Ablation Of Tumor Cells Research Articles

Multi-functional Fe3O4@HMPDA@G5-Au core-releasable satellite nano drug carriers for multimodal treatment of tumor cells

Combination therapy has become an effective strategy for tumor treatment, but the preparation of drug nanocarriers with the high requirements still lacked exploration. In this paper, hollow shell-layer mesoporous polydopamine (HMPDA) was constructed on Fe3O4 nanoparticles (the magnetic core), and small-sized G5-Au nanoparticles (AuNPs) as the releasable satellite carriers for tumor deep treatment were modified on HMPDA surface, then the nucleus-satellite Fe3O4@HMPDA@G5-Au nano drug delivery carriers were obtained. The therapy drug could be loaded in the mesoporous structure of HMPDA and G5-Au nanoparticles, so the drug loading capacity was relatively large. The Fe3O4@HMPDA@G5-Au composite nano carriers also had good photothermal properties, because polydopamine (PDA) and AuNPs were both good photothermal agents. Combination of photothermal therapy (PTT) and drug therapy could significantly enhance the ablation of tumor cells with minor side effects. In addition, the decomposition of H2O2 in the tumor site catalyzed by the AuNPs could also produce oxygen to alleviate tumor hypoxia. In addition, because of the magnetic properties of Fe3O4 nanoparticles, the Fe3O4@HMPDA@G5-Au nano drug delivery carriers also had magnetic targeting performance and could reach the specified position under the guidance of external magnetic field. The results showed that the average DOX loaded amount of the prepared carriers was 473.83 mg/g, the drug release rate in 24 h could achieve 61.3 %. The cytotoxicity test showed that the drug loaded carriers had a significant inhibitory effect on HepG2 cells. The drug-loaded core-satellite nanocarriers could play a good synergistic treatment effect on cancer under the multi effect synergy of PPT, drug therapy, magnetic targeting and pH-responsive drug release.

NIR light-powered halloysite-based nanomotors for CT imaging diagnosis and synergistic chemo-photothermal cancer therapy

Near-infrared (NIR) light-powered nanomotors with active motion have attracted extensive attention in the chemo-photothermal therapy of cancer. However, there are also some limitations such as complicated synthesis process, low permeability of drugs and viscous physiological environment. Herein, we developed a facile route to synthesize novel NIR light-powered DOX/Au-m-HTAS nanomotor based on natural halloysite (HNTs) for active chemo-photothermal therapy. Such nanomotor exhibited NIR light controlled on/off motion with a maximum speed of 64.5 μm/s. Owing to the synergetic NIR light-powered motion and chemo-photothermal therapy, DOX/Au-m-HTAS nanomotor could effectively adhere tumor cells, leading to deeper cell penetration, higher cellular uptake, and better ablation of tumor cells. Meanwhile, DOX/Au-m-HTAS nanomotors also had enhanced ability for CT imaging of local tumor, demonstrating the enhanced anticancer efficiency. This strategy provided a new insight into the chemo-photothermal synergistic therapy of tumors.

Injectable light-assisted thermo-responsive methylcellulose-sodium humate hydrogel proposed for photothermal ablation and localized delivery of cisplatin.

This study aimed to develop injectable light-assisted thermo-responsive methylcellulose hydrogels filled with sodium humate, which were proposed for photothermal ablation and localized cisplatin delivery. Sodium humate converts light energy from laser beams into thermal energy, which causes methylcellulose to gel, thereby controlling the release of chemotherapy agents. Meanwhile, light emission causes to the photothermal ablation of tumor cells. For determining the optimal production conditions, different concentrations of sodium humate and light emission times were investigated. Results show that hydrogel uniformity is highly dependent on variables. An increase in sodium humate concentration and emission time resulted in a slight reduction in swelling ratio and an increase in durability. According to the simulation conditions, the cisplatin release profile was consistent with a non-Fickian mechanism with a predominant erosion contribution. In conjugation with increasing light emission time and sodium humate content, the storage modulus and viscosity increased, demonstrating hydrogel’s sol-gel transition and long-lasting durability. The intrinsic fluorescence spectroscopy study revealed that the hydrogel-model protein complex empowered hydrogel bio-performance. Laser emission and cisplatin release synergistically reduced the number of viable osteosarcoma cell lines, suggesting the possibility of tumor ablation. This study describes the potential of simultaneous photothermal therapy and chemotherapy in osteosarcoma treatment, laying the groundwork for future preclinical and clinical trials.

