propagation and attenuation of the high-energy shock wave in coal,the shock wave and bubble pulsation work together to produce an enhanced permeability effect on the coal seam.The stronger the strength of the CSW is,the more cracks created in the coal is,and the greater the length,width and area of the cracks being.The repeated shock on the coal seam is conducive to the formation of complex network fracture system as well as the reduction of coal seam strength,but excessive shock frequency will also damage the coal structure,resulting in the limited effect of the enhanced gas extraction.Under the influence of ground stress,the crack propagation in coal seam will be restrained.The difference of horizontal principal stress has a significant impact on the shape,propagation direction and connectivity of the CSW induced cracks.The permeability enhancement effect of CSW is affected by the breakage degree of coal seam.The shock wave is absorbed by the broken coal,which may hinder the propagation of CSW,resulting in a poor effect of permeability enhancement.When arranging two adjacent boreholes for CSW permeability enhancement test,the spacing of boreholes should not be too close,which may lead to negative pressure mutual pulling in the early stage of drainage.At present,the accurate method for effectively predicting the CSW permeability enhanced range should be further investigated.

The enhanced permeability and retention effect based nanomedicine at the site of injury

The enhanced permeability retention(EPR)effect based nanomedicine has been widely used for tumor targeting during the past decades.Here we unexpectedly observed the similar"EPR effect"at the site of iniury.We found that the temporary dilated and leaky blood vessels caused by the potent vasodilator histamine in response to injury allowed the injected nanoparticles to pass through the vasculature and reached the injured tissue.Our finding shows the potential underline mechanism of"EPR effect"at the injured site.By loading with antibiotics,we further demonstrated a new strategy for prevention of infection at the site of injury.

Numerical modelling rock deformation subject to nitrogen cooling to study permeability evolution

How to model the permeability evolution of rock subjected to liquid nitrogen cooling is a key issue. This paper proposes a simple but practical method to study the permeability evolution of rocks subject to liquid nitrogen cooling. FLAC with FISH function was employed to numerically model the rock behavior under cooling. The enhanced perme- ability of the volumetric strain was defined, and the permeability was directly evaluated based on element＇s volumetric strain. Detailed procedures for implementing the evolution model of permeability in this paper were presented. A case study was carried out to simulate a coal bed where liquid nitrogen was injected in the bore hole. And a semi-submerged test of liquid nitrogen was performed. The method to model the permeability evolution of rocks subject to liquid nitrogen shock in this paper was proved to be right by the test results. This simulation results are discussed with the hope to provide some insight into understanding the nitrogen cooling practice.

A numerical investigation of hydraulic fracturing on coal seam permeability based on PFC‑COMSOL coupling method

Hydraulic fracturing and permeability enhancement are effective methods to improve low-permeability coal seams.However,few studies focused on methods to increase permeability,and there are no suitable prediction methods for engineering applications.In this work,PFC2D software was used to simulate coal seam hydraulic fracturing.The results were used in a coupled mathematical model of the interaction between coal seam deformation and gas flow.The results show that the displacement and velocity of particles increase in the direction of minimum principal stress,and the cracks propagate in the direction of maximum principal stress.The gas pressure drop rate and permeability increase rate of the fracture model are higher than that of the non-fracture model.Both parameters decrease rapidly with an increase in the drainage time and approach 0.The longer the hydraulic fracturing time,the more complex the fracture network is,and the faster the gas pressure drops.However,the impact of fracturing on the gas drainage effect declines over time.As the fracturing time increases,the difference between the horizontal and vertical permeability increases.However,this difference decreases as the gas drainage time increases.The higher the initial void pressure,the faster the gas pressure drops,and the greater the permeability increase is.However,the influence of the initial void pressure on the permeability declines over time.The research results provide guidance for predicting the anti-reflection effect of hydraulic fracturing in underground coal mines.

ULTRASOUND ENHANCED SKIN OPTICAL CLEARING:MICROSTRUCTURAL CHANGES

Our previous studies demonstrated the ultrasound-induced skin optical clearing enhancement with topical application of optical clearing agents on in vitro porcine skin and in vivo human skin.The objective of this study was to investigate the possible mechanisms of the enhanced skin optical clearing by ultrasound medications.Optical clearing effects of ex vivo guinea pig abdomen skin topically applied with 60% glycerol or the combination of 60% glycerol and ultrasound were studied by optical coherence tomography(OCT).Microstructure of skin surface was examined by scanning electron microscopy(SEM).Ultrasound with a frequency of 1MHz and a power of 0.75W over a 3-cm probe was simultaneously applied with glycerol solution for 15min.The combination of 60% glycerol and ultrasound results in a 19% increase in OCT 1/e light penetration depth after 30min,which is much better than 60% glycerol alone.SEM images demonstrated that changes in skin microstructure due to the tight order of the lipid bilayers in the stratum corneum disrupted and the separation of keratinocytes by the application of ultrasound contribute to the ultrasound-enhanced intact skin optical clearing effects.

Biological Permeability Enhancement Technology for Coal Reservoir

Objective Despite the adoption of various permeability enhancement technologies,the low permeability of coal reservoir has not been fundamentally improved for the development of coalbed methane（CBM）on the ground or the control of gas underground.

