Isoindigo nanoparticles for photoacoustic imaging-guided tumor photothermal therapy

The key factor in photothermal therapy lies in the selection of photothermal agents.Traditional photothermal agents generally have problems such as poor photothermal stability and low photothermal conversion efficiency.Herein,we have designed and synthesized an isoindigo(IID)dye.We used isoindigo as the molecular center and introduced common triphenylamine and methoxy groups as rotors.In order to improve the photothermal stability and tumor targeting ability,we encapsulated IID into nanoparticles.As a result,the nanoparticles exhibited high photothermal stability and photothermal conversion efficiency(67%)upon 635 nm laser irradiation.Thus,the nanoparticles demonstrated a significant inhibitory effect on live tumors in photothermal therapy guided by photoacoustic imaging and provided a viable strategy to overcome the treatment challenges.

CA IX-targeted Ag_(2)S quantum dots bioprobe for NIR-II imaging-guided hypoxia tumor chemo-photothermal therapy

Hypoxia is the common characteristic of almost all solid tumors,which prevents therapeutic drugs from reaching the tumors.Therefore,the development of new targeted agents for the accurate diagnosis of hypoxia tumors is widely concerned.As carbonic anhydrase IX(CA IX)is abundantly distributed on the hypoxia tumor cells,it is considered as a potential tumor biomarker.4-(2-Aminoethyl)benzenesulfonamide(ABS)as a CA IX inhibitor has inherent inhibitory activity and good targeting effect.In this study,Ag_(2)S quantum dots(QDs)were used as the carrier to prepare a novel diagnostic and therapeutic bioprobe(Ag_(2)S@polyethylene glycol(PEG)-ABS)through ligand exchange and amide condensation reaction.Ag_(2)S@PEG-ABS can selectively target tumors by surface-modified ABS and achieve accurate tumor imaging by the near infrared-II(NIR-II)fluorescence characteristics of Ag_(2)S QDs.PEG modification of Ag_(2)S QDs greatly improves its water solubility and stability,and therefore achieves high photothermal stability and high photothermal conversion efficiency(PCE)of 45.17%.Under laser irradiation,Ag_(2)S@PEG-ABS has powerful photothermal and inherent antitumor combinations on colon cancer cells(CT-26)in vitro.It also has been proved that Ag_(2)S@PEG-ABS can realize the effective treatment of hypoxia tumors in vivo and show good biocompatibility.Therefore,it is a new efficient integrated platform for the diagnosis and treatment of hypoxia tumors.

Fluorescent Silicon Nanorods-Based Nanotheranostic Agents for Multimodal Imaging-Guided Photothermal Therapy

The utilization of diagnosis to guide/aid therapy procedures has shown great prospects in the era of personalized medicine along with the recognition of tumor heterogeneity and complexity.Herein,a kind of multifunctional silicon-based nanostructure,i.e.,gold nanoparticles-decorated fluorescent silicon nanorods(Au@SiNRs),is fabricated and exploited for tumor-targeted multimodal imaging-guided photothermal therapy.In particular,the prepared Au@SiNRs feature high photothermal conversion efficiency(~43.9%)and strong photothermal stability(photothermal performance stays constant after five-cycle NIR laser irradiation),making them high-performance agents for simultaneously photoacoustic and infrared thermal imaging.The Au@SiNRs are readily modified with targeting peptide ligands,enabling an enhanced tumor accumulation with a high value of^8.74%ID g?1.Taking advantages of these unique merits,the Au@SiNRs are superbly suitable for specifically ablating tumors in vivo without appreciable toxicity under the guidance of multimodal imaging.Typically,all the mice treated with the Au@SiNRs remain alive,and no distinct tumor recurrence is observed during 60-day investigation.

