External-stimuli responsive systems for cancer theranostic

Key Laboratory of Smart Drug Delivery,Ministry of Education,School of Pharmacy,Fudan University,826 Zhangheng Road,Shanghai 201203,China

External-stimuli responsive systems for cancer theranostic

Jianhui Yao,Jingxian Feng,Jun Chen*

Key Laboratory of Smart Drug Delivery,Ministry of Education,School of Pharmacy,Fudan University,826 Zhangheng Road,Shanghai 201203,China

A R T I C L EI N F O

Article history:

Received 30 March 2016

Received in revised form 13 May 2016

Accepted 3 June 2016

Available online 15 June 2016

Nanotechnology

Stimuli-responsive

Light

Magnetic feld

Ultrasound

Theranostics

The upsurge of novel nanomaterials and nanotechnologies has inspired the researchers who are striving for designing safer and more effcient drug delivery systems for cancer therapy. Stimuli responsive nanomaterial offered an alternative to design controllable drug delivery system on account of its spatiotemporally controllable properties.Additionally,external stimuli(light,magnetic feld and ultrasound)could develop into theranostic applications for personalized medicine use because of their unique characteristics.In this review,we give a brief overview about the signifcant progresses and challenges of certain externalstimuli responsive systems that have been extensively investigated in drug delivery and theranostics within the last few years.

©2016 Shenyang Pharmaceutical University.Production and hosting by Elsevier B.V.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

1.Introduction

Based on advances in nanotechnologies and insight into the pathology of cancer at the cellular and molecular levels,a large sum of well-tailored nanoscale carrier platforms have been developed such as liposome,dendrimer,polymer nanoparticle and inorganic nanoparticles made of iron oxide,quantum dots,gold or other metal frameworks.(Fig.1)

Nanotechnologies hold numerous advantages in drug delivery feld including their ability to incorporate payloads with different solubility into carriers[1],improve thein vivopharmacokinetic(PK)process of drugs[2],enhance their stability and longevity in the blood circulation with or without additional structure modifcations[3]and modify the carriers with targeting ligands on their surface for tissue or cell-specifc delivery to minimize side-effects[4].Among myriads of successful applications,stimuli-responsive“smart”nanocarriers have emerged as a promising nanotechnology in comparison with conventional nanoscale materials as a result of their unique stimuli-responsive nature.In addition,compared with various internal cues in the microenvironment of cancer,triggers from outside offered better spatially and temporally controllable features for activation and release of the loaded cargoes.

Fig.1–Schematic illustrations summarized various external stimuli employed for responsive nanosystems following systemic administration of different nanopreparations.

This review aims to discuss such novel nanomaterials that can be responsive to external stimuli,which have been exploited for cancer therapy and simultaneously can be used for diagnosis.In the interest of brevity,this review does not elaborate equally important internal stimuli and other felds that have not been widely studied yet,thus,the external stimuli we single out are light,magnetic feld and ultrasound.Not only can they be used for fabricating stimuli-responsive systems but can potentially integrate therapy and imaging into single platform for theranostic applications which indicate a promising future in the forthcoming personalized medicine.

2.General concepts of stimuli-responsive system

The working mechanisms of stimuli-responsive systems are always alike:after injecting intravenously(or other administration mode like intraperitoneal injection),nanocarriers would leak through neovascular and accumulate at the tumor lesion via passive targeting(enhanced permeability and retention effect)or active targeting(i.e.based on the receptor-ligand affnity principle,exploiting folic acid-modifed nanocarriers to actively bind to folic acid receptor over-expressed tumor cells so that could improve nanocarriers accumulation in tumor site), then,delivery systems can be activated by single or several specifc triggers from inner or outer body and release the bioactive cargoes in the intended sites.

Specifc triggers could be roughly divided into two categories:The frst part is termed“intrinsic-stimuli”since they are local stimuli within the tumor microenvironment.As sophisticated as tumor,the microenvironment of pathological site have certain peculiar attributes compared with healthy one and these peculiarities could be used to design internal-stimuli sensitive delivery system.For example,pH-sensitive nanocarries have been applied continually to construct responsive systems for drug delivery since they can stabilize the integral particle at physiological pH during circulation in vasculature but release payloads while the system reaching tumor site and triggered by the lower pH value of the tumor microenvironment[5].Thus the payloads just release specifcally within the tumor site and reduce the unwanted side effect[6].Other intrinsic stimuli such as temperature,redox,and enzyme activity have been exploited extensively in biomedical research as well.

There are a number of other parameters beyond the inner body which are termed as“external stimuli”including magnetic felds,ultrasound,light,etc.Compared with the“internalstimuli”that make use of characteristics within tumor microenvironment like lower pH value,higher temperature as mentioned above,the external stimuli responsive systems could intrinsically or introduce contrast agents to visualize the accumulation of nanoparticles in the target tissues,cells or organelles and then activate the nanocarriers out of body by light or other triggers at desired time.Therefore,the controlled release is more spatiotemporal and has higher potential for clinical applications.

