Local Hyperthermia Research Articles

Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumours.

An effective nanotherapeutic transport from the vasculature to the tumour is crucial for cancer treatment with minimal side effects. Here we demonstrate that, in addition to the endothelial barrier, the tumour vascular basement membrane surrounding the endothelium acts as a formidable mechanical barrier that entraps nanoparticles (NPs) in the subendothelial void, forming perivascular NP pools. Breaking through this basement membrane barrier substantially increases NP extravasation. Using inflammation triggered by local hyperthermia, we develop a cooperative immunodriven strategy to overcome the basement membrane barrier that leads to robust tumour killing. Hyperthermia-triggered accumulation and inflammation of platelets attract neutrophils to the NP pools. The subsequent movement of neutrophils through the basement membrane can release the NPs entrapped in the subendothelial void, resulting in increased NP penetration into deeper tumours. We show the necessity of considering the tumour vascular basement membrane barrier when delivering nanotherapeutics. Understanding this barrier will contribute to developing more effective antitumour therapies.

PH-Responsive Upconversion Mesoporous Silica Nanospheres for Combined Multimodal Diagnostic Imaging and Targeted Photodynamic and Photothermal Cancer Therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) have gained considerable attention as potential alternatives to conventional cancer treatments. However, these approaches remain limited by low solubility, poor stability, and inefficient targeting of many common photosensitizers (PSs) and photothermal agents (PTAs). To overcome the aforementioned limitations, we engineered biocompatible and biodegradable tumor-targeted upconversion nanospheres with imaging capabilities. The multifunctional nanospheres consist of a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium, and gadolinium) and the PTA bismuth selenide (NaYF4:Yb/Er/Gd,Bi2Se3) enveloped in a mesoporous silica shell that encapsulates a PS, chlorin e6 (Ce6), within its pores. NaYF4:Yb/Er converts deeply penetrating near-infrared (NIR) light to visible light, which excites Ce6 to generate cytotoxic reactive oxygen species (ROS), while Bi2Se3 efficiently converts absorbed NIR light to heat. Additionally, Gd enables magnetic resonance imaging of the nanospheres. The mesoporous silica shell is coated with DPPC/cholesterol/DSPE-PEG to retain the encapsulated Ce6 and prevent serum protein adsorption and macrophage recognition that hinder tumor targeting. Finally, the coat is conjugated to the acidity-triggered rational membrane (ATRAM) peptide, which promotes specific and efficient internalization into malignant cells in the mildly acidic microenvironment of tumors. The nanospheres facilitated tumor magnetic resonance and thermal and fluorescence imaging and exhibited potent NIR laser light-induced anticancer effects in vitro and in vivo via combined ROS production and localized hyperthermia, with negligible toxicity to healthy tissue, hence markedly extending survival. Our results demonstrate that the ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) offer multimodal diagnostic imaging and targeted combinatorial cancer therapy.

Drug-Loaded Lipid Magnetic Nanoparticles for Combined Local Hyperthermia and Chemotherapy against Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is a devastating tumor of the central nervous system, currently missing an effective treatment. The therapeutic gold standard consists of surgical resection followed by chemotherapy (usually with temozolomide, TMZ) and/or radiotherapy. TMZ does not, however, provide significant survival benefit after completion of treatment because of development of chemoresistance and of heavy side effects of systemic administration. Improvement of conventional treatments and complementary therapies are urgently needed to increase patient survival and quality of life. Stimuli-responsive lipid-based drug delivery systems offer promising prospects to overcome the limitations of the current treatments. In this work, multifunctional lipid-based magnetic nanovectors functionalized with the peptide angiopep-2 and loaded with TMZ (Ang-TMZ-LMNVs) were tested to enhance specific GBM therapy on an in vivo model. Exposure to alternating magnetic fields (AMFs) enabled magnetic hyperthermia to be performed, that works in synergy with the chemotherapeutic agent. Studies on orthotopic human U-87 MG-Luc2 tumors in nude mice have shown that Ang-TMZ-LMNVs can accumulate and remain in the tumor after local administration without crossing over into healthy tissue, effectively suppressing tumor invasion and proliferation and significantly prolonging the median survival time when combined with the AMF stimulation. This powerful synergistic approach has proven to be a robust and versatile nanoplatform for an effective GBM treatment.