RBC Membrane Camouflaged Semiconducting Polymer Nanoparticles for Near-Infrared Photoacoustic Imaging and Photothermal Therapy

Semiconducting conjugated polymer nanoparticles(SPNs)represent an emerging class of phototheranostic materi-als with great promise for cancer treatment.In this report,low-bandgap electron donoracceptor(DA)-conjugated SPNs with sur-face cloaked by red blood cell membrane(RBCM)are developed for highly e ective photoacoustic imaging and photothermal therapy.The resulting RBCM-coated SPN(SPN@RBCM)displays remarkable near-infrared light absorption and good photosta-bility,as well as high photothermal conver-sion e ciency for photoacoustic imaging and photothermal therapy.Particularly,due to the small size(<5 nm),SPN@RBCM has the advantages of deep tumor penetration and rapid clearance from the body with no appreciable toxicity.The RBCM endows the SPNs with prolonged systematic circulation time,less reticuloendothelial system uptake and reduced immune-recognition,hence improving tumor accumulation after intravenous injection,which provides strong photoacoustic signals and exerts excellent photothermal therapeutic e ects.Thus,this work provides a valuable paradigm for safe and highly e cient tumor pho-toacoustic imaging and photothermal therapy for further clinical translation.

Fluorescence life-time imaging microscopy(FLIM)monitors tumor cell death triggered by photothermal therapy with MoS_(2) nanosheets

Recently,photothermal therapy(PTT)has been proved to have great potential in tumor therapy.In the last several years,MoS_(2),as one novel member of nanomaterials,has been applied into PTT due to its excellent photothermal conversion efficacy.In this work,we applied fuorescence lifetime imaging microscopy(FLIM)techniques into monitoring the PPT-triggered cell death under MoS_(2) nanosheet treatment.Two types of MoS_(2) nanosheets(single layer nanosheets and few layer nanosheets)were obtained,both of which exhibited presentable photothermal conversion fficacy,leading to high cell death rates of 4T1 cells(mouse breast cancer cells)under PTT.Next,live cell images of 4T1 cells were obtained via directly labeling the mitochondria with Rodamine123,which were then continuously observed with FLIM technique.FLIM data showed that the fuorescence lifetimes of mitochondria targeting dye in cells treated with each type of MoS_(2) nanosheets significantly increased during PTT treatment.By contrast,the fuorescence lifetime of the same dye in control cells(without nanomaterials)remained constant after laser irradiation.These findings suggest that FLIM can be of great value in monitoring cell death process during PTT of cancer cells,which could provide dynamic data of the cellular microenvironment at single cell level in multiple biomedical applications.

Multifunctional conjugated polymer nanoparticles for photoacoustic-based multimodal imaging and cancer photothermal therapy

Photoacoustic imaging(PAI)is a hybrid imaging method based on photoacoustic(PA)effects,which is able to capture the structure,function,and molecular information of biological tissues with high resolution.To date,therapeutic techniques under the guidance of PAI have provided new strategies for accurate diagnosis and precise treatment of tumors.In particular,conjugated polymer nanoparticles have been extensively inspected for PA-based cancer theranostics largely due to their superior optical properties such as tunable spectrum and large absorption coefficient and their good biocompatibility,and abundant functional groups.This mini-review mainly focuses on the recent advances toward the development of novel conjugated polymer nanoparticles for PA-based multimodal imaging and cancer photothermal therapy.

Fe3O4-based Nanoparticles for pH-responsive Dual-modality Imaging and Photothermal Therapy

The study designed a polyacrylic acid(PAA)modified Fe3O4@MnO2 nanoparticles(Fe3O4@MnO2@PAA)for T1/T2 dualmode imaging.In addition,this nano-drug has pH response and anti-tumor photothermal therapy.First,using Fe3O4 as the core can significantly reduce the signal of Fe3O4@MnO2@PAA nanoparticles.MnO2 nanoshells can be decomposed into paramagnetic Mn2+under the acidic environment in the tumor,which enhanced the T1 signal.The pH-responsive T1/T2 dual-mode magnetic resonance imaging(MRI)contrast agent had good sensitivity and specificity,providing more comprehensive and detailed information for tumor diagnosis.In addition,Fe3O4@MnO2@PAA nanoparticles showed excellent absorption capacity in the near-infrared region(NIR),which could be used as a good photothermal conversion material to mediate photothermal treatment of tumors.Therefore,the pHresponsive dual-mode MRI nanoparticle-mediated photothermal therapy showed good application potential in tumor treatment and diagnosis.