All in all,the primary principles of responsive delivery system could be described as follow:upon exposing to specifc stimuli from the interior or exterior,their chemical composition or physical structure would undergo a given transformation that induces the release of payloads or activation of prodrugs and reacting in a controllable way.

3.Light responsive systems

Since 1994 the frst photosensitizer has been approved by the U.S.Food and Drug Administration(FDA),and the advent of photo-responsive therapy has made an inspiring impact on the feld of cancer therapy owing to its non-invasiveness and spatiotemporally controllable ability.

Once exposed to irradiation in specifc wavelength range directly,photosensitizer molecules would absorb the energy from light and turn into highly unstable state,then transfer energy to surrounding oxygen molecules,generate reactive oxygen species(ROS)to damage nearby biomolecules,or convert absorbed energy into heat,raising local temperature[7]or the energy would be released by emitting photons that possesslower power and eventually,the activated molecules turn back to ground state.

Hence,in the light of the different function mechanisms of photosensitive materials,light-triggered treatment could be divided into three different types including photodynamic therapy(PDT),photothermal therapy(PTT),and light-triggered cargo release.

3.1.Photodynamic therapy

Activation of photosensitizers with specifc wavelength light leads to energy transfer cascades that ultimately yield cytotoxic ROS which can induce local tissue apoptosis and necrosis [8].Therefore,harnessing this function mechanism in tumor therapy provides a safe and controllable way to selectively eradicate tumor with reduced systemic toxicity and side effects on healthy tissues[9].

Photodynamic therapy is a powerful tool for cancer treatment;however,the lack of stability,solubility and biological utility limited the application of photosensitizers.Lovell et al. have created a liposome like nanovesicle by porphyrin bilayers named Porphysome which possess excellent biocompatible, structure-dependent fuorescence quenching and high absorption of near-infrared light[10].In one of his recent published papers,porphysomes were conjugated folate as targetingtriggered activatable nano-sized beacons for PDT.Before folatemediated endocytosis by tumor cells,the intact porphysomes could transfer photon energy to thermal energy,but the nanoparticles would switch back to effcient photodynamic activityoncetheyareinternalizedanddisruptedthe nanostructure intracellularly,thus this biocompatible responsive system showed potent clinical application potential[11].

Due to the rarely short half-life of reactive oxygen species generated based on photodynamic mechanism and the limited scope it diffuse to,the effcacy of photodynamic therapy highly depends on the subcellular location of the photosensitizers[12]. Zinc phthalocyanine(ZnPc),a lipophilic photosensitizer which can localize to membrane and have strong phototoxicity upon NIR irradiation,is anchored into liposomes with given molar ratio to construct membrane fusogenic liposomes(MFLs).Compared to the non-fusogenic liposomes,cells treated with MFLs showed signifcantly lower viability in the MTT test,which means photosensitizers localized in the plasma membrane would induce more membrane disruption and cell death upon irradiation[13].

Besides its non-invasive and spatiotemporal controllability,combining with chemotherapy is helpful to overcome limitations that are encountered by each modality when used alone.Multi-drug resistance(MDR)effect is a common symptom in the course of chemotherapy treatment.To solve such problem,higher dose and more frequent administration of chemotherapy are applied clinically[14].However,combining PDT with chemotherapy can fgure out the dilemma[15].ROS produced by photosensitizers can not only induce tumor cells apoptosis directly,but also disrupt the cytomembrane and endolysosomes to prevent the chemo-drugs from being pumped out by P-glycoprotein(P-gp),etc.and being degraded by enzyme. A novel drug delivery system was designed by incorporating the photosensitizer chlorine 6 chemically in the shell and the chemo-drug doxorubicin physically in the core of D-α-tocopheryl polyethylene glycol 1000 succinate-poly(lactic acid)(TPGSPLA)nanoparticles with a targeting ligand tLyp-1 peptide to achieve synergetic effect from combination therapy;and photosensitizer plays a crucial role in the treatment process by releasing ROS to oxidize cell membrane and degradationrelated enzymes.The effective anti-tumor effciency has been proved by the longer survival time in thein vivotumorbearing mice test[16].

3.2.Photothermal therapy

The disordered and irregular vasculature of tumor tissue leads to lower pH and oxygen level within tumor environment,which makes tumor more sensitive to hyperthermia than normal tissues.When temperature rises up to 40°C～45°C,tumor cells would undergo mitochondrial swelling,protein denaturation and membrane rupture,etc,and yet,normal tissues exposure to this temperature range for one hour,cells do not observed signifcant injury[17].