Waste to Wealth: Near-Infrared/pH Dual-Responsive Copper-Humic Acid Hydrogel Films for Bacteria-Infected Cutaneous Wound Healing.

The clinical applications of currently used photosensitizers are limited by high costs, inconvenient preparation, suboptimal biodegradability, and a lack of biological activity. Humic acids (HAs) show photothermal activity and can be used as a photosensitizer for photothermal therapy. In the presence of various functional groups, HAs are endowed with anti-inflammatory and antioxidant activities. The solubility of HAs is dependent on the pH value, which is soluble in neutral to alkaline conditions and undergoes a conformational change to a coiled and compact structure in acidic conditions. Additionally, Cu2+ is an emerging therapeutic agent for cutaneous wounds and can be chelated by HAs to form complexes. In this study, we explore the ability of HAs to modulate the inflammatory response, particularly macrophage polarization, and the potential underlying mechanism. We fabricate a near-infrared (NIR)/pH dual-responsive Cu-HAs nanoparticle (NP)-based poly(vinyl alcohol) (PVA) hydrogel film loaded with SEW2871 (SEW), a macrophage recruitment agent, to treat bacteria-infected cutaneous wounds. The results show that HAs could promote M2 macrophage polarization in a dose-dependent manner. The Cu-HAs NPs successfully eradicated bacterial infection through NIR-induced local hyperthermia. This PVA@Cu-HAs NPs@SEW hydrogel film improves tissue regeneration by promoting M2 macrophage polarization, alleviating oxidative stress, enhancing angiogenesis, and facilitating collagen deposition. These findings highlight the therapeutic potential of PVA@Cu-HAs NPs@SEW hydrogel film for the treatment of bacterially infected cutaneous wound healing.

Biosynthesized gold nanoparticles that activate Toll-like receptors and elicit localized light-converting hyperthermia for pleiotropic tumor immunoregulation

Manipulating the tumor immune contexture towards a more active state can result in better therapeutic outcomes. Here we describe an easily accessible bacterial biomineralization-generated immunomodulator, which we name Ausome (Au + [exo]some). Ausome comprises a gold nanoparticle core covered by bacterial components; the former affords an inducible hyperthermia effect, while the latter mobilizes diverse immune responses. Multiple pattern recognition receptors actively participate in Ausome-initiated immune responses, which lead to the release of a broad spectrum of pro-inflammatory cytokines and the activation of effector immune cells. Upon laser irradiation, tumor-accumulated Ausome elicits a hyperthermic response, which improves tissue blood perfusion and contributes to enhanced infiltration of immunostimulatory modules, including cytokines and effector lymphocytes. This immune-modulating strategy mediated by Ausome ultimately brings about a comprehensive immune reaction and selectively amplifies the effects of local antitumor immunity, enhancing the efficacy of well-established chemo- or immuno-therapies in preclinical cancer models in female mice.

Mesoporous polydopamine nanoplatforms loaded with calcium ascorbate for amplified oxidation and photothermal combination cancer therapy

AbstractDestruction of cellular redox homeostasis to induce cancer cell apoptosis is an emerging tumor therapeutic strategy. To achieve this goal, elevating exogenous oxidative stress or impairing the antioxidant defense system of cancer cells is an effective method. Herein, we firstly report a biocompatible and versatile nanoplatform based on mesoporous polydopamine (MpDA) nanoparticles and a phase‐change material (PCM) for delivering calcium ascorbate (Vc‐Ca), simultaneously enabling combination therapy of hyperthermia, reactive oxygen species (ROS) generation, and suppression of tumor antioxidant capability. In this design, Vc‐Ca encapsulated in MpDA using PCM is controllably released due to the melting of PCM matrix in response to photothermal heating upon near‐infrared irradiation. Vc‐Ca is proved to be a pro‐oxidant that can promote the production of ROS (H2O2) in the tumor site. Remarkably, MpDA can not only act as a photothermal agent but also can break the redox balance of cancer cells through depleting the primary antioxidant glutathione, thus amplifying Vc‐Ca‐mediated oxidative therapy. Both in vitro and in vivo results demonstrate the significantly enhanced antitumor activity of boosted ROS combined with local hyperthermia. This study highlights the potential applications of Vc‐Ca in cancer treatment, and the prepared multifunctional nanoplatform provides a novel paradigm for high‐efficiency oxidation‐photothermal therapy.

