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.

Rod-like mesoporous silica nanoparticles facilitate oral drug delivery via enhanced permeation and retention effect in mucus

The physiochemical characteristics of nanoparticles affect their in vitro and in vivo performance significantly,such as diameter,surface chemistry,and shape.This paper disclosed the effect of enhanced permeation and retention(EPR)in mucus caused by nanoparticle shape on improving oral absorption.The spherical and rod-like mesoporous silica nanoparticles(MSNs)were used to evaluate shape effect of EPR in mucus.Fenofibrate was loaded in MSNs as model drug.The in vitro release of fenofibrate from MSNs was dependent on nanoparticle shapes,but faster than that of raw drug.The drug release slowed down with the increase of aspect ratio due to longer channels in rod-like MSNs with higher aspect ratio.However,in vivo study showed that the oral bioavailability of fenofibrate was the highest after loading in rod-like MSNs with aspect ratio of 5.The in vitro study of mechanisms revealed that superior mucus diffusion ability of rod-like MSNs with aspect ratio of 5 was conductive to higher bioavailability.Meanwhile,more rod-like MSNs with higher aspect ratio were able to diffuse into mucus and reside there compared to spherical and short counterparts,which demonstrated higher aspect ratio was beneficial to EPR effect of nanoparticles in mucus.This study provides significant implication in rational oral drug carrier design.

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.

Irradiation Effects on the Retention of Hydrogen in Al_2O_3

Substantial defects are produced in Al2O3 by 4 MeV Au ion irradiation with a fluence of 4.4×10^15 cm^-2. Ruther- ford baekscattering spectrometry/channeling and cross-sectional transmission electron microscopy methods are used to investigate the irradiation damage. The 190keV H ions with a fuence of 1×10^17 cm^-2 are used for implanting pristine and Au ion irradiated Al2O3 to explore the irradiation damage effects on the hydrogen retention in Al2O3. The time-of-flight secondary ion mass spectrometry method is used to obtaJn the single hydrogen depth profile and ions mass spectra （IMS）, in which we find that implanted hydrogens interacted with defects produced by Au ion irradiation. In IMS, we also obtain the hydrogen retention at a certain depth. Comparing the hydrogen retention in different Al2O3 samples, it is concluded that the irradiation damage improves the tritium permeation resistance property of Al2O3 under given conditions. This result means that Al2O3 may strengthen its property of reduc/ng tritium permeation under the harsh irradiation environment in fusion reactors.

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.

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.

Nanomedicine-based treatment:An emerging therapeutical strategy for pulmonary hypertension

Pulmonary hypertension(PH)can cause breathing difficulty,a rapid decline of exercise capacity,heart failure,eventually death of the patients.The latest epidemiological study demonstrates that PH has a much higher incidence than previously thought.PH is still a highly fatal disease due to the many disadvantages of the current drugs,such as short half-life,lack of targeting,potent side effects.The PH pathological features offer great opportunities for nanomedicines for PH.Recently,emerging nanomedicines demonstrated great advantages in the therapeutic effect of PH by enhancing the accumulation of drugs in PH lesion,optimizing drug efficacy,minimizing drug side effects.However,this promising field of cross-cutting research is far from being widely explored due to the huge professional barriers.To solve this problem,we provide a comprehensive review for the latest progresses of nanomedicines in the treatment of PH.Firstly,we systematical summarized the PH pathological features and the current clinical drug treatment of PH.The advantages of nanomedicines are also deeply discussed in the treatment of PH.Subsequently,we focused on the research progresses of nanomedicines in PH through three aspects:advanced nano-drug delivery system for traditional drugs and new target drugs,gene therapy-based nanomedicines,other nanomedicines for the treatment of PH.Finally,we also discussed the prospects and challenges for the clinical application of nanomedicines in PH,provided directions for the research and development of nanomedicines for PH treatment in the future.

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.