There are several nanomaterials that could respond to near infrared(NIR)and transform light energy into thermo,which includes gold-based materials(like Au nanoshell,Au nanorod, Au nanocage,etc.),carbon-based materials(including carbon nanotube,CNT and graphene oxide,GO)and CuS-related materials[18].Amongtheseresponsivematerialsgold nanoparticles achieved wide investigation due to their excellent light energy to heat transfer effciency and inertness.Gold nanoparticles can strongly absorb light from NIR region through localized surface plasmon resonance(LSPR)and release the amount of heat for the ablation of surrounding cells[19]. Graphene oxide possesses special surface properties and superior photo-thermal conversion effciency,which makes it often serves as platforms for combing other diagnosis agents or drugs via either covalent or non-covalent conjugation[20].Both Au nanoparticle and GO possess excellent PTT effcacy;what if both of them were integrated into one platform?One article has seededAu onto GO surface through redox reaction and then a NIR dye Cy5.5 labeled-matrix metalloproteinase-14(MMP-14)peptide substrate(CP)was conjugated onto the GO/Au complex to form a fuorescence-guided photothermal therapy system(CPGA).Before CPGA arrived in the tumor region,the fuorescence signal of Cy5.5 was quenched by Au nanoparticles via surface plasmon resonance,but upon degradation of the peptide by the MMP-14,an endopeptidase that is overexpressed in tumor microenvironment,strong fuorescence signal would boost,which can analyze the accumulation behaviors at tumor region and guide the subsequent photothermal therapy as well. The laser irradiation density is relatively low(0.75 W cm−2),but the tumors were effciently ablated after systemic administration[21].

Although Au nanoparticles have an outstanding performance in photothermal therapy,there are still several faws that restricted their further clinical application,such as the NIR absorbance peak of Au nanoparticles which is related to the particle size and morphology[22];and after a long period of laser irradiation the Au nanoparticles’NIR absorbance peak would diminish due to the“melting effect”[23],which weakened their conversion effciency.In the recent years,copperbased semiconductors have drawn attention as biocompatible, low cost,low cytotoxic photothermal agents.The NIRabsorption of Copper sulfde stems from d-d transition of Cu2+ions,which leads to a relatively higher NIR region absorption (～900 nm)than Au nanoparticles,and this region is more suitable forin vivoapplication[24].Furthermore,CuS nanoparticles are not affected by the particle size and shape,and have no“melting effect”phenomenon.To further improve the therapeutic effects from PTT,the combination of both PTT and chemotherapy has attracted increasing attention.Photothermal agent CuS and chemo-drug doxorubicin(DOX)integrated into a thermosensitive composite MEO2MA@MEO2MA-co-OEGMA(G)to fabricate an on-demand drug release and photothermal therapy system G-Cus-DOX.Because the low critical solution temperature(LCST)of MEO2MA@MEO2MA-co-OEGMA is 42°C,once G-CuS-DOX is exposed to NIR laser at 915 nm,the boosted thermal energy would ablate the surrounding tumor cells and the high temperature can melt the MEO2MA@MEO2MA-co-OEGMA for the release of DOX[25].

Given the working mechanisms of photodynamic therapy, there are three prerequisites to be satisfed:light,photosensitizers and oxygen.Hence,suffcient oxygen content is an indispensable element for an optimal effcacy.However,Photothermal therapy(PTT)turned photon energy into substantial heat diffused to the tissues nearby,so that PTT is independent from oxygen concentration within tumors,which offered an alternative way to excise the deeper core of solid tumor[26]. Thus,it is meaningful to compare the two different modalities:PDT and PTT.The unique properties of liposome like porphyrin bilayers developed by Gang Zheng group provide the opportunity to directly compare PDT and PTT using matched light doses and matched porphyrin photosensitizer doses(when the photosensitizer porphyrin were encapsulated in the intact nanostructure there will be no PDT but only PTT;once the nanostructure is not existent,the effective PDT of porphyrin would be recurrent).The treatment scheme is shown in Table 1. To investigate PDT and PTT in tumor hyperopia and hypoxia conditionsin vivo,they developed a multi-pronged approach to generate tumor hypoxia and hyperopiain vivoin single mouse.After systematic treatment and tumor volume measurement,the results showed that(1)the tumors receiving photofrin PDT under hyperoxic conditions showed extensively damaged areas but tumor remained unaffected when PDT was conducted under hypoxia conditions,which means PDT effcacy occurred with suffcient oxygen supply within tumor but not in a hypoxia condition;(2)the tumors in both hyperoxic and hypoxic conditions were ablated by the heat following porphysome PTT showing that PTT is an alternative phototherapy that remains effective even under hypoxia conditions.

Table 1–Treatment scheme of PDT and PTT.

3.3.Light-triggered drug delivery

Except for the two strategies mentioned above,light-sensitive materials have gained great attention in recent decades.Variety of mechanisms that can cause light-triggered cargoes released from nanocarriers have been exploited for designing light-responsive systems,including photo-isomerization,photocrosslinking,photosensitization-induced oxidation,lighttriggered switch in polarity,photo-decrosslinking or photodegradation of the polymer backbone[27].

Most photosensitizers used for PDT are activated by light from 600–700 nm,which have a limited penetration depth in live tissues.Interestingly,upconversion materials can absorb light from more than 800 nm but emit visible or NIR light with narrow spectrum bandwidth.To combine chemotherapy and PDT in upconversion nanoparticles(UCNP)platform[28],a new multifunctional UCNPs system was fabricated by loading UCNPs with mPEG-COOH,photosensitizer Ce6 and ROS-cleavable thioketal-conjugated camptothecin(CPT).Under 980 nm laser irradiation,UCNPs can convert light to 645–675 nm region,which excited the loaded photosensitizers and then the released ROS would be used to photodynamic therapy and cleave the thioketal linker to release CPT for chemotherapy,simultaneously.Together,the activated Ce6 has a fuorescence emission that can be exploited to fuorescence imaging[29].