Multifunctional magnetic nanoparticles for magnetic resonance image-guided photothermal therapy for cancer

Key advances in multifunctional magnetic nanoparticles （MNPs） for magnetic resonance （MR） image-guided pho- tothermal therapy of cancer are reviewed. We briefly outline the design and fabrication of such multifunctional MNPs. Bimodal image-guided photothermal therapies （MR/fluorescence and MR/ultrasound） are also discussed.

Synthesis of photostable near-infrared sulfone-rhodamines for photoacoustic imaging-guided photothermal therapy

Photothermal therapy(PTT)is a cutting-edge cancer treatment that can kill cancer cells in hypoxic environments without relying on oxygen.Seeking of the ideal photothermal agents with a high absorption coefficient in the near-infrared region,and a high excellent photothermal conversion efficiency is of great significance.Sulfone-Rhodanmine dye has showed an impressive absorption wavelength over 700 nm,but suffered from a stability issue.In this study,we synthesized five sulfone rhodamines and investigated the substitution effects on stability.SO_(2)R2 showed high stability and strong absorbance at 714 nm with an excellent photothermal conversion efficiency of 53.06%,making it suitable for accurate photoacoustic imaging-guided photothermal therapy in vivo.

Aggregation-induced Emission Probe for Fluorescence/Photoacoustic Dual-modality Imaging and Photodynamic/Photothermal Treatment

The combination of near-infrared(NIR)fluorescence imaging(FLI)and photoacoustic imaging(PAI)can effectively compensate for each other’s inherent limitations,which can provide reliable and rich information on tumor biology.Therefore,the development of FL/PA dual-modality imaging probes is beneficial for achieving precision cancer diagnosis and treatment.Herein,we designed an efficient phototherapy agent methoxy bithiophene indene(OTIC),which was based on aggregation-induced emission(AIE)active fluorophores.To improve the water dispersion and enrichment of OTIC at the tumor site,OTIC nanoparticles(OTIC NPs)were prepared by a nanoprecipitation method.The balance between radiation and non-radiation energy dissipation was regulated by the strong donor-acceptor interaction and intramolecular motion.So OTIC NPs exhibited bright NIR fluorescence,photoacoustic signals,efficient generation of reactive oxygen species,and high photothermal conversion efficiency under NIR irradiation.Accurate imaging of the tumor and mice sentinel lymph nodes(SLNs)with OTIC NPs was visualized by NIR FL/PA dual-modal imaging.With the comprehensive imaging information provided by OTIC NPs in vivo,tumors were ablated under laser irradiation,which greatly improved the therapeutic efficacy.OTIC NPs would be possible to realize the precise guidance of FL/PA imaging for tumor treatment in the future clinical application.

Self-assembled amphiphilic NIR-Ⅱ emissive nano-micelles for imaging-guided photothermal therapy of colorectal cancer

Colorectal cancer(CRC) is one of the major causes of cancer-related mortality worldwide. Most near-infrared(NIR) agents used in clinical CRC treatment are at NIR-I(700–900 nm) window, which has limitations on deep tissue, and fluorescent probes in the second NIR(1,000–1,700 nm) allow high-resolution bioimaging with deep tissue penetration. However, existing NIR-II fluorophores used in clinical are still rare. Herein, based on shielding-donor-acceptor-donor-shielding(S-D-A-D-S) scaffold, we developed an organic small-molecule fluorophore IR-BTGP with NIR-II emission for imaging-guided photothermal therapy(PTT) in CRC mice model. Amphiphilic IR-BTGP can be self-assembled into spherical nano-micelles, which presents reliable water solubility and photothermal conversion efficiency(30.2%). In vitro experiments indicate that cancer cells treated with IRBTGP were significantly killed upon 808 nm light irradiation. Furthermore, in vivo NIR-II fluorescence imaging confirms that IR-BTGP accumulates in the tumor region. Remarkably, a significant tumor inhibition rate(78.5%) was observed in tumorbearing mice when treated with IR-BTGP plus 808 nm irradiation. Therefore, this work shows that IR-BTGP holds great promise as an NIR-II fluorescence imaging-guided PTT platform for CRC in the future.

