Hyaluronidase with pH‐responsive Dextran Modification as an Adjuvant Nanomedicine for Enhanced Photodynamic‐Immunotherapy of Cancer

The condensed tumor extracellular matrix (ECM) consisting of cross‐linked hyaluronic acid (HA) is one of key factors that results in the aberrant tumor microenvironment (TME) and the resistance to various types of therapies. Herein, hyaluronidase (HAase) is modified by a biocompatible polymer, dextran (DEX), via a pH‐responsive traceless linker. The formulated DEX‐HAase nanoparticles show enhanced enzyme stability, reduced immunogenicity, and prolonged blood half‐life after intravenous injection. With efficient tumor passive accumulation, DEX‐HAase within the acidic TME would be dissociated to release native HAase, which afterward triggers the breakdown of HA to loosen the ECM structure, subsequently leading to enhanced penetration of oxygen and other therapeutic agents. The largely relieved tumor hypoxia would promote the therapeutic effect of nanoparticle‐based photodynamic therapy (PDT), accompanied by the reverse of the immunosuppressive TME to boost cancer immunotherapy. Interestingly, the therapeutic responses achieved by the combination of PDT and anti‐programmed death‐ligand 1 (anti‐PD‐L1) checkpoint blockade therapy could be significantly enhanced by pretreatment with DEX‐HAase. In addition to destructing tumors with direct light exposure, a robust abscopal effect is achieved after such treatment, which is promising for tumor metastasis inhibition. The work presents a new type of adjuvant nanomedicine to assist photodynamic‐immunotherapy of cancer, by effective modulation of TME.     

Fluorinated Polyethylenimine to Enable Transmucosal Delivery of Photosensitizer‐Conjugated Catalase for Photodynamic Therapy of Orthotopic Bladder Tumors Postintravesical Instillation

Photodynamic therapy (PDT) by insertion of an optical fiber into the bladder cavity has been applied in the clinic for noninvasive treatment of bladder tumors. To avoid systemic phototoxicity, bladder intravesical instillation of a photosensitizer may be an ideal approach for PDT treatment of bladder cancer, in comparison to conventional intravenous injection. However, the instillation‐based PDT for bladder cancer treatment remains to be less effective due to the poor urothelial uptake of photosensitizer, as well as the tumor hypoxia‐associated PDT resistance. Herein, it is uncovered that fluorinated polyethylenimine (F‐PEI) achieved by mixing with Chorin‐e6‐conjugated catalase (CAT‐Ce6) is able to form self‐assembled CAT‐Ce6/F‐PEI nanoparticles, which show greatly improved cross‐membrane, transmucosal, and intratumoral penetration capacities compared with CAT‐Ce6 alone or nonfluorinated CAT‐Ce6/PEI nanoparticles. Owing to the decomposition of tumor endogenous H₂O₂ by CAT‐Ce6/F‐PEI nanoparticles penetrating into bladder tumors, the tumor hypoxia would be effectively relieved to further favor PDT. Therefore, bladder intravesical instillation with CAT‐Ce6/F‐PEI nanoparticles could offer remarkably improved photodynamic therapeutic effect to destruct orthotopic bladder tumors with reduced systemic toxicity compared to hematoporphyrin, the first‐line photosensitizer used for bladder cancer PDT in clinic. This work presents a unique photosensitizer nanomedicine formulation, promising for clinical translation in instillation‐based PDT to treat bladder tumors.     

Imaging‐Guided pH‐Sensitive Photodynamic Therapy Using Charge Reversible Upconversion Nanoparticles under Near‐Infrared Light