Compared with small organic molecule dyes,the backbone of conjugated polyelectrolytes(CPEs)has plenty of lightabsorbing units,which featured high absorption coeffcients and fuorescence under laser irradiation[30].Combining CPEs that can generate ROS[31]with thioketal groups that can be readily cleaved by ROS and anticancer drug DOX in single ondemand drug release system generated a light-triggered ROS-sensitive drug delivery system.Under illumination,ROS generated by CPEs causes Dox release through the cleavage of the linker,thus the delivery system can implement PDT and chemotherapy effectively and has an on-demand responsive feature[32].Nanotechnologies improved the pharmacokinetics of several traditional chemotherapy drugs like DOX and PTX; however,encapsulating drugs inside carriers result in the ineffcient intracellular drug release and that remains the ratelimiting step in reaching the drug therapeutic window.To fx that awkward nut,responsive release systems seem like a reasonable solution.Arylboronic ester is another ROS sensitive linker except for the thioketal group,and it is well studied for imaging and targeting of tumor cells.Making use of arylboronic ester fabricated an ROS triggering nanosystem,and this system was assembled from amphiphilic polymer composed of D-αtocopherol polyethylene glycol 1000 succinate(TPGS),hyaluronicacid(HA)and arylboronic esters,and thein vitrodrug release assay showed that the drug concentration(DOX)can rise rapidly to reach the therapeutic concentration under illustration.

3.4.Light in theranostics

Integrating imaging functionality into therapeutic procedures could be advantageous to therapy selection,objective response monitoring and follow-up therapy planning based on the specifc molecular characteristics of diseases[33],which could greatly enhance the safety and effcacy in treatment process.

Taking advantage of positron emission tomography(PET) imaging to monitor and quantitatively analyze the cargos and localization of drug delivery[34]systems(DDS)is meaningful to optimize therapeutic regimen and gain individualized medicine[35].Attaching radio-metal onto gold nanoparticles via metal chelator is the most common way to integrate PET imaging to GNPs;however,this pattern may infuence the surface properties of the GNPs and limit their ability to load other targeting or therapeutic agents.It is feasible to integrate64Cu to PEG-stabilized Au NPs via chemical reduction of64CuCl2under mild reaction conditions.Thein vivoexperiments proved that the stability of radiochemical and the noninvasive PET imaging provide an accurate and sensitive localization of Au NPs.Thus,64Cu radio-labeling protocol could be applied to develop a visualized photothermal therapy and that is very meaningful to clinical application[36].

Photosensitizes could be multifunctional in both therapy and diagnosis since upon illumination,they would generate ROS and emit strong fuorescence simultaneously without additional fuorescent dyes[37].However,most of photosensitive materials are hydrophobic and has low selectivity to target sites [38].Via Michael-type polymerization[39]the pH-responsive block copolymer micelles were prepared using hydrophilic MPEG and poly(β-amino ester).Subsequently,the hydrophobic photosensitizers Protoporphyrin IX were loaded into micelles by solvent evaporation method and the loading effciency could reach up to 70–80%when the Protoporphyrin IX content in the polymeric micelles is less than 10 wt%.In tumor bearing mice, these micelles showed clear fuorescent imaging and the tumors are eradicated completely[40].Indocyanine green(ICG)is an NIR dye for clinical application approved by the FDA and it can not only transfer energy from light to ROS for PDT[41],but can also raise local temperature for PTT;therefore,ICG could serve as a desired agent for theranostic.Employing 4T1 breast cancer cells in subcutaneously incubated nude mice as the animal modal,free ICG and HSA-ICG NPs were intravenously injected respectively.Fluorescent signals from injected free ICG mice mainly observed in liver and completely disappeared after 24 h postinjection;in contrast,in the case of HSA-ICG NPs mice, strong fuorescent signals have been detected within tumor region and 7 days after injection signal still could be observed[42].

4.Magnetically responsive system

Among the broad spectrum of nanoscale materials being investigated for biomedical application,magnetic nanoparticles (MNPs)have attracted signifcant attention due to their intrinsic magnetic properties,which enable tracking through radiology and magnetic resonance(MR)imaging[43].Moreover,in contrast to optical-dependent therapy that cannot be applied unless the penetration depth is less than centimeters,magnetic felds,particularly with frequencies below 400 Hz, are not signifcantly absorbed by tissues,allowing remote implementation without physical contact[44].In response to different types of magnetic feld,permanent magnetic(PMF)or alternating magnetic feld(AMF),MNPs would generate various treatment modalities,which can be applied to magnetictriggered drug delivery,hyperthermia and imaging-guided therapy[45].

4.1.Magnetic feld-assistant drug delivery

Although magnetic feld is always served as an imaging tool clinically,it is also extensively applied in other scenarios [46].

