A Water‐Soluble,NIR‐Absorbing Quaterrylenediimide Chromophore for Photoacoustic Imaging and Efficient Photothermal Cancer Therapy

Precision phototheranostics, including photoacoustic imaging and photothermal therapy, requires stable photothermal agents. Developing such agents with high stability and high photothermal conversion efficiency (PTCE) remains a considerable challenge. Herein, we introduce a new photothermal agent based on water‐soluble quaterrylenediimide (QDI) that can self‐assemble into nanoparticles (QDI‐NPs) in aqueous solution. Incorporating polyethylene glycol (PEG) into the QDI core significantly enhances both physiological stability and biocompatibility of QDI‐NPs. The highly photostable QDI‐NPs offer advantages including intense absorption in the near‐infrared (NIR) and high PTCE of up to 64.7±4 %. This is higher than that of commercial indocyanine green (ICG). Their small size (ca. 10 nm) enables sustained retention in deep tumor sites and also proper clearance from the body. QDI‐NPs allow high‐resolution photoacoustic imaging and efficient 808 nm laser‐triggered photothermal therapy of cancer in vivo.     

A Water‐Soluble,NIR‐Absorbing Quaterrylenediimide Chromophore for Photoacoustic Imaging and Efficient Photothermal Cancer Therapy

Precision phototheranostics, including photoacoustic imaging and photothermal therapy, requires stable photothermal agents. Developing such agents with high stability and high photothermal conversion efficiency (PTCE) remains a considerable challenge. Herein, we introduce a new photothermal agent based on water‐soluble quaterrylenediimide (QDI) that can self‐assemble into nanoparticles (QDI‐NPs) in aqueous solution. Incorporating polyethylene glycol (PEG) into the QDI core significantly enhances both physiological stability and biocompatibility of QDI‐NPs. The highly photostable QDI‐NPs offer advantages including intense absorption in the near‐infrared (NIR) and high PTCE of up to 64.7±4 %. This is higher than that of commercial indocyanine green (ICG). Their small size (ca. 10 nm) enables sustained retention in deep tumor sites and also proper clearance from the body. QDI‐NPs allow high‐resolution photoacoustic imaging and efficient 808 nm laser‐triggered photothermal therapy of cancer in vivo.     

Copper Sulfide Nanoparticles with Phospholipid‐PEG Coating for In Vivo Near‐Infrared Photothermal Cancer Therapy

In this work, small sizes of hydrophobic copper sulfide nanoparticles (CuS NPs, ～3.8 nm in diameter) have been successfully prepared from the reaction of copper chloride with sodium diethyldithiocarbamate (SDEDTC) inside a heated oleylamine solution. These CuS NPs displayed strong absorption in the 700–1100 nm near‐infrared (NIR) region. By coating CuS NPs with DSPE‐PEG2000 on the surface, the as‐synthesized CuS@DSPE‐PEG NPs exhibited good water solubility, significant stability and biocompatibility, as well as excellent photothermal conversion effects upon exposure to an 808 nm laser. After intravenous administration to mice, the CuS@DSPE‐PEG NPs were found to passively target to the tumor site, and tumor tissues could be ablated efficiency under laser irradiation. In addition, CuS@DSPE‐PEG NPs do not show significant toxicity by histological and blood chemistry analysis, and can be effectively excreted via metabolism. Our results indicated that CuS@DSPE‐PEG NPs can act as an ideal photothermal agent for cancer photothermal therapy.     

Polydopamine(PDA)-activated cobalt sulfide nanospheres responsive to tumor microenvironment(TME)for chemotherapeutic-enhanced photothermal therapy

Most recently,cobalt sulfide(CoS) nanospheres(NSs) have been demonstrated as an ideal high-efficient photothermal agent for tumor elimination.Howeve r,the surface of CoS NSs is lack of functio nal chemical groups or active radicals to incorporate therapeutic agents,which tremendously hinders their versatile utilization in medical field.Here,surface activation of CoS NSs was realized through the growth of polydopamine(PDA) in situ via alkaline-triggered polymerization.Upon the formation of CoS@PDA NSs,thiol-polyethylene glycol(SH-PEG) and chemotherapeutic agent of doxorubicin(DOX) were loaded onto the particle surface by means of π-π electrostatic interaction and Michael addition reactions.Assynthesized CoS@PDA/PEG/DOX(CoPPD) NSs exhibited an admirable photothermal property and high loading capacity of DOX(44.6%).Furthermore,drug release can be accelerated under a more acidic pH condition mimicking tumor microenvironment(TME),ascribed to the protonation of amino group in DOX molecules.Finally,a strong chemotherapeutic-enhanced photothermal therapeutic effect was demonstrated toward solid tumor under near-infrared(NIR) light irradiation without causing significant systemic toxicity.In this regard,this paradigm may offer valuable guidance for the design of multifunctional CoS-based nanoagents for medical treatment.     