Supramolecular phthalocyanine assemblies-enhanced synergistic photodynamic and photothermal therapy guided by photoacoustic imaging

Phototherapeutic nanoplatforms that combine photodynamic therapy(PDT)and photothermal therapy(PTT)with the guidance of photoacoustic(PA)imaging are an effective strategy for the treatment of tumors,but establishing a universal method for this strategy has been challenging.In this study,we present a supramolecular assem-bly strategy based on Förster resonance energy transfer to construct a supramolecular nanostructured phototherapeutic agent(PcDA)via the anion and cation supramolec-ular interaction between two water-soluble phthalocyanine ramifications,PcD and PcA.This approach promotes the absorption of energy,thus enhancing the genera-tion of reactive oxygen species(ROS)and heat by PcDA,improving its therapeutic efficacy,and overcoming the low photon utilization efficiency of conventional PSs.Notably,after the intravenous injection of PcDA,neoplastic sites could be clearly visualized using PA imaging,with a PA signal-to-liver ratio as high as 11.9.Due to these unique features,PcDA exhibits excellent antitumor efficacy in a preclinical model at a low dose of light irradiation.This study thus offers a general approach for the development of efficient phototherapeutic agents based on the simultaneous effect of PDT and PTT against tumors with the assistance of PA imaging.

Facile Approach to Synthesize Gold Nanorod@Polyacrylic Acid/Calcium Phosphate Yolk–Shell Nanoparticles for Dual-Mode Imaging and pH/NIR-Responsive Drug Delivery

A facile strategy to fabricate gold nanorod@polyacrylic acid/calcium phosphate(Au NR@-PAA/Ca P) yolk–shell nanoparticles(NPs) composed with a PAA/Ca P shell and an Au NR yolk is reported. The asobtained Au NR@PAA/Ca P yolk–shell NPs possess ultrahigh doxorubicin(DOX) loading capability(1 mg DOX/mg NPs), superior photothermal conversion property(26%)and p H/near-infrared(NIR) dual-responsive drug delivery performance. The released DOX continuously increased due to the damage of the Ca P shell at low p H values. When the DOX-loaded Au NR@PAA/Ca P yolk–shell NPs wereexposed to NIR irradiation, a burst-like drug release occurs owing to the heat produced by the Au NRs. Furthermore,Au NR@PAA/Ca P yolk–shell NPs are successfully employed for synergic dual-mode X-ray computed tomography/photoacoustic imaging and chemo-photothermal cancer therapy. Therefore, this work brings new insights for the synthesis of multifunctional nanomaterials and extends theranostic applications.