Since magnetite Fe3O4and maghemite γ-Fe2O3are superior to other metal oxide nanoparticles because of their biocompatibility and stability,making them the most commonly employed MNPs for biomedical applications by far[47], magnetic-responsive nanocarriers generally incorporate the bioactive carriers along with a magnetically active component,either magnetite(Fe3O4)or maghemite(γ-Fe2O3),in a pharmaceutically stable formulation[48].To avoid limitations of physical entrapment,there are some preparations using covalent-bond to connect magnetic nanocarriers and drugs for improved drug loading and higher accumulation in target sites. For example,Hua et al.framed a novel core-shell shaped drug nanocarrier using the polymer poly[aniline-co-N-(1-onebutyric acid)aniline](SPAnH)coated on Fe3O4cores to form magnetic nanoparticles(MNP)and the chemotherapeutic agent BCNU was immobilized successfully on MNPs by covalent bonding between the−NH of BCNU and the−COOH of MNPs. In the presence of magnetic feld beneath the culture plates, the MNPs uptake of C6 cells was notably increased and the IC50 of bound-BCNU was lowered to 16.1 ug/mL,hence,it is possible to use lower concentration of drugs to provide more effcient tumor suppression,concurrently,reducing the likelihood of adverse systemic effects[49].

RecentlyChoietal.reportedablockcopolymer poly(ethylene-oxide)-poly(propylene-oxide)-poly(ethyleneoxide)(PEO-PPO-PEO)and this triblock polymer has a range of critical micellization temperature(CMT)for volume/ hydrophobicity trisection[50].Inspired by this featured temperature sensitive copolymer,Liu et al.fabricated a magnetic triggered drug release system with a collapsible magnetic core of iron oxide immersed in a water solution of vitamin B12 and a fast-breathing nanosized two-layer shell of thermally responsive PEO-PPO-PEO polymer,and a cross-linked outer shell that stabilizes the nanoshell while maintaining the CMT.Upon exposure to external-placed magnetic feld, the nanocapsule will be heated and volume will change; fnally,the outer shell will be disrupted and drug will burst out[51].When submitted to high frequency alternating magnetic feld(HAMF),the superparamagnetic cores of nanocarriers will generate heat which can boost drugs release,and thisphenomenon has been denominated as the magnetic hyperthermia effect[52].

Magnetotactic bacteria are a particular sort of microorganisms that can orient and migrate along the geomagnetic fled lines[53].This distinctive feature is based on bacterial magnetosomes,which are the magnetic inclusions produced by magnetotactic bacteria with core-shell structure[54].The main chemical composition of magnetosomes are the membrane enclosed inorganic crystals of magnetite or greigite that make magnetotactic bacteria more sensitive to magnetic feld [55]and that makes bacterial magnetosomes possess unique advantages including superparamagnetic property,uniform particle size,fne dispersion and large specifc surface area,all of these properties demonstrating that bacterial magnetosomes could be served as potential magnetic drug carriers[56].Furthermore,bacterial magnetosomes can overcome the defciency of artifcial synthetic magnetic nanoparticles when applying to targeted drug delivery,such as low drug loading capability, agglomeration tendency and diffculties in size or shape control. The mechanism of bacterial magnetosomes used for targeting therapy is that magnetosomes complex nanoparticle loaded with drugs can locally target lesion site under an external magnetic feld.In these magnetic drug targeting strategy, magnetosomes used as the carriers for the chemotherapeutic agent,gene vaccine or contrast agent would centralize at the desirable site,and therefore increasing drug concentration at the targeted site,which minimizes the distribution in healthy tissues[57].Bacterial magnetosomes have novel magnetic,physical,and other properties that can and have been developed and investigated in a variety of scientifc,medical and commercial applications.However,despite the fact that bacterial magnetosomes hold tremendous potential as drug carriers,there are still many obstacles that may restrain the clinical application for bacterial magnetosomes.Alphandéry et al.extracted bacterial magnetite magnetosomes chains from AMB-1 magnetotactic bacteria and incubated with suspension containing MDA-MB-231,it was demonstrated that up to 100%of cells were destroyed when exposed to an alternative magnetic feld of frequency 183 kHz and feld strengths of 20,40, or 60 mT compared with cells incubated in the absence of an alternative magnetic feld,which the viability of these cells still remained high.The anti-tumor activity of these chains of magnetosomes was demonstrated further by showing that they can be used to fully eradicate a tumor xenografted under the skin of a mouse.When comparing extracted chains of magnetosomes with various other materials obtained from different approaches,the higher effciency of magnetosomes may be explicated to the following factors:higher specifc absorption rate and more effcient penetration within cell membrane under the application of the alternative magnetic feld[58].The effects of magnetic trapping of mitochondria using aptamer conjugated to bacterial magnetic nanoparticles that allowed targeting of the mitochondrial cytochrome c in the treatment of cancer cells has been reported recently,which offers a new approach for targeted cell therapy[59].Tang et al.suggested that the bacterial magnetite particles can be used as a novel and effcient gene vaccine delivery system.In their study, magnetosomes were used as carriers of a recombinant DNA composed of a secondary lymphoid tissue chemokine,human papillomavirus type E7(HPV-E7)and Ig-Fc fragment(pSLC-E7-Fc). Subcutaneous injection of BMP-V with a 600-mT static magnetic feld exposure for 10 min elicited systemic HPV-E7-specifc immunity leading to signifcant tumor inhibition in a mouse model[60].