Tailored Synthesis of Octopus‐type Janus Nanoparticles for Synergistic Actively‐Targeted and Chemo‐Photothermal Therapy

A facile, reproducible, and scalable method was explored to construct uniform Au@poly(acrylic acid) (PAA) Janus nanoparticles (JNPs). The as‐prepared JNPs were used as templates to preferentially grow a mesoporous silica (mSiO₂) shell and Au branches separately modified with methoxy‐poly(ethylene glycol)‐thiol (PEG) to improve their stability, and lactobionic acid (LA) for tumor‐specific targeting. The obtained octopus‐type PEG‐Au‐PAA/mSiO₂‐LA Janus NPs (PEG‐OJNP‐LA) possess pH and NIR dual‐responsive release properties. Moreover, DOX‐loaded PEG‐OJNP‐LA, upon 808 nm NIR light irradiation, exhibit obviously higher toxicity at the cellular and animal levels compared with chemotherapy or photothermal therapy alone, indicating the PEG‐OJNP‐LA could be utilized as a multifunctional nanoplatform for in vitro and in vivo actively‐targeted and chemo‐photothermal cancer therapy.     

Synthesis of degradable functional poly(ethylene glycol) analogs as versatile drug delivery carriers

Poly(ethylene glycol) (PEG) is widely used as a water soluble carrier for polymer-drug conjugates. Herein, we report degradable linear PEG analogs (DPEGs) carrying multifunctional groups. The DPEGs were synthesized by a Michael addition based condensation polymerization of dithiols and PEG diacrylates (PEGDA) or dimethacrylates (PEGDMA). They were stable at pH 7.4 but quickly degraded at pH 6.0 and 5.0. Thus, DPEGs could be used as drug carriers without concern for their retention in the body. DPEGs could be made to carry such functional groups as terminal thiol or (meth)acrylate and pendant hydroxyl groups. The functional groups were used for conjugation of drugs and targeting groups. This new type of PEG analog will be useful for drug delivery and the PEGylation of biomolecules and colloidal particles.     

A sialic acid-targeted near-infrared theranostic for signal activation based intraoperative tumor ablation

Agents enabling tumor staging are valuable for cancer surgery. Herein, a targetable sialic acid-armed near-infrared profluorophore (SA-pNIR) is reported for fluorescence guided tumor detection. SA-pNIR consists of a sialic acid entity effective for in vivo tumor targeting and a profluorophore which undergoes lysosomal acidity-triggered fluorogenic isomerization. SA-pNIR displays a number of advantageous biomedical properties in mice, e.g. high tumor-to-normal tissue signal contrast, long-term retention in tumors and low systemic toxicity. In addition, SA-pNIR effectively converts NIR light into cytotoxic heat in cells, suggesting tumor-activatable photothermal therapy. With high performance tumor illumination and lysosome-activatable photothermal properties, SA-pNIR is a promising agent for detection and photothermal ablation of surgically exposed tumors.     

Degradable Vanadium Disulfide Nanostructures with Unique Optical and Magnetic Functions for Cancer Theranostics

Multifunctional biodegradable inorganic theranostic nano‐agents are of great interest to the field of nanomedicine. Upon lipid modification, VS₂ nanosheets could be converted into ultra‐small VS₂ nanodots encapsulated inside polyethylene glycol (PEG) modified lipid micelles. Owing to paramagnetism, high near‐infrared (NIR) absorbance, and chelator‐free ^99mTc⁴⁺ labeling of VS₂, such VS₂@lipid‐PEG nanoparticles could be used for T1‐weighted magnetic resonance (MR), photoacoustic (PA),and single photon emission computed tomography (SPECT) tri‐modal imaging guided photothermal ablation of tumors. Importantly, along with the gradual degradation of VS₂, our VS₂@lipid‐PEG nanoparticles exhibit effective body excretion without appreciable toxicity. The unique advantages of VS₂ nanostructures with highly integrated functionalities and biodegradable behaviors mean they are promising for applications in cancer theranostics.     