Chemophototherapeutic Ablation of Doxorubicin-Resistant Human Ovarian Tumor Cells.

Porphyrin-phospholipid (PoP) liposomes loaded with Doxorubicin (Dox) have been demonstrated to be an efficient vehicle for chemophototherapy (CPT). Multidrug resistance (MDR) of cancer cells is a problematic phenomenon in which tumor cells develop resistance to chemotherapy. Herein, we report that Dox-resistant tumor cells can be ablated using our previously described formulation termed long-circulating Dox loaded in PoP liposomes (LC-Dox-PoP), which is a PEGylated formulation containing 2 mol. % of the PoP photosensitizer. In vitro studies using free Dox and LC-Dox-PoP showed that human ovarian carcinoma A2780 cells were more susceptible to Dox compared to the corresponding Dox-resistant A2780-R cells. When CPT was applied with LC-Dox-PoP liposomes, effective killing of both nonresistant and resistant A2780 cell lines was observed. An invivo study to assess the efficiency of LC-Dox-PoP showed effective tumor shrinkage and prolonged survival of athymic nude mice bearing subcutaneous Dox-resistant A2780-R tumor xenografts when they were irradiated with a red laser. Biodistribution analysis demonstrated enhanced tumoral drug uptake in Dox-resistant tumors with CPT, suggesting that increased drug delivery was sufficient to induce ablation of resistant tumor cells.

Photothermal nanobomb blocking metabolic adenosine-A2AR potentiates infiltration and activity of T cells for robust antitumor immunotherapy

Immunotherapy has partly achieved striking outcomes in the clinic for specific tumors. However, the responses are still limited for tumors that have restricted filtration and decreased activity of cytotoxic T cells due to the tumor stroma physical obstacles and immune-suppressive factors. Here we report an effective synergistic strategy for tumor therapy via integrating photothermal therapy and blockade of metabolic immune pathway adenosine based on a novel black phosphorus nanobomb. By rational conjugation of adenosine A2A receptor inhibitor SCH442416 (SCH) and targeting aptamer AS1411 (Apt) on black phosphorus nanosheets (BPs), we fabricate an immunostimulant nanobomb Apt@SCH@BPs. Apt@SCH@BPs shows good targeting and accumulation in melanoma. By synergism of photothermia and adenosine blockade, Apt@SCH@BPs could not only directly ablate tumor cells, but also boost maturation of dendritic cells, inhibit the regulatory T cells, stimulate the cytotoxic T cells, and elicit their filtration by attenuating tumor stromal barriers (e. g., cancer-associated fibroblasts and collagen). This synergistical therapy efficiently suppresses the growth of melanoma, and might be potential for other solid tumors.

MXene-Assisted Ablation of Cells with a Pulsed Near-Infrared Laser.

Innovative therapies are urgently needed to combat cancer. Thermal ablation of tumor cells is a promising minimally invasive treatment option. Infrared light can penetrate human tissues and reach superficial malignancies. MXenes are a class of 2D materials that consist of carbides/nitrides of transition metals. The transverse surface plasmons of MXenes allow for efficient light absorption and light-to-heat conversion, making MXenes promising agents for photothermal therapy (PTT). To date, near-infrared (NIR) light lasers have been used in PTT studies explicitly in a continuous mode. We hypothesized that pulsed NIR lasers have certain advantages for the development of tailored PTT treatment targeting tumor cells. The pulsed lasers offer a wide range of controllable parameters, such as power density, duration of pulses, pulse frequency, and so on. Consequently, they can lower the total energy applied and enable the ablation of tumor cells while sparing adjacent healthy tissues. We show for the first time that a pulsed 1064 nm laser could be employed for selective ablation of cells loaded with Ti3C2Tx MXene. We demonstrate both low toxicity and good biocompatibility of this MXene in vitro, as well as a favorable safety profile based on the experiments in vivo. Furthermore, we analyze the interaction of MXene with cells in several cell lines and discuss possible artifacts of commonly used cellular metabolic assays in experiments with MXenes. Overall, these studies provide a basis for the development of efficient and safe protocols for minimally invasive therapies for certain tumors.