Photodynamic therapy (PDT) based on upconversion nanoparticles (UCNPs) can effectively destroy cancer cells under tissue‐penetrating near‐infrared light (NIR) light. Herein, we synthesize manganese (Mn²⁺)‐doped UCNPs with strong red light emission at ca. 660 nm under 980 nm NIR excitation to activate Chlorin e6 (Ce6), producing singlet oxygen (¹O₂) to kill cancer cells. A layer‐by‐layer (LbL) self‐assembly strategy is employed to load multiple layers of Ce6 conjugated polymers onto UCNPs via electrostatic interactions. UCNPs with two layers of Ce6 loading (UCNP@2xCe6) are found to be optimal in terms of Ce6 loading and ¹O₂ generation. By further coating UCNP@2xCe6 with an outer layer of charge‐reversible polymer containing dimethylmaleic acid (DMMA) groups and polyethylene glycol (PEG) chains, we obtain a UCNP@2xCe6‐DMMA‐PEG nanocomplex, the surface of which is negatively charged and PEG coated under pH 7.4; this could be converted to have a positively charged naked surface at pH 6.8, significantly enhancing cell internalization of nanoparticles and increasing in vitro NIR‐induced PDT efficacy. We then utilize the intrinsic optical and paramagnetic properties of Mn²⁺‐doped UCNPs for in vivo dual modal imaging, and uncover an enhanced retention of UCNP@2xCe6‐DMMA‐PEG inside the tumor after intratumoral injection, owing to the slightly acidic tumor microenvironment. Consequently, a significantly improved in vivo PDT therapeutic effect is achieved using our charge‐reversible UCNP@2xCe6‐DMMA‐PEG nanoparticles. Finally, we further demonstrate the remarkably enhanced tumor‐homing of these pH‐responsive charge‐switchable nanoparticles in comparison to a control counterpart without pH sensitivity after systemic intravenous injection. Our results suggest that UCNPs with finely designed surface coatings could serve as smart pH‐responsive PDT agents promising in cancer theranostics.     

A Charge Reversible Self‐Delivery Chimeric Peptide with Cell Membrane‐Targeting Properties for Enhanced Photodynamic Therapy

The cell membrane is the most important protective barrier in living cells and cell membrane targeted therapy may be a high‐performance therapeutic modality for tumor treatment. Here, a novel charge reversible self‐delivery chimeric peptide C₁₆–PRP–DMA is developed for long‐term cell membrane targeted photodynamic therapy (PDT). The self‐assembled C₁₆–PRP–DMA nanoparticles can effectively target to tumor by enhanced permeability and retention effect without additional carriers. After undergoing charge reverse in acidic tumor microenvironment, C₁₆–PRP–DMA inserts into the tumor cell membrane with a long retention time of more than 14 h, which is very helpful for in vivo applications. It is found that under light irradiation, the reactive oxygen species generated by the inserted C₁₆–PRP–DMA would directly disrupt cell membrane and rapidly induce cell necrosis, which remarkably increases the PDT effect in vitro and in vivo. This novel self‐delivery chimeric peptide with a long‐term cell membrane targeting property provides a new prospect for effective PDT of cancer.     

Perfluorocarbon‐Loaded and Redox‐Activatable Photosensitizing Agent with Oxygen Supply for Enhancement of Fluorescence/Photoacoustic Imaging Guided Tumor Photodynamic Therapy

The wide clinical application of photodynamic therapy (PDT) is hampered by poor water solubility, low tumor selectivity, and nonspecific activation of photosensitizers, as well as tumor hypoxia which is common for most solid tumors. To overcome these limitations, tumor‐targeting, redox‐activatable, and oxygen self‐enriched theranostic nanoparticles are developed by synthesizing chlorin e6 (Ce6) conjugated hyaluronic acid (HA) with reducible disulfide bonds (HSC) and encapsulating perfluorohexane (PFH) within the nanoparticles (PFH@HSC). The fluorescence and phototoxicity of PFH@HSC nanoparticles are greatly inhibited by a self‐quenching effect in an aqueous environment. However, after accumulating in tumors through passive and active tumor‐targeting, PFH@HSC appear to be activated from “OFF” to “ON” in photoactivity by the redox‐responsive destruction of the vehicle's structure. In addition, PFH@HSC can load oxygen within lungs during blood circulation, and the oxygen dissolved in PFH is slowly released and diffuses over the entire tumor, finally resulting in remarkable tumor hypoxia relief and enhancement of PDT efficacy by generating more singlet oxygen. Taking advantage of the excellent imaging performance of Ce6, the tumor accumulation of PFH@HSC can be monitored by fluorescent and photoacoustic imaging after intravenous administration into tumor‐bearing mice. This PFH@HSC nanoparticle might have good potential for dual imaging‐guided PDT in hypoxic solid tumor treatment.     