УДОВЛЕТВОРЯЕТ ЛИ АКУСТОЯРКОСТНАЯ ТЕМПЕРАТУРА УРАВНЕНИЮ ТЕПЛОПРОВОДНОСТИ?

In medicine, the monitoring of local hyperthermia requires painless measurements of the deep temperature with an error not exceeding 0.5–1 К and spacial resolution no worse than 5 mm. For temperature measurements, the use of passive acoustic thermometry is proposed based on the registration of the inherent thermal acoustic noise of the object. The measurements of the noise signal require a considerable integration time: in the megahertz range, attaining a desired accuracy requires that the signal be averaged during 30–50 s. To reduce this time without loss of accuracy, we propose to restore the temperature using the heat equation with blood flow. Local deep hyperthermia of the human soft tissues was examined. The three-dimensional heat equation (governing the deep temperature) was integrated with respect to depth, with a weight coefficient accounting for the absorption of ultrasound, subject to the instrument function of the receiving detector, to obtain a differential equation for the acoustobrightness temperature (measured signal). It was shown that, during the initial stage of the heating (~ 5 min), the distribution of the acoustobrightness temperature on the body surface satisfies approximately the 2D heat equation whose parameters are uniquely determined by the 3D heat equation governing the distribution of the deep temperature. Computations were carried out using the values of the thermal conductivity coefficient, specific blood flow, and ultrasound absorption coefficient typical for the soft tissues of the human organism as well as typical parameters of the source in the local, five-minute heating of soft tissues. The acoustobrightness temperature was computed in the standard way, using the known integral expression, with and without the detector instrument function, as well as through the solution of the obtained 2D heat equation. The discrepancy between the acoustobrightness temperatures computed through the different procedures grows with time but after five minutes of heating, it does not exceed the measurement error. A condition was introduced to determine the acceptability of the approximation made. The proposed approximation enables determination of the heat equation parameters from acoustobrightness temperature measurements, which makes it possible to compute the deep temperature distribution at any point in time.

A tumor microenvironment-activatable nanoplatform with phycocyanin-assisted in-situ nanoagent generation for synergistic treatment of colorectal cancer

The in-situ generation of therapeutic agents in targeted lesions is promising for revolutionizing oncotherapy but is limited by the low production efficiency. Given the specific tumor microenvironment (TME) of colorectal cancer (CRC), i.e., mild acidity, overexpressed H2O2, glutathione (GSH) and H2S, we develop phycocyanin (PC) encapsulated PZTC/SS/HA nanocapsules (NCs) for TME-responsive, protein-assisted “turn-on’’ therapy of CRC. The NCs are prepared by sequentially assembling Cu2+-tannic acid (TA) coordination shell, disulfide bond-bearing cross-linker, and hyaluronic acid (HA) on the sacrificial template ZIF-8, thus achieving pH-, GSH-responsiveness, and tumor targeting capability, respectively. Once reaching the CRC sites, the NCs can quickly disintegrate and release Cu2+ and PC, accompanied by subsequent endogenous H2S-triggered generation of copper sulfide (CuS). Significantly, the intracellular sulfidation process can be accelerated by PC, thereby enabling efficient photothermal therapy (PTT) under NIR-Ⅱ laser. Besides, Cu2+-associated chemodynamic therapy (CDT) can be simultaneously activated and enhanced by PTT-induced local hyperthermia and disulfide bond-induced GSH consumption. This CRC-targeted and TME-activated synergistic PTT/CDT strategy displays high therapeutic efficacy both in vitro and in vivo, which can open up a new avenue for biomolecule-assisted in-situ nanoagent generation and effective TME-responsive synergistic treatment of CRC.