Abstract 6174: Developing a novel antibody drug conjugate against cervical cancer

Abstract Background: Cervical cancer ranks fourth in incidence and mortality among female tumors, with over 0.6 million patients diagnosed worldwide in 2020. A large percentage of cervical cancer patients will develop advanced diseases (stage IV or recurrent disease) and the 5-year survival rate of these patients was only 15-20% due to the lack of efficacy and adverse effects of first line chemodrugs. Recently, antibody drug conjugates (ADCs) emerge as a novel class of targeted therapeutics that selectively ablate tumor cells without damaging normal organs and tissues, which has shown promising efficacy in treating solid tumors. In this study, we sought to develop a cervical cancer-targeted ADC using a novel molecular target. Methods: Firstly, human cervical cancer and paracancerous tissue were stained by immunohistochemistry (IHC) in order to determine the difference of the expression level of a molecular target. Three human cervical cancer cell lines (C-33A, Si-Ha and Ca-Ski) and one normal cervical cell line (HCerEpiC) were used to determine the subcellular location of an ADC target on the cells by immunofluorescence (IF) staining, flow cytometry and single photon confocal microscopy. Secondly, endocytosis capability of target antibodies was visualized by confocal imaging and was quantified by flow cytometric analysis. Furthermore, a panel of ADC formulations with different chemical linkers and payloads were designed, constructed and characterized as ADC candidates for cervical cancer therapy. We next evaluated in vitro inhibitory activity of these ADC candidates on three cervical cancer cell lines by CCK8 assay. Finally, orthotopic and lung metastasis animal models of cervical cancer were established to determine the in vivo inhibitory activity and biosafety of constructed ADC candidates. Results: IHC staining of clinical specimens showed that the expression level of CD54 in cervical tumor tissues was significantly higher than those of paracancerous tissues. Fluorescence imaging and flow cytometry further determined the overexpression level, plasma membrane location and antigen-mediated endocytosis activity of CD54 in multiple human cervical cancer cell lines. Among several ADC formulations, an optimized CD54-targeted ADC linker and warhead combination was identified by comparing its IC50 with other ADC candidates and standard-of-care chemodrugs for cervical cancer. The optimized CD54 ADC exhibited promising anti-tumor activity on primary and lung metastatic cervical tumor models. Conclusion: In our study, we identified CD54 as a novel ADC target for cervical cancer. An optimized CD54-targeted ADC formulation was determined and its anti-tumor activity and biosafety profile were determined in multiple human cervical cancer cell lines in vitro and orthotopic and lung metastatic cervical tumor models in vivo, providing a promising targeted therapeutic candidate for the targeted treatment of cervical cancer. Citation Format: Shili Yao, Bing Zhu, Xinyan Wang, Rui Xu, Tong Yang, Peng Guo, Huarong Tang, Tao Zhu. Developing a novel antibody drug conjugate against cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6174.

Photothermal effect of indocyanine green modified scaffold inhibits oral squamous cell carcinoma and promotes wound healing.

As the most prevalent malignant tumor of the oral and maxillofacial regions, squamous cell carcinoma (SCC) has relatively high recurrence and low survival rates. Currently, the most common treatment strategies are surgery and chemoradiotherapy. However, incomplete removal of the tumor can allow residual tumor cells to regrow and metastasis, resulting in treatment failure. Although postoperative adjuvant radiotherapy or chemotherapy can reduce recurrence, serious adverse reactions significantly compromise patients' quality of life. Large soft tissue defects after surgery are also difficult to heal. Therefore, therapies that eliminate residual tumor cells and promote tissue regeneration post-surgery are urgently needed. Indocyanine green (ICG) can convert absorbed light into heat to ablate tumor cells. Three-dimensional (3D) scaffolds are efficient drug carriers and support cell migration and proliferation. Here, we fabricated collagen/silk fibroin encapsulated ICG (I-CS) scaffolds by combining 3D printing with freeze-drying methods. The I-CS scaffolds delayed ICG decomposition and clearance, allowing the scaffolds to be used repeatedly for photothermal therapy (PTT). With the laser positioned at 4cm from the 1.0 I-CS scaffold and irradiation for 10min (1.0W/cm2), temperatures above 50°C were achieved, which effectively killed SCC-25 cells in vitro and suppressed tumor growth in vivo. Moreover, the I-CS scaffolds supported attachment and proliferation of rat buccal mucosa fibroblasts (RBMFs) and promoted the repair of buccal mucosal wounds in rats. These results suggested that I-CS scaffolds may be useful in preventing local recurrence and support regeneration of large soft tissue defects after oral SCC surgery.