EPR Effect of Amphiphilic Copolymer Micelles Observed by Fluorescent Imaging

Enhanced permeation and retention（EPR） targeting effect of rhodamine B labeled PEG-b-P（LA-co-DHP） [PEG：poly（ethylene glycol）;LA：L-lactide;DHP：2,2-dihydroxylmethyl-propylene carbonate] micelles（RhB-micelles） was observed in H22 liver cancer bearing mice.The RhB-micelles were prepared by conjugating rhodamine B with the DHP units of amphiphilic block copolymer PEG-b-P（LA-co-DHP） followed by subsequent self-assembling of the conjugate.The parent copolymer PEG-b-P（LA-co-DHP） was synthesized by ring-opening copolymerization of LA and DHP with PEG as macroinitiator and diethyl zinc（ZnEt2） as catalyst.The micelles have a spherical shape and the average diameter is ca.50 nm by TEM（transmission electron microscope） or 80 nm by DLS（dynamic light scattering）.Their in vitro cell uptake experiment by CLSM（confocal laser scanning microscopy） and flow cytometry showed preferential internalization of micelles by MCF-7 human breast cancer cells to free RhB.The in vivo tests by live animal imaging and ex vivo excised organ imaging showed that after vena tail injection,free RhB molecules were distributed in the whole body through the circulation system and then gradually metabolized and excreted and there was no preferential partition in tumor bed from the beginning to the end.But the RhB-micelles were preferentially distributed to the tumor bed so that their concentration（fluorescent intensity） in tumor bed got the level of the liver at a certain time point between 1 and 6 h and reached a maximum relative intensity at around 12 h,indicating an obvious EPR effect of RhB-micelles in H22 liver cancer.

Coupled hydro-thermo-mechanical modeling of hydraulic fracturing in quasi-brittle rocks using BPM-DEM

This paper presents an improved understanding of coupled hydro-thermo-mechanical(HTM) hydraulic fracturing of quasi-brittle rock using the bonded particle model(BPM) within the discrete element method(DEM). BPM has been recently extended by the authors to account for coupled convective econductive heat flow and transport, and to enable full hydro-thermal fluidesolid coupled modeling.The application of the work is on enhanced geothermal systems(EGSs), and hydraulic fracturing of hot dry rock(HDR) is studied in terms of the impact of temperature difference between rock and a flowing fracturing fluid. Micro-mechanical investigation of temperature and fracturing fluid effects on hydraulic fracturing damage in rocks is presented. It was found that fracture is shorter with pronounced secondary microcracking along the main fracture for the case when the convectiveeconductive thermal heat exchange is considered. First, the convection heat exchange during low-viscosity fluid infiltration in permeable rock around the wellbore causes significant rock cooling, where a finger-like fluid infiltration was observed. Second, fluid infiltration inhibits pressure rise during pumping and delays fracture initiation and propagation. Additionally, thermal damage occurs in the whole area around the wellbore due to rock cooling and cold fluid infiltration. The size of a damaged area around the wellbore increases with decreasing fluid dynamic viscosity. Fluid and rock compressibility ratio was found to have significant effect on the fracture propagation velocity.

COMPARATIVE TREATMENT OF ACNE VULGARIS USING PALOMAR LUX APPLIQU´E TECHNIQUE AND DIRECT INTRALESIONAL INJECTION

Intralesional injection of triamcinolone(TMC)preparations is an effective therapy for cystic acne lesions.However,invasive delivery techniques limit the use of this modality to a relatively narrow class of cases.Skin permeability can be enhanced through creating a lattice of microzones(islets)of light-induced limited thermal damage in the upper layers of epidermis.In this paper,we directly compared safety and efficacy of delivering TMC acetonide with this novel technique versus conventional intralesional injection for treatment of inflammatory acne lesions.A combination of an intense pulsed light system and a specially designed appliqu´e with a pattern of absorbing centers has been used to create the lattice of islets of damage(LID).Quantitative analysis has included estimation of the following parameters:redness,diameter,and height of acne lesions.Clinical photography has been used to document dynamics of lesion development at successive visits(two hours,24 hours and one week post-treatment).Seven subjects have participated in the study.No difference in lesion dynamics between the treatment and control groups was observed at two-hours follow-up.At 24-hours/one-week follow-ups,TMC-injected and TMC-LID-delivered groups have demonstrated 82%/93%and 80%/89%improvement in height of lesions in comparison to control(60%/68%).Delivery of TMC with the newly proposed LID technique is at least as effective as intralesional injection for treating inflammatory acne lesions.Enhancement of skin permeability using LID approach is a promising technique for accelerating delivery of various compounds to their target areas in the skin.