4.2.Magnetic hyperthermia

While MNPs are accumulating in the tumor site,permanent magnetic feld(PMF)or alternating magnetic feld(AMF)could be taken into consideration subsequently,according to the mechanism of the design idea.Among the activation approaches,AMF is preferred because of its unique mechanism to actuate localized hyperthermia based on the Néel and Brownian relaxation mechanism[61].Therefore,combining this propertywiththermal-sensitiveorotherfunctional nanocarriers,a broad range of actuation mechanisms for ondemand drug release has been developed[62].

Magnetic-induced hyperthermia and photodynamic therapy, each single treatment,could slightly inhibit tumor growth,while their combination may lead to complete tumor regression.To encapsulate a high concentration of magnetic nanoparticles with liposome core and bring m-THPC,a photosensitizer already used clinically,into the lipid-bilayers,yield liposomes with highly satisfactory ratios of two components.Then the double cargo translated into dual-functionality,generating singlet oxygen by laser excitation and thermal production under alternating magnetic feld stimulation,which coupled PDT to hyperthermia.Thein vivorodent model tests have shown total solid-tumor ablation,which verifed the synergistic potential of a combined therapy[63].

Therapeutic resistance is a major problem in chemotherapy and the problem also exists in hyperthermia therapy. Heat-treated cells can acquire resistance to thermal stress readily and obviously increase cells’survival rate,which is termed thermoresistance[64].Integrating heat shock protein (Hsp)inhibitor[65]and heat generation moiety MNPs to single magnetic triggered nano platform,Yoo et al.fabricated a resistance-free apoptosis-inducing magnetic nanoparticle (RAIN),which can promote thermoresistance-free apoptosis[66].

Temperature needed to induce cell apoptosis is believed to be above 43°C due to the energy dissipation in alternating magnetic feld[67],but the heat removal rate by conduction is notably faster than the energy dissipation velocity by MNPs; moreover,Gordon suggested that the cell membrane would act as an insulator during the thermal conduction[68].Thus,it is reasonable to fabricate cell targeting MNPs that is able to be uptaken by specifc type cells readily and then put them under alternating magnetic feld to burn the cells.Results of cell associated experiments showed that MNPs linked epidermal growth factor receptor(EGFR)induced up to 99.9%reduction in cell viability with a negligible temperature rise[67].

4.3.MRI-guided therapy

Organic dyes can be introduced to nanoplatform for fuorescent imaging;however,the limited penetrating depth and readily fuorescence quenching constrict their application.In contrast,magnetic resonance imaging(MRI)can penetrate tissues deeper and more stable,so that MRI based nanoparticles is widely investigated in precisely detecting diseases at earlystage and tracking the biodistribution of nanocarriersin vivo; furthermore,the non-invasive nature and excellent spatial resolution promote its application in clinical[69].

Generally,MRI has two modes,namelyT1-andT2-weighted MRI,and the former is favored in clinical as they provide positive signals[70],and paramagnetic gadolinium and manganese are commonly used contrast agents for T1weighted MRI[71]. Porphysome created by MacDonald et al.are inherently multimodal;it is capable of directly chelating metal ions like copper and manganese so they can be embedded in the nanoplatform without exogenous components.Thus the insertion of Mn into porphysome can generate MRI sensitivity at a comparable level to the clinically used Gd-DTPA,while retaining high photothermal effciency[72].

Iron oxide like super-paramagnetic γ-Fe2O3is widely known for T2-weighted negative contrast,and compared with noble metals like Mn2+and Gd3+,the toxicity of Fe3O4is negligible and it can provide highly sensitive imaging as well[73]. Superparamagnetic iron oxide nanoparticles(SPIONs)can serve as contrast agents for T2-weighted imaging and according to the static dephasing regime(SDR)theory;it is reasonable to tailor nanoparticle size within a range for maximizing the relaxivity;however,SPIONs with diameters approaching the optimal size often become permanently magnetic[74],resulting in uncontrolled aggregation that diminishes relaxivity and substantially reduces the SPION’s ability to reach target sites. Coating SPIONs with a hyperbranched polyglycerol substituted with a varying number of octadecyl chains(HPG)to form nanoclusters,which can elegantly solve the aggregation problem and achieve high relaxivity of 719 mM−1s−1that is close to the theoretical maximal limit[75].

There is another strong point of iron nanoparticle.Studies have confrmed the feasibility of T1/T2dual-modality contrast agents based on Fe3O4NPs only which means that ironbased MRI can combine the advantages both of T1and T2imaging modes[76].Polydopamine nanospheres(PDAs)are effective photothermal therapy agents with high photo-toheat conversion effciency and excellent biodegradability,and previous studies have shown that PDAs can provide anchor sites for iron ions result from their strong chelate ability;thus,to combine MRI-guided photothermal nanoplatform is feasible.