An Intelligent Nanovehicle Armed with Multifunctional Navigation for Precise Delivery of Toll-Like Receptor 7/8Agonist and Immunogenic Cell Death Amplifiers to Eliminate Solid Tumors and Trigger Durable Antitumor Immunity.

Cancer immunotherapy is revolutionary in oncology and hematology. However, a low response rate restricts the clinical benefits of this therapy owing to inadequate T lymphocyte infiltration and low delivery efficiency of immunotherapeutic drugs.Herein, an intelligent nanovehicle (folic acid (FA)/1-(4-(aminomethyl) benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (IMDQ)-oxaliplatin (F/IMO)@CuS) armed with multifunctional navigation is designed for the accuratedelivery of cargoes to tumor cells and dendritic cells (DCs), respectively. The nanovehicle is based on a near infrared-responsive inorganic CuS nanoparticles, acting as a photosensitizer and carrier of the chemotherapeutic agent oxaliplatin, and enters tumor cells owing to the presence of folic acid on the surface of CuS upon intratumoral injection. Furthermore, a toll-like receptor (TLR) 7/8 agonist-conjugated polymer, anchored on the surface of CuS, is modified with mannose to bind with DCs in the tumor microenvironment. Upon exposure to laserirradiation, nanovehiclesdisassemble, releasing oxaliplatin, to ablate tumor cells and amplify immunogenic cell death in combination with photothermal therapy. Mannose-modified polymer-TLR7/8 agonist conjugates are subsequently exposed, leading to the activation of DCs and proliferation of T cells. Collectively, these intelligent nanovehicles reducetumor burden, exert a robust antitumor immune response, and generatelong-term immune protectionto prevent tumor recurrence.

Selective Vulnerability of Senescent Glioblastoma Cells to BCL-XL Inhibition.

Glioblastoma (GBM) is a rapidly fatal malignancy typically treated with radiation and temozolomide (TMZ), an alkylating chemotherapeutic. These cytotoxic therapies cause oxidative stress and DNA damage, yielding a senescent-like state of replicative arrest in surviving tumor cells. Unfortunately, recurrence is inevitable and may be driven by surviving tumor cells eventually escaping senescence. A growing number of so-called “senolytic” drugs have been recently identified that are defined by their ability to selectively eliminate senescent cells. A growing inventory of senolytic drugs is under consideration for several diseases associated with aging, inflammation, DNA damage, as well as cancer. Ablation of senescent tumor cells after radiation and chemotherapy could help mitigate recurrence by decreasing the burden of residual tumor cells at risk of recurrence. This strategy has not been previously explored for GBM. We evaluated a panel of 10 previously described senolytic drugs to determine whether any could exhibit selective activity against human GBM persisting after exposure to radiation or TMZ. Three of the 10 drugs have known activity against BCL-XL and preferentially induced apoptosis in radiated or TMZ-treated glioma. This senolytic activity was observed in 12 of 12 human GBM cell lines. Efficacy could not be replicated with BCL-2 inhibition or senolytic agents acting against other putative senolytic targets. Knockdown of BCL-XL decreased survival of radiated GBM cells, whereas knockdown of BCL-2 or BCL-W yielded no senolytic effect.

Fenton-like reaction and glutathione depletion by chiral manganese dioxide nanoparticles for enhanced chemodynamic therapy and chemotherapy

Chirality-based nanomaterials, especially semiconductors nanoparticles (NPs), are the emerging research in biomedicine field. Herein, chiral manganese dioxide (L/D-MnO2) NPs were synthesized by using threonine molecules as chiral ligands. Then cisplatin loaded L/D-MnO2 (L/D-MnO2@Pt) NPs were successfully constructed based on the high specific surface area of L/D-MnO2 NPs. L/D-MnO2@Pt NPs could be specifically internalized by tumor cells and efficiently deplete the glutathione (GSH) through redox reaction to release Mn2+ and Pt. The released Mn2+ exhibited strong chemodynamic effect through Fenton-like reaction. The depletion of GSH further improved the chemodynamic therapy (CDT) efficiency. The combination of the CDT of Mn2+ with the chemotherapy of Pt considerably enhanced the tumor therapy efficiency. It was particularly noteworthy that L/D-MnO2@Pt NPs showed chirality-based different internalization by tumor cells and further led to different tumor cell ablation effects, in which D-MnO2@Pt NPs exhibited stronger therapeutic efficiency than L-MnO2@Pt NPs. These findings provided deep insights for novel biomedical applications of chirality-based semiconductors NPs.