Cancer Cell Membrane‐Coated Nanoparticles for Personalized Therapy in Patient‐Derived Xenograft Models

Cell membrane coating nanotechnology, which endows nanoparticles with unique properties, displays excellent translational potential in cancer diagnosis and therapy. However, the preparation and evaluation of these cell membrane‐coated nanoparticles are based on cell lines and cell‐line‐based xenograft mouse models. The feasibility of cell membrane‐camouflaged nanomaterials is tested in a preclinical setting. Head and neck squamous cell carcinoma (HNSCC) patient‐derived tumor cell (PDTC) membranes are coated onto gelatin nanoparticles (GNPs) and the resulting PDTC@GNPs show efficient targeting to homotypic tumor cells and tissues in patient‐derived xenograft (PDX) models. When the donor‐derived cell membrane of PDTC@GNPs matched those of the host cells, significant targeting capability is observed. In contrast, mismatch between the donor and host results in weak targeting. Furthermore, it is demonstrated that autologous separation and administration of cellular membranes and anticancer cisplatin (Pt)‐loaded PDTC@GNPs, respectively, lead to almost complete tumor ablation in a subcutaneous model and effectively inhibit tumor recurrence in a postsurgery model. The work presented here reinforces the translation of these biomimetic nanoparticles for clinical applications and offers a simple, safe, and effective strategy for personalized cancer treatment.     

Overcoming Hypoxia by Multistage Nanoparticle Delivery System to Inhibit Mitochondrial Respiration for Photodynamic Therapy

Hypoxia, as characterized by the low local oxygen, confers on cancer cells resistance to oxygen‐consuming photodynamic therapy (PDT). The limited success reached by current approaches harnessing reoxygenation to enhance PDT outcome promotes the reconsideration of the design of the therapeutic approach. In this study, a multistage delivery system capable of reversing hypoxia is demonstrated. Unlike previous strategies that only expect to affect the peripheral tumor tissue, the size‐shrinkable system allows those deeply located hypoxia regions to be treated. Specifically, therapeutics, including atovaquone and indocyanine green derivatives that are respectively responsible for oxidative phosphorylation blockage and PDT, are encapsulated in a gelatin nanoparticle, whose structure would rupture to promote deep penetration when facing matrix metallopeptidase 2 enzyme overexpression in tumor tissue. The antihypoxic performance of the platform has been evaluated using a variety of analyses including flow‐cytometry assay, immunofluorescence, and micro‐positron‐emission tomography imaging. Tumor regression in animal models confirms the feasibility and effectiveness of conquering the PDT‐resistance through abrogating the oxygen consumption. It is hopeful that such a strategy could shed light on the development of next‐generation PDT‐adjuvant treatment.     

An Acceptor–Donor–Acceptor Structured Small Molecule for Effective NIR Triggered Dual Phototherapy of Cancer

Dual phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is regarded as a more effective method for cancer treatment than single PDT or PTT. However, development of single component and near‐infrared (NIR) triggered agents for efficient dual phototherapy remains a challenge. Herein, a simple strategy to develop dual‐functional small‐molecules‐based photosensitizers for combined PDT and PTT treatment is proposed through: 1) finely modulating HOMO–LUMO energy levels to regulate the intersystem crossing (ISC) process for effective singlet oxygen (¹O₂) generation for PDT; 2) effectively inhibiting fluorescence via strong intramolecular charge transfer (ICT) to maximize the conversion of photo energy to heat for PTT or ISC process for PDT. An acceptor–donor–acceptor (A‐D‐A) structured small molecule (CPDT) is designed and synthesized. The biocompatible nanoparticles, FA‐CNPs, prepared by encapsulating CPDT directly with a folate functionalized amphipathic copolymer, present strong NIR absorption, robust photostability, cancer cell targeting, high photothermal conversion efficiency as well as efficient ¹O₂ generation under single 808 nm laser irradiation. Furthermore, synergistic PDT and PTT effects of FA‐CNPs in vivo are demonstrated by significant inhibition of tumor growth. The proposed strategy may provide a new approach to reasonably design and develop safe and efficient photosensitizers for dual phototherapy against cancer.     