Deep-Tissue Photothermal Therapy Using Laser Illumination at NIR-Ⅱa Window

Photothermal therapy(PTT)using near-infrared(NIR)light for tumor treatment has triggered extensive attentions because of its advantages of noninvasion and convenience.The current research on PTT usually uses lasers in the first NIR window(NIR-I;700–900 nm)as irradiation source.However,the second NIR window(NIR-II;1000–1700 nm)especially NIRIIa window(1300–1400 nm)is considered much more promising in diagnosis and treatment as its superiority in penetration depth and maximum permissible exposure over NIR-I window.Hereby,we propose the use of laser excitation at 1275 nm,which is approved by Food and Drug Administration for physical therapy,as an attractive technique for PTT to balance of tissue absorption and scattering with water absorption.Specifically,CuS-PEG nanoparticles with similar absorption values at 1275 and 808 nm,a conventional NIR-I window for PTT,were synthesized as PTT agents and a comparison platform,to explore the potential of 1275 and 808 nm lasers for PTT,especially in deep-tissue settings.The results showed that 1275 nm laser was practicable in PTT.It exhibited much more desirable outcomes in cell ablation in vitro and deep-tissue antitumor capabilities in vivo compared to that of 808 nm laser.NIR-IIa laser illumination is superior to NIR-I laser for deep-tissue PTT,and shows high potential to improve the PTT outcome.

The appliances and prospects of aurum nanomaterials in biodiagnostics, imaging, drug delivery and combination therapy

Aurum nanomaterials(ANM), combining the features of nanotechnology and metal elements, have demonstrated enormous potential and aroused great attention on biomedical applications over the past few decades. Particularly, their advantages, such as controllable particle size, flexible surface modification, higher drug loading, good stability and biocompatibility, especially unique optical properties, promote the development of ANM in biomedical field. In this review, we will discuss the advanced preparation process of ANM and summarize their recent applications as well as their prospects in diagnosis and therapy. Besides, multi-functional ANM-based theranostic nanosystems will be introduced in details, including radiotherapy(RT), photothermal therapy(PTT), photodynamic therapy(PDT), immunotherapy(IT), and so on.

Functionalized Gold Nanorods for Tumor Imaging and Targeted Therapy

Gold nanorods,as an emerging noble metal nanomaterial with unique properties,have become the new exciting focus of theoretical and experimental studies in the past few years.The structure and function of gold nanorods,especially their biocompatibility, optical property,and photothermal effects,have been attracting more and more attention.Gold nanorods exhibit great potential in applications such as tumor molecular imaging and photothermal therapy.In this article,we review some of the main advances made over the past few years in the application of gold nanorods in surface functionalization,molecular imaging,and photothermal therapy. We also explore other prospective applications and discuss the corresponding concepts,issues,approaches,and challenges,with the aim of stimulating broader interest in gold nanorod-based nanotechnology and improving its practical application.

Single-shot mid-infrared incoherent holography using Lucy-Richardson-Rosen algorithm

In recent years,there has been a significant transformation in the field of incoherent imaging with new possibilities of compressing three-dimensional(3D)information into a two-dimensional intensity distribution without two-beam interference(TBI).Most of the incoherent 3D imagers without TBI are based on scattering by a random phase mask exhibiting sharp autocorrelation and low cross-correlation along the depth.Consequently,during reconstruction,high lateral and axial resolutions are obtained.Imaging based on scattering requires an astronomical photon budget and is therefore precluded in many power-sensitive applications.In this study,a proof-of-concept 3D imaging method without TBI using deterministic fields has been demonstrated.A new reconstruction method called the Lucy-Richardson-Rosen algorithm has been developed for this imaging concept.We believe that the proposed approach will cause a paradigm-shift in the current state-of-the-art incoherent imaging,fluorescence microscopy,mid-infrared fingerprinting,astronomical imaging,and fast object recognition applications.