Microwave absorption-based magnetic liquid metal nano-missiles for thermodynamic/immunological cascade hepatoma therapy

Microwave ablation (MWA) therapy, as a local tumor hyperthermia technology, holds great promise for hepatoma treatment. However, the extensive clinical application of the MWA therapy is mired by incomplete ablation and nonspecific thermal injury. Herein, the microwave (MW) absorption-based magnetic liquid metal (MLM) nanohybrids are designed, serving as “precise strike nano-missiles for tumor” to enhance MWA technique for hepatoma therapy by MW thermodynamic synergistic priming immunomodulatory effects. The nano-missiles were prepared via encapsulating MLM into Alginate (ALG) microgels through a simple sonication process and further coating hyaluronic acid with layer-by-layer self-assembly technique (MLM@ALG-L NMs). It has excellent tumor targeting, and MRI function is introduced to offer imaging navigation for nano-missiles. MW electromagnetic energy can be absorbed by nano-missiles due to multiple loss mechanisms, showing enhanced thermal conversion efficiency to amplify thermodynamic therapy by producing abundant reactive oxygen species (ROS) and depleting glutathione (GSH). Interestingly, the MLM@ALG-L NMs-assisted MWA can activate immunomodulatory effects by increasing the presence of pro-inflammatory M1 macrophages and T lymphocytes in the tumor tissues. The strategy of thermodynamic/immunological cascade therapy shows excellent therapeutic advantages on mice-hepatoma models (enhanced therapeutic effects > 2 fold) over the traditional MWA treatment. This study establishes an innovative perspective to extend the future clinical application of MWA therapy.

Lower limb hyperthermia augments functional hyperaemia during small muscle mass exercise similarly in trained elderly and young humans.

What is the central question of the study? Ageing is postulated to lead to underperfusion of human limb tissues during passive and exertional hyperthermia, but findings to date have been equivocal. Thus, does age have an independent adverse effect on local haemodynamics during passive single-leg hyperthermia, single-leg knee-extensor exercise and their combination? What is the main finding and its importance? Local hyperthermia increased leg blood flow over three-fold and had an additive effect during knee-extensor exercise with no absolute differences in leg perfusion between the healthy, exercise-trained elderly and the young groups. Our findings indicate that age per se does not compromise lower limb hyperaemia during local hyperthermia and/or small muscle mass exercise. Heat and exercise therapies are recommended to improve vascular health across the lifespan. However, the haemodynamic effects of hyperthermia, exercise and their combination are inconsistent in young and elderly people. Here we investigated the acute effects of local-limb hyperthermia and exercise on limb haemodynamics in nine healthy, trained elderly (69±5 years) and 10 young (26±7 years) adults, hypothesising that the combination of local hyperthermia and exercise interact to increase leg perfusion, albeit to a lesser extent in the elderly. Participants underwent 90min of single whole-leg heating, with the contralateral leg remaining as control, followed by 10min of low-intensity incremental single-leg knee-extensor exercise with both the heated and control legs. Temperature profiles and leg haemodynamics at the femoral and popliteal arteries were measured. In both groups, heating increased whole-leg skin temperature and blood flow by 9.5±1.2°C and 0.7±0.2Lmin-1 (>3-fold), respectively (P<0.0001). Blood flow in the heated leg remained 0.7±0.6 and 1.0±0.8Lmin-1 higher during exercise at 6 and 12W, respectively (P<0.0001). However, there were no differences in limb haemodynamics between cohorts, other than the elderly group exhibiting a 16±6% larger arterial diameter and a 51±6% lower blood velocity following heating (P<0.0001). In conclusion, local hyperthermia-induced limb hyperperfusion and/or small muscle mass exercise hyperaemia are preserved in trained older people despite evident age-related structural and functional alterations in their leg conduit arteries.