5.Ultrasonic-responsive

Similarly,ultrasound has a number of attractive characteristics as a trigger for drug delivery.It is appealing because of its non-invasiveness,the absence of ionizing radiations,and the facile regulation of tissue penetration depth by tuning frequency,duty cycles and time of exposure[77].Additionally,it could reach deeper sites into the body than light-trigger(except for NIR-responsive)and the sonoporation phenomenon could act on the cell membrane that facilitate therapeutic molecules entrance into cells,to some extent,could reverse the multi-drug resistance of tumor cells[78].

5.1.Ultrasound in responsive system

Applying ultrasound technology in designing delivery system mainly is based on two physical mechanisms:heat and cavitation.By setting up high intensity focused ultrasound(HIFU) outside of the desired site,the localized temperature can be raised mildly which induced tumor cells apoptosis and necrosis.Au nanocages(AuNCs)is one of the hollow structure nanoplatforms;besides photothermal effect triggered by NIR laser,HIFU can directly transfer acoustic energy in the focal site to raise the temperature rapidly[79].Thus,encapsulating anticancer drugs and phase-change materials(PCMs),which could convert to liquid state when temperature rises up to 39°C, into the hollows of AuNCs to form an ultrasound responsive drug release system.Under ultrasound or NIR laser,the PCM inside the cages would be melted by AuNCs generated heat and then the fuid PCM would escape from the interiors of nanocages through small pores on the surface and release the encapsulated small molecule drugs into the surrounding medium[80].

Beside serving as heat producer under HIFU,when exposed to the exerted cycles of negative and positive pressure, microbubble would become oscillatory and high acoustical pressure could induce more drastic microbubble oscillations,which results in microbubble destruction and such property is named inertial cavitation[81].Liang et al.successfully fabricated a temperature sensitive cerasomes which includes cerasomeforming lipid,DPPC,DSPE-PEG and a temperature sensitive phosphocholine MSPC based on Bangham method in combination of sol–gel reaction and self-assembly process.The thermosensitive cerasomes exhibit excellent biocompatibility and long blood circulation time(half-life＞8.5 h)than conventional temperature sensitive liposomes[82].Low frequency ultrasound(LFUS),which is also termed as unfocused ultrasound,has been used to enhance biological membranes permeability and LFUS is more effective than high frequency ultrasound in releasing DOX from liposomes[83].Loading anticancer agent cisplatin into the nano sterically stabilized liposomes(nSSL)and injecting into tumor-bearing mice intraperitoneally,after accumulating in tumor site by EPR effect, LFUS was settled externally to the abdominal wall and drug release was quantifed.The results showed that nearly 70% cisplatin was released in tumor under the exposure to LFUS; however,the matched group that was not exposed to LFUS had less than 3%release[84].

Mechanisms beyond the ultrasound-based cell uptake enhancement were widely studied:under low acoustic pressures cell endocytosis is enhanced,since higher acoustic pressures favor uptake via membrane pores[85].Hence,it is important to understand whether loading nanoparticles into microbubbles or when they are physically mixed with the microbubbles can enhance the delivery across cellular membrane.In order to complete this task,two different nanoparticles were used,one is fuorescent polystyrene nanospheres,it were chosen as model nanoparticles as they are highly fuorescent,another one is fuorescently labeled mRNA-lipoplexes serve as therapeutical nanoparticles and there are two options whether combine microbubble with nanoparticles or not.The results of thein vitroexperiments elucidated that ultrasound can improve the intracellular delivery of large nanoparticles like mRNA-lipoplexes only when these were loaded into microbubbles and the‘co-administration mode’may only be useful when using small drug molecules since they can readily cross the membrane pores generated by cavitation[86].

5.2.Ultrasound-guided theranostics

Ultrasound has been applied in medical imaging for a long history.Ultrasound image is created by ultrasound waves refected by tissues with a density different from the surrounding medium;however,the contrast may not be obvious enough due to the compressibility of vasculature or other blood containing tissues,so that to enhance the imaging quality contrast agent is indispensable.

Microbubbles,hollow particles that contain gas,are applied as an ultrasound contrast agent recently since they possess acoustic characteristics different from plasma.Calcium carbonate minerals are insoluble at neutral pH but they can produce carbon dioxide in acidic conditions rapidly.In addition,the pH value of intracellular compartments such as endosomes(pH 5-6)and lysosomes(pH 4-5)are distinct to the extracellular environment,carbon dioxide release can only be triggered after being endocytosed by tumor cells and calcium carbonate is almost completely decomposed to carbon dioxide at pH 5[87–89].Hence,encapsulating fne-grained calcium carbonate inside a rabies virus glycoprotein(RVG)modifed Poly(D,L-lactide-co-glycolide)(PLG)nanocomplex via W/O/W double emulsion method can create gas-generating polymer nanoparticles(GNPs)and these GNPs are expected to induce necrotic cell death by releasing gas bubbles under ultrasound trigger.Injected into tumor-bearing mice intravenously, carbon dioxide generated from GNPs can effectively reduce the tumor size upon ultrasound applied extracorporeally[90].