Acid‐Labile Thermoresponsive Copolymers That Combine Fast pH‐Triggered Hydrolysis and High Stability under Neutral Conditions

Biodegradable polymeric materials are intensively used in biomedical applications. Of particular interest for drug‐delivery applications are polymers that are stable at pH 7.4, that is, in the blood stream, but rapidly hydrolyze under acidic conditions, such as those encountered in the endo/lysosome or the tumor microenvironment. However, an increase in the acidic‐degradation rate of acid‐labile groups goes hand in hand with higher instability of the polymer at pH 7.4 or during storage, thus posing an intrinsic limitation on fast degradation under acidic conditions. Herein, we report that a combination of acid‐labile dimethyldioxolane side chains and hydroxyethyl side chains leads to acid‐degradable thermoresponsive polymers that are quickly hydrolyzed under slightly acidic conditions but stable at pH 7.4 or during storage. We ascribe these properties to high hydration of the hydroxy‐containing collapsed polymer globules in conjunction with autocatalytic acceleration of the hydrolysis reactions by the hydroxy groups.     

Near‐Infrared Light and pH‐Responsive Polypyrrole@Polyacrylic acid/Fluorescent Mesoporous Silica Nanoparticles for Imaging and Chemo‐Photothermal Cancer Therapy

We have rationally designed a new theranostic agent by coating near‐infrared (NIR) light‐absorbing polypyrrole (PPY) with poly(acrylic acid) (PAA), in which PAA acts as a nanoreactor and template, followed by growing small fluorescent silica nanoparticles (fSiO₂ NPs) inside the PAA networks, resulting in the formation of polypyrrole@polyacrylic acid/fluorescent mesoporous silica (PPY@PAA/fmSiO₂) core–shell NPs. Meanwhile, DOX‐loaded PPY@PAA/fmSiO₂ NPs as pH and NIR dual‐sensitive drug delivery vehicles were employed for fluorescence imaging and chemo‐photothermal synergetic therapy in vitro and in vivo. The results demonstrate that the PPY@PAA/fmSiO₂ NPs show high in vivo tumor uptake by the enhanced permeability and retention (EPR) effect after intravenous injection as revealed by in vivo fluorescence imaging, which is very helpful for visualizing the location of the tumor. Moreover, the obtained NPs inhibit tumor growth (95.6 % of tumors were eliminated) because of the combination of chemo‐photothermal therapy, which offers a synergistically improved therapeutic outcome compared with the use of either therapy alone. Therefore, the present study provides new insights into developing NIR and pH‐stimuli responsive PPY‐based multifunctional platform for cancer theranostics.     

Synthesis of a Near‐Infrared BODIPY Dye for Bioimaging and Photothermal Therapy

The development of robust photothermal agents for near‐infrared (NIR) imaging is a great challenge. Herein, we report the design and synthesis of a new photothermal agent, based on the aza‐boron‐dipyrromethene framework (azaBDP). This compound possessed excellent photostability and high photothermal‐conversion efficiency (50 %) under NIR laser irradiation. When the photothermal properties of this compound were utilized for tumor inhibition, stable long‐term fluorescence was observed in living animals. Photothermal treatment efficiently suppressed tumor growth, as evidenced by in vitro and in vivo experiments. Furthermore, NIR emission could be detected by using an imaging system and therapeutic self‐monitoring was achieved by using NIR imaging.     

Coordinatively Unsaturated Fe3+ Based Activatable Probes for Enhanced MRI and Therapy of Tumors

Exogenous Fe^III can be used for cancer magnetic resonance (MR) imaging and potentially for cancer treatment by a ferroptosis pathway or photothermal ablation. To achieve this, effective and accurate delivery of Fe^III to cancerous sites is critical, requiring a balance of release kinetics of Fe³⁺ in tumorous and normal tissues. A nanoprobe is described consisting of upconversion luminescence (UCL) nanoparticles as a core and a coordinatively unsaturated Fe^III‐containing Fe³⁺/gallic acid complex as a shell. Owing to the introduction of an unsaturated coordination structure, Fe^III in the nanoprobe can be released only in the tumor microenvironment in response to the lightly acidic pH. The multiple UCLs are used for quantitatively visualizing the release of Fe³⁺ in vivo, whilst the release resultant serves as a photothermal agent. This nanoprobe exhibited ligand‐free tumor targeting ability, activatable MR imaging performance, and efficacious therapeutic effects against tumors in vivo.     