Bimetallic PdPt-based nanocatalysts for Photothermal-Augmented tumor starvation and sonodynamic therapy in NIR-II biowindow assisted by an oxygen Self-Supply strategy

Tumor starvation by depleting intratumoral glucose has been validated as a promising therapeutic strategy to combat cancer. However, inadequate oxygenation in hypoxic tumorous tissue significantly compromises the treatment efficacy. Herein, PdPt bimetallic nanocatalyst conjugated with glucose oxidase (GOx) and sonosensitizer IR780 is developed for photothermal-augmented tumor starvation and sonodynamic therapy (SDT) in near-infrared (NIR)-II biowindow, assisted by an oxygen self-supply strategy. As a catalase-mimicking nanozyme, PdPt@GOx/IR780 (PGI) can facilitate the alleviation of tumor hypoxia through catalyzing H2O2 decomposition into O2. Furthermore, GOx-mediated intratumoral glucose consumption may block the essential energy and nutrient supply to achieve tumor starvation. The resultant H2O2 production enables a continuous supply of local O2, which subsequently aggravates glucose depletion. Meanwhile, the hypoxia alleviation also promotes the production of 1O2 for a more efficacious SDT with the aid of sonosensitizer IR780. In another aspect, hyperthermia generation by PGI under NIR-II laser irradiation leads to the thermal ablation of tumor cells, which effectively incorporates with tumor starvation and SDT for a complete tumor eradication. More importantly, the combination therapy can trigger strong immunogenic cell death (ICD), which favors the overcoming of immune suppression and the enhancement of antitumor immunity. The admirable tumor suppression effect by PGI is demonstrated on tumor-bearing mice with minimal adverse effect. Taken together, this paradigm provides a useful strategy for PdPt functionalization in the pursuit of effective tumor therapy with high clinical relevance.

A Novel Yolk–Shell Fe3O4@ Mesoporous Carbon Nanoparticle as an Effective Tumor-Targeting Nanocarrier for Improvement of Chemotherapy and Photothermal Therapy

Owing to their good stability and high photothermal conversion efficiency, the development of carbon-based nanoparticles has been intensively investigated, while the limitation of unsatisfactory cellular internalization impedes their further clinical application. Herein, we report a novel strategy for fabrication of Fe3O4 yolk–shell mesoporous carbon nanocarriers (Fe3O4@hmC) with monodispersity and uniform size, which presented significantly higher cell membrane adsorption and cellular uptake properties in comparison with common solid silica-supported mesoporous carbon nanoparticles with core–shell structure. Moreover, the MRI performance of this novel Fe-based nanoparticle could facilitate precise tumor diagnosis. More importantly, after DOX loading (Fe3O4@hmC-DOX), owing to synergistic effect of chemo–phototherapy, this therapeutic agent exhibited predominant tumor cell ablation capability under 808 nm NIR laser irradiation, both in vitro and in vivo. Our work has laid a solid foundation for therapeutics with hollowed carbon shell for solid tumor diagnosis and therapy in clinical trials.

Double-crosslinked bifunctional hydrogels with encapsulated anti-cancer drug for bone tumor cell ablation and bone tissue regeneration

Many biomaterials are made and studied to provide anticancer therapy, and many other biomaterials have been developed to assist body tissue regeneration. It has been a challenge to design and produce effective multifunctional, or bifunctional, biomaterials for clinical applications to prevent cancer recurrence and, at the same time, to promote new tissue formation after surgical removal of the tumor for millions of cancer patients. In this study, bifunctional UV and Sr2+ double-crosslinked alginate (ALG)/allylated gelatin (GelAGE) hydrogels incorporated with polydopamine (PDA) particles were designed and made. Furthermore, doxorubicin hydrochloride (DOX), an anticancer drug, was incorporated in PDA particles. It was aimed for the new ALG/GelAGE-PDA@DOX hydrogels to exhibit anticancer synergy and hence provide combined chemotherapy and phototherapy (PTT) for bone tumor cell ablation. In vitro experiments using MG63 osteosarcoma cells showed that ALG/GelAGE-PDA@DOX hydrogels could effectively kill tumor cells through the synergy of controlled DOX release and hyperthermia ablation. It was also aimed for the new hydrogels to facilitate bone tissue regeneration at the original bone tumor site. The results of in vitro experiments demonstrated that owing to the release of Sr2+, the new hydrogels could promote the proliferation of rat bone mesenchymal stem cells (rBMSCs) and also the alkaline phosphatase (ALP) activity of cells, indicating their osteogenic promotion ability. The ALG/GelAGE-PDA@DOX hydrogels have therefore exhibited great potential for the treatment of bone tumor-related defects.