Laser Pulse Duration Optimization for Photothermal Therapy with Gold Nanostars

Photothermal therapy (PTT), which utilizes light radiation to create localized heating effect in the targeted areas, is a promising solution for highly specific yet minimally invasive cancer therapy. PTT uses photothermal agents, which are usually nanoparticles that absorb strongly in the near-infrared optical window where minimal tissue absorption occurs. Photothermal agents are also highly functionalized to target at specific tumor sites. Gold nanostar is an ideal candidate for photothermal agents, because it not only has a Surface Plasmon Resonance in the near-infrared, but also can be easily produced and purified, and is extremely versatile in the drug delivery process. In order to achieve maximum amount of localized heating, pulse lasers are usually used in laser ablation processes like photothermal therapy. However, intensive laser radiation can cause damage to regular tissues as well the nanostructures themselves. Therefore, identifying the optimal pulse duration to effectively generate localized heating in the tumorous tissues while keeping the normal tissues and the nanostructures intact is important to achieving optimal photo-therapeutic results. This manuscript provides a numerical calculation method with Comsol Multiphysics to optimize the pulse condition of the gold nanostars under photothermal therapy settings. Based on results, gold nanostar displays significant temperature heterogeneity under femtosecond and picosecond laser radiation, while nanosecond laser only induces rather uniform heating effects across the entire gold nanostar particle. This finding indicates that femtosecond laser, which is the most common type of laser used for ablation, is likely to melt the tip of the gold nanostar before the nanostar body reaches a reasonably high temperature. Picosecond and nanosecond lasers are much less likely to induce such dramatic morphology change. This study offers important insight into finding the optimal condition for photothermal therapy with maximal efficacy and minimal damage.

PLG-g-mPEG Mediated Multifunctional Nanoparticles for Photoacoustic Imaging Guided Combined Chemo/Photothermal Antitumor Therapy

Under laser irradiation,photothermal therapy(PTT)effectively ablates tumors above 50℃.However,hyperthermia can cause additional damage due to the inevitable heat spread to surrounding healthy tissue.Herein,nanoparticles named as GI@P NPs were designed for enhanced PTT with heat shock protein 90(HSP90)inhibition at temperatures below 50℃to achieve optimal cancer therapy and avoid surrounding damage.GI@P NPs were done by co-loading Garcinia cambogia acid(GA)and photosensitizer IR783 in polymer PLG-g-mPEG to form a nanomedicine,where IR783 with excellent photoacoustic(PA)signal acted as an excellent photothermal therapeutic agent that converted the laser energy into heat to kill tumor cells,GA was used as antitumor drug for chemotherapy and an inhibitor of HSP90 to overcome the heat resistance of tumors for efficient cryo-photothermal therapy,and PLG-g-mPEG can encapsulate IR783 and GA to increase biocompatibility and accumulate effectively in the tumor.After GI@P NPs were injected into the mice,we could observe that the PA signals gradually increased in the tumor region and showed the strongest PA signals at 12 h.Under laser irradiation,the tumor temperature of the mice could raise to about 43.5℃,and the tumor was significantly inhibited after long-term monitoring by PA imaging.As a result,gentle PTT produced by GI@P NPs exhibited good antitumor effects at relatively low temperature and minimized nonspecific thermal damage to normal tissues.The GI@P NPs as nanomedicine enriched our understanding of various applications of polymeric carriers,especially in the biomedical field.

Interstitial photoacoustic technique and computational simulation for temperature distribution and tissue optical properties in interstitial laser photothermal interaction

Interstitial laser immunotherapy(ILIT)is designed to use photothermal and immunological inter-actions for treatment of metastatic cancers.The photothermal ffect is crucial in inducing anti-tumorimmune responses in the host.Tissue temperature and tssue optical properties are important factorsin this process.In this study,a device combining interstitial photoacoustic(PA)technique andinterstitial laser photothermal interaction is proposed.Together with computational simulation,thisdevice was designed to determine temperature distributions and tissue optical properties during lasertreatment.Experiments were performed usinger-ivoFporcine liver tissue.Our results demonstratedthat interstitial PA signal amplitude was linearly dependent on tisue temperature in the tempera-ture ranges of 20-60℃,as wll as 65-80℃,with a dfferent slope,due to the change of tissue opticalproperties.Using the directly measured temperature in the tissue around the interstitial optical fiberdiffusion tip for calibration,the theoretical temperature distribution predicted by the bioheatequation was used to extract optical properties of tssue.Finally,the three-dimensional temperature distribution was simulated to guide tumor destruction and immunological stimulation,Thus,thisnovel device and method could be used for monitoring and controlling ILIT for cancer treatment.