Gold Nanorod‐Assembled PEGylated Graphene‐Oxide Nanocomposites for Photothermal Cancer Therapy

Gold nanorod‐attached PEGylated graphene‐oxide (AuNR‐PEG‐GO) nanocomposites were tested for a photothermal platform both in vitro and in vivo. Cytotoxicity of AuNR was reduced after encapsulation with PEG‐GO along with the removal of cetyltrimethylammonium bromide (CTAB) from AuNR by HCl treatment. Cellular internalization of the CTAB‐eliminated AuNR‐PEG‐GO nanocomposites was examined using dark‐field microscopy (DFM), confocal Raman microscopy and transmission electron microscopy (TEM). To determine the photothermal effect of the AuNR‐PEG‐GO nanocomposites, A431 epidermoid carcinoma cells were irradiated with Xe‐lamp light (60 W cm^?2) for 5 min after treatment with the AuNR‐PEG‐GO nanocomposites for 24 h. Cell viability significantly decreased by ~40% when the AuNR‐PEG‐GO‐encapsulated nanocomposites were irradiated with light as compared with the cells treated with only the AuNR‐PEG‐GO nanocomposites without any illumination. In vivo tumor experiments also indicated that HCl‐treated AuNR‐PEG‐GO nanocomposites might efficiently reduce tumor volumes via photothermal processes. Our graphene and AuNR nanocomposites will be useful for an effective photothermal therapy.     

Semiconducting Polycomplex Nanoparticles for Photothermal Ferrotherapy of Cancer

This study reports the development of iron‐chelated semiconducting polycomplex nanoparticles (SPFeN) for photoacoustic (PA) imaging‐guided photothermal ferrotherapy of cancer. The hybrid polymeric nanoagent comprises a ferroptosis initiator (Fe³⁺) and an amphiphilic semiconducting polycomplex (SP_C) serving as both the photothermal nanotransducer and iron ion chelator. By virtue of poly(ethylene glycol) (PEG) grafting and its small size, SPFeN accumulates in the tumor of living mice after systemic administration, which can be monitored by PA imaging. In the acidic tumor microenvironment, SPFeN generates hydroxyl radicals, leading to ferroptosis; meanwhile, under NIR laser irradiation, it generates localized heat to not only accelerate the Fenton reaction but also implement photothermal therapy. Such a combined photothermal ferrotherapeutic effect of SPFeN leads to minimized dosage of iron compared to previous studies and effectively inhibits the tumor growth in living mice, which is not possible for the controls.     

A Dual‐Targeted Organic Photothermal Agent for Enhanced Photothermal Therapy

The development of highly effective anticancer drugs that cause minimal damage to the surrounding normal tissues is a challenging topic in cancer therapy. Herein, we demonstrate a dual‐targeted organic molecule that functions as a photothermal agent by actively targeting tumor tissue and mitochondria to selectively kill cancer cells. The synthesized photothermal agent exhibited high photothermal conversion efficiency, low cytotoxicity, and good biological compatibility. In vivo experiments showed an excellent tumor inhibitory effect of the dual‐targeted photothermal agent.     

Recent advances in photothermal and RNA interfering synergistic therapy

As a new treatment technique,photothermal therapy(PTT) has aroused worldwide attention in cancer treatment,mainly due to its excellent absorption ability,easy regulation,and biodegradability.Photothermal conversion materials with enhanced permeability and retention effect can be targeted easily to tumor tissue.They can accumulate efficiently to tumor tissues and allow normal tissues and organs not to be affected by temperature,thus significantly helping to reduce the systemic toxicity and improve the antitumor effect.However,PTT alo ne often suffers from the rapeutic resistance and reduced therapeutic efficacy,due to photothermal nanomaterial-mediated fundamental cellular defense mechanism of heat shock response,which could be inhibited by small interfering RNA(siRNA).Nevertheless,photothermal conversion materials as an excellent siRNA delivery carrier may conside rably enhance the delivery efficiency of siRNA.Therefore,photothermal and RNA interfering(RNAi) synergistic therapy has recently aroused extensive attention in tumor treatment.In this review,we mainly summarize the recent advances of photothermal and RNAi synergistic therapy,including some synergistic therapeutic nanoplatforms of inorganic and organic photothermal materials and other combined therapies such as combining with small molecular antitumor agents or PDT/imaging.The combination of various treatment techniques may considerably improve the synergistic therapeutic effect of PTT and RNAi in the treatment of cancers.     