Traditional ultrasound imaging has rarely been employed for cancer therapy because the size of microbubbles(3 to 10 μm in diameter)makes the permeation of tumor microvessels low probability[90].Porphyrin-lipid possesses unique multimodal imaging features intrinsically,using porphyrin-lipid to form an organic shell around perfuorocarbon gas fabricated porphyrin microbubbles(pMBs).On exposure to low frequency ultrasound,the microbubble consists of a bacteriochlorophyll–lipid shell around a perfuoropropane gas burst and form smaller nanoparticles that possess the same optical properties as the original microbubbles.

The pMBs peak size distribution was between 2 and 8 μm by volume with 99.9%＜10 μm by number,after low frequency ultrasound pulse,the pMBs burst into pNPs which polydisperse in size between 5 and 500 nm with 99%of pNPs in all samples having dimensions of＜500 nm[91].Encapsulating low boiling point perfuorocarbon,a thermosensitive liquid,to vaporize as gas,has been widely exploited;however, instead of using gaseous or perfuorocarbon,liquid H2O2can be easily introduced by the hydrophilic core of polymer and the H2O2plays a crucial role in concurrently providing O2for echogenic refectivity and·OH as the therapeutic reactive oxygen species(ROS).Meanwhile,encapsulating H2O2in the hydrophilic core with Fe3O4nanoparticles packed in the shell of the polymersome,once exposed to ultrasound,the encapsulated H2O2was liberated and moved through the disruption of PLGA polymersome to react with Fe3O4thus yielding·OH following a Fenton reaction[92].

6.Challenges and outlooks

Stimuli-responsive drug delivery systems have a rapid progress in the past few decades.These strategies exhibit tremendous therapeutic and detection potency for cancer at both research and clinical levels.Nanomaterials,including polymers,lipids and inorganic materials,which were introduced into stimuli responsive system,hold incredible promise in overcoming the limitations and drawbacks of conventional drug delivery mode.Additionally,they offered unprecedented control over spatiotemporal drug release and delivery profles leading to superiorin vitroandin vivotheranostic effciency.

Despite emerging progress made in external stimuliresponsive drug delivery research,there remain many challenges that need to be addressed;some of them have been listed in Table 2.Light-responsive systems need illumination to activate the light-sensitive materials;however,not all regions of the spectrum are appropriate for clinical use,which is also the major drawback of light treatments.Light from the ultraviolet-visible(UV)region always has a poor penetration ability for 10 mm at most due to the strong absorption and scattering of skin,blood and soft tissues[77].Except for the light wavelength problem of light-based treatments,laser power density is also an important factor that should be considered.It’s considered that laser power density beyond 1 W cm−2is harmful to health.Yet such dilemma could be avoided by using photosensitive groups that respond to higher wavelength like near-infrared(NIR)and that have less absorption and scattering but deeper penetration capability for almost 1 cm and minimal photo-toxicity.It is also feasible to apply twophoton technology,which is possible to shift the UV light source to reach NIR.Consequently,light-responsive systems are potent which is promising for clinical applications.

Table 2–The summary of the advantages and limitations of light-responsive systems,magnetic feld-responsive systems and ultrasound-responsive systems.

Magnetic feld is widely used in clinical application;it is a relatively mature technology but also has shortcomings like the degradation problem of noble-metal contrast agents and the relatively higher treatment cost than other diagnosis tools like CT imaging.

To date,a major disadvantage of microbubbles as drug carriers is their relatively large size(1–6 μm).Due to this feature, microbubbleshavearathershorthalf-life.Uponinjectionofthe microbubbles,they will circulate for a few times,but will inevitably get stuck in the lungs where gas exchange occurs[81]. Consequently,microbubble ultrasound triggered drug delivery will be mainly restricted to cardiovascular targets and to tumor endothelia.More importantly,ultrasound-mediated enhancement of vessel permeability can also be the cause of possible drawbacks such as metastatic dissemination.Fortunately,this diffcultymaybeovercomebythedevelopmentofperfuorocarbon (PFC)nanoemulsionswhichareabletoconvertintomicrobubbles under the activation of therapeutic ultrasound.The bubbles are formed through acoustic droplet vaporization and are subjectedtocavitation,thuspromotingcellularuptakeand/orrelease of the entrapped drugs in the tumor site[77].

Further fundamental understanding of the spatial and temporal patterns offers essential criteria for designing more effective and precise delivery vehicles.Meanwhile,more specifc designs should be taken into account for enhancing delivery effcacy.Further,eventual clinical translation of stimuliresponsive drug delivery requires comprehensive evaluation of biocompatibility of relevant formulations and there is a long way to go.

Acknowledgments

This work was supported by National Natural Science Foundation of China(81373353),Shanghai Science and Technology Committee(13NM1400500),and Program for New Century Excellent Talents in University(NCET-12-0130).

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*< class="emphasis_italic">Corresponding author.

.Key Laboratory of Smart Drug Delivery,Ministry of Education,School of Pharmacy,Fudan University,826 Zhangheng Road,Shanghai 201203,China.Tel.:+86 021 51980066;fax:+86 021 51980066.

E-mail address:chenjun@fudan.edu.cn(J.Chen).

http://dx.doi.org/10.1016/j.ajps.2016.06.001

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