A Novel Theranostic Nanoplatform Based on Pd@Pt‐PEG‐Ce6 for Enhanced Photodynamic Therapy by Modulating Tumor Hypoxia Microenvironment

Photodynamic therapy (PDT), which utilizes reactive oxygen species to kill cancer cells, has found wide applications in cancer treatment. However, the hypoxic nature of most solid tumors can severely restrict the efficiency of PDT. Meanwhile, the hydrophobicity and limited tumor selectivity of some photosensitizers also reduce their PDT efficacy. Herein, a photosensitizer‐Pd@Pt nanosystem (Pd@Pt‐PEG‐Ce6) is designed for highly efficient PDT by overcoming these limitations. In the nanofabrication, Pd@Pt nanoplates, exhibiting catalase‐like activity to decompose H₂O₂ to generate oxygen, are first modified with bifunctional PEG (SH‐PEG‐NH₂). Then the Pd@Pt‐PEG is further covalently conjugated with the photosensitizer chlorin e6 (Ce6) to get Pd@Pt‐PEG‐Ce6 nanocomposite. The Pd@Pt‐PEG‐Ce6 exhibits good biocompatibility, long blood circulation half‐life, efficient tumor accumulation, and outstanding imaging properties. Both in vitro and in vivo experimental results clearly indicate that Pd@Pt‐PEG‐Ce6 effectively delivers photosensitizers to cancer cells/tumor sites and triggers the decomposition of endogenous H₂O₂ to produce oxygen, resulting in a remarkably enhanced PDT efficacy. Moreover, the moderate photothermal effect of Pd@Pt nanoplates also strengthen the PDT of Pd@Pt‐PEG‐Ce6. Therefore, by integrating the merits of high tumor‐specific accumulation, hypoxia modulation function, and mild photothermal effect into a single nanoagent, Pd@Pt‐PEG‐Ce6 readily acts as an ideal nanotherapeutic platform for enhanced cancer PDT.     

A Self‐Transformable pH‐Driven Membrane‐Anchoring Photosensitizer for Effective Photodynamic Therapy to Inhibit Tumor Growth and Metastasis

Poor tumor selectivity and short life span of reactive oxygen species (ROS) are two major challenges in photodynamic therapy (PDT). In this study, a self‐transformable pH‐driven membrane anchoring photosensitizer (pHMAPS) is used to realize tumor‐specific accumulation and in situ PDT on tumor cell membrane to maximize the therapeutic potency. It is found that pHMAPS was able to form α‐helix structure under acidic condition (pH 6.5 or 5.5), while remain random coil at normal pH of 7.4. This pH‐driven secondary structure switch enables the successful insertion of pHMAPS into membrane lipid bilayer, especially for cancerous cell membrane in the acidic tumor microenvironment. Under laser irradiation, cytotoxic ROS is generated in the immediate vicinity of cell membrane, resulting in superior cell killing effect in vitro and significant inhibition of tumor growth in vivo. Importantly, benefited from this membrane‐specific PDT, tumor growth‐induced hepatic, pulmonary, as well as osseous metastases of breast cancer cells are also retarded after PDT treatment. Thus, the membrane localized PDT by pHMAPS provides a simple but effective strategy to enhance the medical performance of photosensitizing agents in cancer therapy.     

Bismuth Ferrite‐Based Nanoplatform Design: An Ablation Mechanism Study of Solid Tumor and NIR‐Triggered Photothermal/Photodynamic Combination Cancer Therapy

Although nanomaterial‐mediated phototherapy, in particular photothermal therapy (PTT) and photodynamic therapy (PDT), is extensively investigated in recent years, the ablation mechanism, evolution, and rehabilitation process of in vivo solid tumor after phototherapy are rarely explored yet and remain a terra incognita. Herein, a kind of bismuth ferrite nanoparticles (abbreviated as BFO NPs) are strategically designed and synthesized with a desirable size and bioactivity as a brand‐new phototherapeutic agent for the phototherapy, which are of strong near infrared (NIR) absorbance, excellent biocompatibility, and outstanding photophysical activity for the hyperthemia and reactive oxygen species generation. Resultantly, BFO NPs can realize simultaneous PTT/PDT synergistic therapy outcome against cancer cells and solid tumor under NIR laser irradiation. Meanwhile, for the first time, more attentions are paid to demonstrate ablation mechanism and evolution process of in vivo solid tumor after phototherapy by B‐mode ultrasonography/magnetic resonance imaging as well as histopathological analysis, all of which verify a series of physiological processes, being in order of necrosis of parenchymal cells, in situ tissue disintegration, liquefaction, and finally encapsulation process.     