High‐Fidelity End‐Functionalization of Poly(ethylene glycol) Using Stable and Potent Carbamate Linkages

Commercial PEG‐amine is of unreliable quality, and conventional PEG functionalization relies on esterification and etherification steps, suffering from incomplete conversion, harsh reaction conditions, and functional‐group incompatibility. To solve these challenges, we propose an efficient strategy for PEG functionalization with carbamate linkages. By fine‐tuning terminal amine basicity, stable and high‐fidelity PEG‐amine with carbamate linkage was obtained, as seen from the clean MALDI‐TOF MS pattern. The carbamate strategy was further applied to the synthesis of high‐fidelity multi‐functionalized PEG with varying reactive groups. Compared to with an ester linkage, amphiphilic PEG‐PS block copolymers bearing carbamate junction linkage exhibits preferential self‐assembly tendency into vesicles. Moreover, nanoparticles of the latter demonstrate higher drug loading efficiency, encapsulation stability against enzymatic hydrolysis, and improved in vivo retention at the tumor region.     

Photoactivated Polymersome Nanomotors: Traversing Biological Barriers

Synthetic nanomotors are appealing delivery vehicles for the dynamic transport of functional cargo. Their translation toward biological applications is limited owing to the use of non‐degradable components. Furthermore, size has been an impediment owing to the importance of achieving nanoscale (ca. 100 nm) dimensions, as opposed to microscale examples that are prevalent. Herein, we present a hybrid nanomotor that can be activated by near‐infrared (NIR)‐irradiation for the triggered delivery of internal cargo and facilitated transport of external agents to the cell. Utilizing biodegradable poly(ethylene glycol)‐b‐poly(d,l ‐lactide) (PEG‐PDLLA) block copolymers, with the two blocks connected via a pH sensitive imine bond, we generate nanoscopic polymersomes that are then modified with a hemispherical gold nanocoat. This Janus morphology allows such hybrid polymersomes to undergoing photothermal motility in response to thermal gradients generated by plasmonic absorbance of NIR irradiation, with velocities ranging up to 6.2±1.10 μm s^?1. These polymersome nanomotors (PNMs) are capable of traversing cellular membranes allowing intracellular delivery of molecular and macromolecular cargo.     

Interactions of Renal‐Clearable Gold Nanoparticles with Tumor Microenvironments: Vasculature and Acidity Effects

The success of nanomedicines in the clinic depends on our comprehensive understanding of nano–bio interactions in tumor microenvironments, which are characterized by dense leaky microvasculature and acidic extracellular pH (pH_e) values. Herein, we investigated the accumulation of ultrasmall renal‐clearable gold NPs (AuNPs) with and without acidity targeting in xenograft mouse models of two prostate cancer types, PC‐3 and LNCaP, with distinct microenvironments. Our results show that both sets of AuNPs could easily penetrate into the tumors but their uptake and retention were mainly dictated by the tumor microvasculature and the enhanced permeability and retention effect over the entire targeting process. On the other hand, increased tumor acidity indeed enhanced the uptake of AuNPs with acidity targeting, but only for a limited period of time. By making use of simple surface chemistry, these two effects can be synchronized in time for high tumor targeting, opening new possibilities to further improve the targeting efficiencies of nanomedicines.     

Mo2C‐Derived Polyoxometalate for NIR‐II Photoacoustic Imaging‐Guided Chemodynamic/Photothermal Synergistic Therapy

To overcome the current limitations of chemodynamic therapy (CDT), a Mo₂C‐derived polyoxometalate (POM) is readily synthesized as a new CDT agent. It permits synergistic chemodynamic and photothermal therapy operating in the second near‐infrared (NIR‐II) biological transparent window for deep tissue penetration. POM aggregated in an acidic tumor micro‐environment (TME) whereby enables specific tumor targeting. In addition to the strong ability to produce singlet oxygen (¹O₂) presumably via Russell mechanism, its excellent photothermal conversion enhances the CDT effect, offers additional tumor ablation modality, and permits NIR‐II photoacoustic imaging. Benefitting from the reversible redox property of molybdenum, the theranostics based on POM can escape from the antioxidant defense system. Moreover, combining the specific responsiveness to TME and localized laser irradiation, side‐effects shall be largely avoided.