Regulated Polyion Complex Vesicles for Efficient Photothermal Therapy

AbstractPolyion complex (PIC) vesicles have attracted considerable attention as soft yet functional delivery vehicles. However, most of the PIC vesicles suffer from insufficient stability and functionality which hinder their applications. Herein, a new type of PIC vesicles obtained by co‐assembly of neutral‐cationic diblock copolymers with a supramolecular coordination polyelectrolyte is reported. The latter exhibits tunable structures and properties that endows regulated stability and functionalities of the vesicles. With lanthanide‐based coordination polymers, PIC vesicles are constructed with not only enhanced stability against salt, but also tunable fluorescent or magnetic properties associated with particular Ln3+ ions. Moreover, the vesicle lumen is applied to load PEGlated indocyanine green as a model photothermal transduction agent. The designed vesicles finally display high stability, good biocompatibility, and efficient photothermal conversion, and therefore behave well for thermal ablation of both tumor cells and tumor in mice. The well‐regulated stability and functions of the PIC vesicles are assigned the adaptive structure and properties of the supramolecular coordination polyelectrolytes, which hardly be achieved with conventional covalent polyelectrolytes. This study therefore demonstrates a facile strategy to regulate the stability and function of PIC vesicles, and shall be inspirational for developing novel vesicular materials for potential biomedical applications.

Tunable Assembly of Organic-Inorganic Molecules into Hierarchical Superstructures as Ligase Mimics for Enhancing Tumor Photothermal Therapy.

The assembly of molecules into hierarchical superstructures is ubiquitous in the construction of novel geometrically complex hierarchical superstructures, attracting great attention. Herein, a metal-ligand cross-linking strategy is developed for the fabrication of ferric ion-dopamine coordination hierarchical superstructures. A range of superstructures with highly complex morphologies, such as flower-like, octopus-like, and hedgehog-like superstructures, are synthesized. The mechanism for formation of hierarchical superstructures involves the pre-cross-linking of ferric ion with dopamine molecules, the fabrication of iron-dopamine precursors aggregated into the spherical aggregates, the nanoscale aggregates sintering and ordering themselves upon equilibration, the nanodots polymerizing into nanorods, and finally the nanorods self-assembling into hierarchical superstructures. In-depth research illustrates that as the permittivity (ξ) of the reaction system increases, the resulting hierarchical superstructures tend to converge into spherical shape. As a proof of concept, the 0D nanospheres, 1D nanorods, and 3D hierarchical superstructures are fabricated through adjusting system permittivity. The hierarchical superstructure is utilized as peroxidase-like ligase mimics to enhance the effect of tumor photothermal treatment. Further in vitro and in vivo assays demonstrate that the hierarchical superstructure can effectively ablate tumor cells. This work opens new horizons in hierarchical superstructures with complex architectures, and has great potential in nanozymology, biomedical science, and catalysis.

PH-Responsive Au@Pd bimetallic core-shell nanorods for enhanced synergistic targeted photothermal-augmented nanocatalytic therapy in the second near-infrared window.