Tumor Microenvironment‐Responsive Mesoporous MnO2‐Coated Upconversion Nanoplatform for Self‐Enhanced Tumor Theranostics

The insufficient blood flow and oxygen supply in solid tumor cause hypoxia, which leads to low sensitivity of tumorous cells and thus causing poor treatment outcome. Here, mesoporous manganese dioxide (mMnO₂) with ultrasensitive biodegradability in a tumor microenvironment (TME) is grown on upconversion photodynamic nanoparticles for not only TME‐enhanced bioimaging and drug release, but also for relieving tumor hypoxia, thereby markedly improving photodynamic therapy (PDT). In this nanoplatform, mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO₂) with covalently loaded chlorin e6 are obtained as near‐infrared light mediated PDT agents, and then a mMnO₂ shell is grown via a facile ultrasonic way. Because of its unique mesoporous structure, the obtained nanoplatform postmodified with polyethylene glycol can load the chemotherapeutic drug of doxorubicin (DOX). When used for antitumor application, the mMnO₂ degrades rapidly within the TME, releasing Mn²⁺ ions, which couple with trimodal (upconversion luminescence, computed tomography (CT), and magnetic resonance imaging) imaging of UCNPs to perform a self‐enhanced imaging. Significantly, the degradation of mMnO₂ shell brings an efficient DOX release, and relieve tumor hypoxia by simultaneously inducing decomposition of tumor endogenous H₂O₂ and reduction of glutathione, thus achieving a highly potent chemo‐photodynamic therapy.     

Low‐Dose X‐ray Activation of W(VI)‐Doped Persistent Luminescence Nanoparticles for Deep‐Tissue Photodynamic Therapy

Although photodynamic therapy (PDT) has served as an important strategy for treatment of various diseases, it still experiences many challenges, such as shallow penetration of light, high‐dose light irradiation, and low therapy efficiency in deep tissue. Here, a low‐dose X‐ray‐activated persistent luminescence nanoparticle (PLNP)‐mediated PDT nanoplatform for depth‐independent and repeatable cancer treatment has been reported. In order to improve therapeutic efficiency, this study first synthesizes W(VI)‐doped ZnGa₂O₄:Cr PLNPs with stronger persistent luminescence intensity and longer persistent luminescence time than traditional ZnGa₂O₄:Cr PLNPs. The proposed PLNPs can serve as a persistent excitation light source for PDT, even after X‐ray irradiation has been removed. Both in vitro and in vivo experiments demonstrate that low‐dose (0.18 Gy) X‐ray irradiation is sufficient to activate the PDT nanoplatform and causes significant inhibitory effect on tumor progression. Therefore, such PDT nanoplatform will provide a promising depth‐independent treatment mode for clinical cancer therapy in the future.     

Hyperbranched Polyglycerol‐Doped Mesoporous Silica Nanoparticles for One‐ and Two‐Photon Activated Photodynamic Therapy

Two‐photon activated photodynamic therapy (TPA‐PDT) is a recently developed technique that shows a potential for medical application. In contrast to traditional one‐photon activated PDT, TPA‐PDT can increase the treatment depth and decrease the damage to healthy tissue by using a near‐infrared two‐photon laser. However, this technique also suffers from the fact that approved photosensitive drugs have a low two‐photon absorption cross section. In this study, it is demonstrate that doped polyglycerol mesoporous silica nanoparticles can carry a photosensitizer, Rose bengal, and can be applied in one‐ and two‐photon PDT. TPA dye‐doped mesoporous silica nanoparticles have been synthesized using a surfactant‐free route, which can be considered a TPA‐PDT platform after loading normal photosensitive drugs. The doped TPA dyes in the silica nanoparticles can transfer energy to the loading drugs via an intraparticle fluorescence resonance energy transfer (FRET) mechanism. The fluorescence lifetime and confocal laser scanning microscopy (CLSM) images obtained under different conditions demonstrated a FRET effect through both one‐ and two‐photon activated modes. The results of cytotoxicity experiments proved that this TPA‐PDT system could induce cellular apoptosis under one‐ or two‐photon irradiation. This system in principle extends the application range of TPA‐PDT.     