Nanotechnology-based delivery systems to overcome drug resistance in cancer

Cancer nanomedicine is defined as the application of nanotechnology and nanomaterials for the formulation of cancer therapeutics that can overcome the impediments and restrictions of traditional chemotherapeutics.Multidrug resistance(MDR)in cancer cells can be defined as a decrease or abrogation in the efficacy of anticancer drugs that have different molecular structures and mechanisms of action and is one of the primary causes of therapeutic failure.There have been successes in the development of cancer nanomedicine to overcome MDR;however,relatively few of these formulations have been approved by the United States Food and Drug Administration for the treatment of cancer.This is primarily due to the paucity of knowledge about nanotechnology and the fundamental biology of cancer cells.Here,we discuss the advances,types of nanomedicines,and the challenges regarding the translation of in vitro to in vivo results and their relevance to effective therapies.

Nano-bio interactions: the implication of size-dependent biological effects of nanomaterials

Due to their many advantageous properties,nanomaterials(NMs)have been utilized in diverse consumer goods,industrial products,and for therapeutic purposes.This situation leads to a constant risk of exposure and uptake by the human body,which are highly dependent on nanomaterial size.Consequently,an improved understanding of the interactions between different sizes of nanomaterials and biological systems is needed to design safer and more clinically relevant nano systems.We discuss the sizedependent effects of nanomaterials in living organisms.Upon entry into biological systems,nanomaterials can translocate biological barriers,distribute to various tissues and elicit different toxic effects on organs,based on their size and location.The association of nanomaterial size with physiological structures within organs determines the site of accumulation of nanoparticles.In general,nanomaterials smaller than 20 nm tend to accumulate in the kidney while nanomaterials between 20 and 100 nm preferentially deposit in the liver.After accumulating in organs,nanomaterials can induce inflammation,damage structural integrity and ultimately result in organ dysfunction,which helps better understand the size-dependent dynamic processes and toxicity of nanomaterials in organisms.The enhanced permeability and retention effect of nanomaterials and the utility of this phenomenon in tumor therapy are also highlighted.

Targeting orthotopic gliomas with renal-clearable luminescent gold nanoparticles

A major clinical translational challenge in nanomedicine is the potential of toxicity associated with the uptake and long-term retention of non-degradable nanoparticles （NPs） in major organs. The development of inorganic NPs that undergo renal clearance could potentially resolve this significant biosafety concern. However, it remains unclear whether inorganic NPs that can be excreted by the kidneys remain capable of targeting tumors with poor permeability. Glioblastoma multiforme, the most malignant orthotopic brain tumor, presents a unique challenge for NP delivery because of the blood-brain barrier and robust blood-tumor barrier of reactive microglia and macroglia in the tumor microenvironment. Herein, we used an orthotopic murine glioma model to investigate the passive targeting of glutathione-coated gold nanoparticles （AuNPs） of 3 nm in diameter that undergo renal clearance and 18-nm AuNPs that fail to undergo renal clearance. Remarkably, we report that 3-nm AuNPs were able to target intracranial tumor tissues with higher efficiency （2.3× relative to surrounding non-tumor normal brain tissues） and greater specificity （3.0×） than did the larger AuNPs. Pharmacokinetics studies suggested that the higher glioma targeting ability of the 3-nm AuNPs may be attributed to the longer retention time in circulation. The total accumulation of the 3-nm AuNPs in major organs was significantly less （8.4×） than that of the 18-nm AuNPs. Microscopic imaging of blood vessels and renal-clearable AuNPs showed extravasation of NPs from the leaky blood-tumor barrier into the tumor interstitium. Taken together, our results suggest that the 3-nm AuNPs, characterized by enhanced permeability and retention, are able to target brain tumors and undergo renal clearance.

Nanomedicine for tumor therapy-current status and challenges

The field of nanomedicine in controlled drug delivery systems, especially for tumor targeting, has tremendously progressed over the past decades because of its plentiful benefits, such as biocompatibility, stability in blood circulation, and ability to reduce side effects. Although a large number of relevant papers are published every year, few nanodrugs are available for clinical treatment. The present review aimed to explore the barriers in nanomedicine delivery and tumor targeting. Rational design of nanomedicine should consider not only tumor heterogeneity, in vivo metabolism, and physicochemical properties, but also more efficient innovations in particulate formulations for clinical application.

Nanocarrier drugs in the treatment of brain tumors

Nanoparticle-mediated targeted delivery of drugs might significantly reduce the dosage and optimize their release properties,increase specificity and bioavailability,improve shelf life,and reduce toxicity.Some nanodrugs are able to overcome the blood-brain barrier that is an obstacle to treatment of brain tumors.Vessels in tumors have abnormal architecture and are highly permeable;moreover,tumors also have poor lymphatic drainage,allowing for accumulation of macromolecules greater than approximately 40 kDa within the tumor microenvironment.Nanoparticles exploit this feature,known as the enhanced permeability and retention effect,to target solid tumors.Active targeting,i.e.surface modification of nanoparticles,is a way to decrease uptake in normal tissue and increase accumulation in a tumor,and it usually involves targeting surface membrane proteins that are upregulated in cancer cells.The targeting molecules are typically antibodies or their fragments;aptamers;oligopeptides or small molecules.There are currently several FDA-approved nanomedicines,but none approved for brain tumor therapy.This review,based both on the study of literature and on the authors own experimental work describes a comprehensive overview of preclinical and clinical research of nanodrugs in therapy of brain tumors.