Nanotheranostic agents based on plasmonic nanostructures with their resonance wavelengths located in the second near-infrared window (NIR-II) have gained significant attention in profound tumor photothermal therapy. However, the modulation of localized surface plasmon resonance of gold nanomaterials from the first near-infrared (NIR-I) window to the NIR-II window is still challenging. The structures and compositions of the plasmonic nanomaterials have demonstrated promising characteristics in controlling the optical properties of plasmonic nanostructures. Here, gold nanorod (Au NR) coated with an ultrathin palladium (Pd) shell was developed for tumor-targeted NIR-II photothermal-augmented nanocatalytic therapy through the combination of compositional manipulation and structural evolution strategies. These Au@Pd core-shell hybrid NRs (HNRs) were functionalized with biocompatible chitosan (CS) to acquire lower toxicity and higher stability in physiological systems. Further, Au@Pd-CS HNRs were endowed with an excellent targeting ability by conjugating with folic acid (FA). The as-synthesized Au@Pd-CS-FA HNRs show efficient and complete photothermal ablation of tumor cells upon 1064 nm laser irradiation. The remarkable photothermal conversion efficiency of 69.0% was achieved, which is superior to many reported photothermal agents activated in the NIR-II region. Excitingly, Au@Pd-CS-FA HNRs have peroxidase and catalase activities, simultaneously producing ˙OH for catalytic therapy and O2 for relieving tumor hypoxia and photodynamic therapy. Additionally, in vivo tumor photothermal therapy was carried out, where the biocompatible Au@Pd-CS-FA HNRs penetrate intensely into the tumor cells and consequently show remarkable therapeutic effects. The idea about plasmonic modulation behind the bimetallic core-shell nanostructure in this report can be extended to construct new classes of metal-based nanotheranostic agents with dual-modal combined therapy as an alternative to traditional chemotherapy.

Fabrication of injectable hydrogels from an anticancer peptide for local therapeutic delivery and synergistic photothermal-chemotherapy.

The susceptibility of anticancer peptides to proteolytic degradation is often considered as a major weakness that limits systemic therapeutic applications. However, localized delivery of anticancer peptides via injectable hydrogels is expected to improve drug efficacy and reduce systemic toxicity. Herein, an injectable hydrogel with drug releasing properties, NIR responsiveness and pH sensitivity was developed from an anticancer peptide (KL), Fe3+ ions and protocatechualdehyde via dynamic and reversible interactions. Benefiting from the formation of Fe(III)-catechol complexes between Fe3+ ions and protocatechualdehyde within gel networks, the obtained hydrogel exhibited intrinsic NIR absorption properties for photothermal ablation of tumor cells, and remote light control of drug release. Besides, the pH-labile imine bonds between KL and protocatechualdehyde endowed the injectable gel with pH sensitivity for sustained release of KL under a mildly acidic environment, inducing membrane destabilization and facilitating the cell uptake of DOX for combinational chemotherapy. Both in vitro and in vivo experiments revealed that the injectable hydrogel exhibited a synergistic therapeutic effect on inhibiting tumor growth via combinational photothermal-chemotherapy. Therefore, this work provides a promising attempt to develop a therapeutic hydrogel from an anticancer peptide, which could work as a localized drug delivery platform for synergistic photothermal-chemotherapy.

