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.

Unraveling the hydraulic properties of loess for landslide prediction:A study on variations in loess landslides in Lanzhou,Dingxi,and Tianshui,China

Loess has distinctive characteristics,leading to frequent landslide disasters and posing serious threats to the lives and properties of local re sidents.The involvement of water repre sents a critical factor in inducing loess landslides.This study focuses on three neighboring cities sequentially situated on the Loess Plateau along the direction of aeolian deposition of loess,namely Lanzhou,Dingxi,and Tianshui,which are densely populated and prone to landslide disasters.The variations in hydraulic properties,including water retention capacity and permeability,are investigated through Soil Water Characteristic Curve(SWCC)test and hydraulic conductivity test.The experimental findings revealed that Tianshui loess exhibited the highest water retention capacity,followed by Dingxi loess,while Lanzhou loess demonstrated the lowest water retention capacity.Contrastingly,the results for the saturated permeability coefficient were found to be the opposite:Tianshui loess showed the lowest permeability,whereas Lanzhou loess displayed the highest permeability.These results are supported and analyzed by scanning electron microscopy(SEM)observation.In addition,the water retention capacity is mathematically expressed using the van Genuchten model and extended to predict unsaturated hydraulic properties of loess.The experimental results exhibit a strong accordance with one another and align with the regional distribution patterns of disasters.

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.

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.

Wearability of Copper Ion Complex Bamboo Pulp Knitted Fabrics with Chitosan Pretreatment

Wearability is one of important factors for the textile product quality. The wearability of bamboo pulp knitted fabrics was mainly discussed which were treated with chitosan and cupper ammonia solution. Tensile and bursting properties, abrasion resistance,drapability,air permeability,moisture-penetrability and warmth retention properties of fabrics were tested to investigate the changes. The results showed that chitosan pretreatment improved the tensile and bursting strengths,abrasion resistance and moisture penetrability,but decreased the drapability and air permeability.Copper ammonia solution treatments decreased the tensile and bursting strengths,abrasion resistance and air permeability,but increased the drapability, moisture penetrability and warmth retention properties.

Performance of Nonwoven Filter Materials Based on the Operating Condition

The practical condition of needle-punched filters applied in coal-fired power plants is investigated. According to the actual operating conditions, two common filters (glass fiber filter and polyphenylene sulfide (PPS) filter) are selected for experiment. The performance of these two kinds of filter is compared based on a series of tests such as resistance to the acid and alkali, oxidation resistance,hydrolysis resistance,and wear resistance. Experimental results show that PPS filter materials have better properties than those of glass filter material except oxidation resistance. Composite filter mixed glass fiber and PPS is recommended for polluters because of its good properties in all aspects.

An experimental study on optimizing parameters for sand consolidation with organic-inorganic silicate solutions

Sand production along with the oil/gas detrimentally affects the oil production rate,downhole&subsurface facilities.Mechanical equipment and various chemicals like epoxy resin,furan resin,phenolic resin,etc.are used in the industry to reduce or eliminate this problem.In the present study,a blend of organic and inorganic silicates are used to consolidate loose sand in the presence and absence of crude oil using a core flooding apparatus.The effects of chemical concentration,pH,curing temperature and time,and the presence of residual oil on the consolidation treatment results such as compressive strength and permeability retention,were investigated and optimized.FT-IR and FE-SEM characterization techniques were employed to investigate the interaction between the chemical molecules and the sand grains.The current binding agent exhibited a viscosity of less than 6 cP at room temperature,which facilitates efficient pumping of binding agent into the desired formation through the well bore.The developed mixture demonstrated consolidation properties across all pH conditions.Furthermore,during the experimental investigation,the curing time and temperature was carefully optimized at 12 h and 423.15K,respectively to achieve the highest compressive strength of 2021 psi while achieving the permeability retention of 64%.The current chemical system exhibited improved consolidation capacity and can be effectively utilized for sand consolidation treatment in high-temperature formations.

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.