Modulation of Hypoxia in Solid Tumor Microenvironment with MnO2 Nanoparticles to Enhance Photodynamic Therapy

Hypoxia not only promotes tumor metastasis but also strengthens tumor resistance to therapies that demand the involvement of oxygen, such as radiation therapy and photodynamic therapy (PDT). Herein, taking advantage of the high reactivity of manganese dioxide (MnO₂) nanoparticles toward endogenous hydrogen peroxide (H₂O₂) within the tumor microenvironment to generate O₂, multifunctional chlorine e6 (Ce6) loaded MnO₂ nanoparticles with surface polyethylene glycol (PEG) modification (Ce6@MnO₂‐PEG) are formulated to achieve enhanced tumor‐specific PDT. In vitro studies under an oxygen‐deficient atmosphere uncover that Ce6@MnO₂‐PEG nanoparticles could effectively enhance the efficacy of light‐induced PDT due to the increased intracellular O₂ level benefited from the reaction between MnO₂ and H₂O₂, the latter of which is produced by cancer cells under the hypoxic condition. Owing to the efficient tumor homing of Ce6@MnO₂‐PEG nanoparticles upon intravenous injection as revealed by T1‐weighted magnetic resonance imaging, the intratumoral hypoxia is alleviated to a great extent. Thus, in vivo PDT with Ce6@MnO₂‐PEG nanoparticles even at a largely reduced dose offers remarkably improved therapeutic efficacy in inhibiting tumor growth compared to free Ce6. The results highlight the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome current limitations of cancer therapies.     

Mitochondria‐Targeted Small‐Molecule Fluorophores for Dual Modal Cancer Phototherapy

Mitochondria are recognized as the ideal target for cancer treatment because they play a central role in oxidative metabolism and apoptosis. In this work, a mitochondria‐targeted near‐infrared (NIR) photosensitizer (PS) for synchronous cancer photodynamic therapy (PDT) and photothermal therapy (PTT) is synthesized. This multifunctional small‐molecule PS is developed from a variety of synthesized heptamethine cyanine dyes, which are modified with various N‐alkyl side chains on the lipophilic cationic heptamethine core. It is demonstrated to preferentially accumulate in cancer cells by organic‐anion transporting polypeptide mediated active transport and retain in mitochondria by its lipophilic cationic property. As mitochondria are susceptible to hyperthermia and excessive reactive oxygen species, this new PS integrating PTT and PDT treatment exhibits highly efficient phototherapy in multiple cancer cells and animal xenograft models. Furthermore, this targeted PS with NIR imaging property also enables tumors and their margins clearly visualized, providing the potential for precisely imaging‐guided phototherapy and treatment monitoring. This is the first report that a small‐molecule PS integrates both cancer PTT and PDT treatment by targeting mitochondria, significantly increasing the photosensitization. This work may also present a practicable strategy to develop small‐molecule‐based cancer theranostic agents for simultaneous cancer targeting, imaging, and therapy.     

Modulation of Intracellular Oxygen Pressure by Dual‐Drug Nanoparticles to Enhance Photodynamic Therapy

Oxygen plays an essential role in the photodynamic therapy (PDT) of cancer. However, hypoxia inside tumors severely attenuates the therapeutic effect of PDT. To address this issue, a novel strategy is reported for cutting off the oxygen consumption pathway by using sub‐50 nm dual‐drug nanoparticles (NPs) to attenuate the hypoxia‐induced resistance to PDT and to enhance PDT efficiency. Specifically, dual‐drug NPs that encapsulate photosensitizer (PS) verteporfin (VER) and oxygen‐regulator atovaquone (ATO) with sub‐50 nm diameters can penetrate deep into the interior regions of tumors and effectively deliver dual‐drug into tumor tissues. Then, ATO released from NPs efficiently reduce in advance cellular oxygen consumption by inhibition of mitochondria respiratory chain and further heighten VER to generate greater amounts of ¹O₂ in hypoxic tumor. As a result, accompanied with the upregulated oxygen content in tumor cells and laser irradiation, the dual‐drug NPs exhibit powerful and overall antitumor PDT effects both in vitro and in vivo, and even tumor elimination. This study presents a potential appealing clinical strategy in photodynamic eradication of tumors.     