ROBUST INFLAMMATORY RESPONSE AFTER BRONCHOSCOPIC PHOTODYNAMIC THERAPY IN A PATIENT ON IMMUNOTHERAPY

TOPIC: Lung Cancer TYPE: Fellow Case Reports INTRODUCTION: It is well established that photodynamic therapy (PDT) results in both direct tumor cell death as well as immune cell stimulation through processing of antigens from destroyed tumor cells by dendritic cells, which in turn serve as antigen presenting cells to T cells. However, tumor cells adapt varying degrees of immune cell evasion. Systemic immunotherapy with blockade of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is increasingly used to treat various cancers. CASE PRESENTATION: Our patient is a 55-year-old male smoker with a history of stage III (T3N1M0) non-small cell lung cancer (squamous) of the right lower lobe who is status post definitive treatment with carboplatin/taxol and radiation therapy followed by maintenance durvalumab. Several months after treatment, he underwent bronchoscopy that showed endobronchial lesions in the left and right upper lobes as well as in the left lower lobe. Pathology showed squamous cell carcinoma in situ features suspicious for superficial invasion. The decision was made to perform endobronchial photodynamic therapy (PDT) using 630 nm laser at a dose of 200 Joules/cm. In the days after PDT, he routinely underwent repeat bronchoscopy for removal of necrotic tissue resulting from the treatment. However, at one month post-PDT treatment, surveillance bronchoscopy showed ongoing inflammatory changes and necrotic tissue which again required debridement with cryotherapy. He appeared to have a particularly robust response to the PDT therapy which was evident on serial bronchoscopies. DISCUSSION: It is unclear whether the robust response to PDT while on darvalumab was beneficial, detrimental, or neutral to our patient. There are interesting recent experiments using mouse cancer models that show that combining PDT induces increased tumor expression of PD-L1, and that combining local PDT with systemic immunotherapy may actually potentiate the effects of immunotherapy even at distant metastases (Bao et al., Xu et al.). In humans, it is possible that a PDT dose adjustment is needed for patients on systemic immunotherapy. Alternatively, since this robust response was likely the result of increased immunologic activity, it is possible that more immunologic memory is generated which could protect against recurrence or distant spread.Our current arsenal to treat cancer has many modalities, including surgery, chemotherapy, immunotherapy, radiation therapy, and endoscopic modalities. As more modalities are developed and refined, it is crucial to investigate how they can be combined synergistically to provide the best outcomes for patients. CONCLUSIONS: It is unclear whether systemic immunotherapy has an impact on PDT in humans. As both modalities rely on patients' immune systems, studying the combination of PDT with immunotherapy is a compelling area for future research. REFERENCE #1: Shafirstein G et al. Photodynamic Therapy of Non-Small Cell Lung Cancer. Narrative Review and Future Directions. Ann Am Thorac Soc. 2016 Feb;13(2):265-75 REFERENCE #2: Bao R et al. Enhancing Anti-PD-1/PD-L1 Immune Checkpoint Inhibitory Cancer Therapy by CD276-Targeted Photodynamic Ablation of Tumor Cells and Tumor Vasculature. Mol Pharm. 2019 Jan 7;16(1):339-348. REFERENCE #3: Xu J et al. Near-Infrared-Triggered Photodynamic Therapy with Multitasking Upconversion Nanoparticles in Combination with Checkpoint Blockade for Immunotherapy of Colorectal Cancer. ACS Nano. 2017 May 23;11(5):4463-4474. DISCLOSURES: No relevant relationships by Martin Vonau, source=Web Response Consultant relationship with Pinnacle Biologics Please note: $1001 - $5000 by Benjamin Young, source=Web Response, value=Consulting fee Removed 04/20/2021 by Benjamin Young, source=Web Response Consultant relationship with Auris Surgical Robotics Please note: $1001 - $5000 by Benjamin Young, source=Web Response, value=Consulting fee Removed 04/20/2021 by Benjamin Young, source=Web Response Consultant relationship with Pinnacle Biologics Please note: 2018-2019 Added 04/30/2021 by Benjamin Young, source=Web Response, value=Consulting fee

Polydopamine nanoparticles with different sizes for NIR-promoted gene delivery and synergistic photothermal therapy

The combination of photothermal therapy and gene therapy has received increasing attention in tumor treatment. However, how to improve synergistic efficacy has become a new challenge. NIR light has a great potential in tumor treatment because of its considerable penetration depth and spatiotemporal controllability. Polydopamine is a popular photothermal conversion agent, which has desirable photothermal conversion ability and good biocompatibility. In this research, polydopamine-polyethyleneimine nanoparticles with diameters of 13 nm (SPPNPs) and 236 nm (LPPNPs) were prepared as gene carriers. The size of polydopamine nanoparticles had great effect on the complexes formation, photothermal conversion ability and gene transfection efficiency. After loading gene, the SPPNPs/gene and LPPNPs/gene complexes were about 60–80 nm and 240 nm respectively, indicating different styles of complexes formation. Both SPPNPs/gene and LPPNPs/gene complexes without NIR irradiation could achieve similar gene transfection efficiency as commercial lipofectamine 2000, while with lower cytotoxicity. Due to better photothermal conversion ability, the transfection level of LPPNPs/pGL-3 complexes increased to 4.5 times after NIR irradiation (2.6 W/cm2, 15 min), which ascribed to the quick escape of gene complexes from the endosome. The produced heat under NIR irradiation could also ablate tumor cells. So LPPNPs were chosen to deliver tumor suppressor gene p53 DNA to investigate the synergistic efficacy of gene/photothermal therapy. The tumor in KB tumor-bearing mice was almost eliminated after intratumoral injection, and the tumor inhibition efficacy of gene/photothermal synergistic therapy achieved to 99%. By combining NIR-promoted gene transfection and gene/photothermal synergistic therapy, the LPPNPs hold great promise in practical tumor treatment.