All‐in‐One Phototheranostics: Single Laser Triggers NIR‐II Fluorescence/Photoacoustic Imaging Guided Photothermal/Photodynamic/Chemo Combination Therapy

Development of single near‐infrared (NIR) laser triggered phototheranostics for multimodal imaging guided combination therapy is highly desirable but is still a big challenge. Herein, a novel small‐molecule dye DPP‐BT is designed and synthesized, which shows strong absorption in the first NIR window (NIR‐I) and fluorescence emission in the second NIR region (NIR‐II). Such a dye not only acts as a dual‐modal contrast agent for NIR‐II fluorescence and photoacoustic (PA) imaging, but also serves as a combined therapeutic agent for photothermal therapy (PTT) and photodynamic therapy (PDT). The single NIR laser triggered all‐in‐one phototheranostic nanoparticles are constructed by encapsulating the dye DPP‐BT, chemotherapy drug DOX, and natural phase‐change materials with a folic acid functionalized amphiphile. Notably, under NIR laser irradiation, DOX can effectively release from such nanoparticles via NIR‐induced hyperthermia of DPP‐BT. By intravenous injection of such nanoparticles into Hela tumor‐bearing mice, the tumor size and location can be accurately observed via NIR‐II fluorescence/PA dual‐modal imaging. From in vitro and in vivo therapy results, such nanoparticles simultaneously present remarkable antitumor efficacy by PTT/PDT/chemo combination therapy, which is triggered by a single NIR laser. Overall, this work provides an innovative strategy to design and construct all‐in‐one nanoplatforms for clinical phototheranostics.     

PEGylated Micelle Nanoparticles Encapsulating a Non‐Fluorescent Near‐Infrared Organic Dye as a Safe and Highly‐Effective Photothermal Agent for In Vivo Cancer Therapy

Photothermal therapy (PTT), as a minimally invasive and highly effective cancer treatment approach, has received widespread attention in recent years. Tremendous effort has been devoted to explore various types of photothermal agents with high near‐infrared (NIR) absorbance for PTT cancer treatment. Despite many exciting progresses in the area, effective yet safe photothermal agents with good biocompatibility and biodegradability are still highly desired. In this work, a new organic PTT agent based on polyethylene glycol (PEG) coated micelle nanoparticles encapsulating a heptamethine indocyanine dye IR825 is developed, showing a strong NIR absorption band and a rather low quantum yield, for in vivo photothermal treatment of cancer. It is found that the IR825–PEG nanoparticles show ultra‐high in vivo tumor uptake after intravenous injection, and appear to be an excellent PTT agent for tumor ablation under a low‐power laser irradiation, without rendering any appreciable toxicity to the treated animals. Compared with inorganic nanomaterials and conjugated polymers being explored in PTT, the NIR‐absorbing micelle nanoparticles presented here may have the least safety concern while showing excellent treatment efficacy, and thus may be a new photothermal agent potentially useful in clinical applications.     

Tumor‐Specific Aptamer‐Conjugated Polymeric Photosensitizer for Effective Endo‐Laparoscopic Photodynamic Therapy

Recent advances in medical technology and endo‐laparoscopic devices have enabled the treatment of gastrointestinal (GI) cancers to be minimally invasive through endo‐laparoscopic photodynamic therapy (PDT). To achieve an efficient regional or endo‐laparoscopic PDT, it is necessary to develop a highly target specific photosensitizer (PS) that can be easily treated to the lesion site with endo‐laparoscopic device. Here, an ideal polymeric PS is demonstrated for effective endo‐laparoscopic PDT. In the synthetic process, conventional PS (i.e., Chlorin e6, Ce6) is conjugated with an Aptamer (i.e., AS1411) targeting nucleolin (also called C23) overexpressed on the cancer cell membrane using a water‐soluble polymeric linker (i.e., polyethylene glycol, PEG). The synthesized Aptamer‐PEG‐Ce6 could target nucleolin‐overexpressing tumor cells efficiently and visualize the tumor tissues through optical and fluorescent imaging both in vitro and ex vivo, and effectively kills cancer cells under laser irradiation. Tumor staining with Aptamer‐PEG‐Ce6 is easily accomplished through endoscopic equipment within a few minutes. Furthermore, after laser irradiation, Aptamer‐PEG‐Ce6 is found to penetrate deeply into the tumor tissue and induce apoptosis of tumor cells. Taken together, the tumor‐specific Aptamer‐conjugated polymeric PS developed in this study has great potential as an ideal photomedicine for effective tumor treatment using endo‐laparoscopic PDT.