3-year experience of hyperthermic intravesical chemotherapy use in patients with high risk non-muscular-invasive bladder cancer

Cur rently, the search for additional organ-sparing methods of intravesical therapy for non-muscular-invasive bladder cancer (NMIBC) is actively continuing, which could become an effective alternative to standard treatment using the Bacillus Calmette-Guérin (BCG) vaccine. The aim of this work was to analyze the safety profile and long-term results of treatment of patients with the high-risk non-muscular-invasive bladder cancer who received adjuvant intravesical chemotherapy using the Combat BRS HIVEC® device for local hyperthermia (HIVEC® therapy group; n=53) in comparison with patients who received adjuvant therapy after transurethral resection of bladder performed with the Bacillus Calmette-Guérin vaccine (BCG therapy group; n=54). As a result, the median follow-up was 30 months (range 7-36). According to Common Terminology Criteria for Adverse Events (CTCAE) v 5.0, the most relevant side effects in HIVEC®/BCG therapy groups were adverse events grade 1-2: fever – 1%/8%; dysuria – 9%/13%; bladder spasms – 7%/12%; hematuria – 3%/4% and urinary tract infection – 3%/10%. Tumor recurrence was reported in 23 patients receiving intravesical BCG therapy and in 10 patients receiving intravesical hyperthermic chemotherapy (42.6% versus 18.9%, p=0.008). Tumor progression was recorded in 11 patients receiving intravesical BCG therapy and in 4 patients receiving intravesical hyperthermic chemotherapy (20.4% versus 7.5%, p=0.046). The study allows us to conclude that the method of hyperthermic intravesical chemotherapy has a better safety profile compared to intravesical Bacillus Calmette–Guérin vaccine therapy, while such indicators of oncological efficacy as 3-year recurrence-free survival and the incidence of progression were better in the HIVEC® therapy group.

Photosensitizer-immunotherapy integrated microneedles for preventing tumor recurrence and metastasis

Microneedles-based tumor therapy has obtained much focus in both biomedical research and clinical applications, while their efficient and synergetic strategy with minimal adverse effects remains highly expected. Herein, we develop a novel photosensitizer-immunotherapy integrated microneedles (MNs) with the required functions to prevent breast cancer recurrence and metastasis after surgery. Utilizing the enhanced penetration capability of MNs, the nanophotosensitizers with significant photodynamic and photothermal effects can be precisely targeted delivered and aggregated in the deep residual tumor tissue. Besides, with the hyperthermia of infrared ray (NIR) irradiation, the penetrated MNs can melt to release intrinsic photosensitizer in situ, achieving controllable drug release. As the reactive oxygen species and local hyperthermia generated from NIR-triggered nanophotosensitizers can induce the immunogenic death of residual cancer cells and evoke DCs maturation for system immunity, the proposed MNs can effectively protect against local tumor relapse and distant metastasis synergy with immune checkpoint inhibitors in the murine model. Thus, we believe that the photosensitizer-immunotherapy integrated MNs hold great potential for clinical translation.

Activatable Mn2+-Armed nanoagonist augments antitumor immunity in colorectal cancer: A NIR-II Photonic neoadjuvant paradigm

Postoperative recurrence frequently occurs in patients with colorectal cancer (CRC) due to residual microtumors and host cellular immune dysfunction, leading to major setbacks in clinical outcomes and CRC staging. As an increasingly prevalent therapeutic option for CRC patients, neoadjuvant chemoradiotherapy bears unmet challenges of limited tumor targeting and common side effects of gastrointestinal reaction and radiodermatitis. It is highly desirable to develop neoadjuvant treatment paradigms that impart both tumor-targeting accuracy and protection against recurrence of resectable CRC. Here we report a versatile photo-regulated nanoagonist of plasmonic gold blackbody (AuPB) with a polydopamine (PDA) coating carrying manganese ion (Mn2+) payloads (AuPB@PDA/Mn). When armed with second near-infrared (NIR-II) light, AuPB@PDA/Mn with broad-band localized surface plasmon resonance generates local hyperthermia and discharges Mn2+ ions, which evidently amplify the effects of immunogenic cell death in tumor cells and activate the cyclic GMP-AMP synthase/stimulator of interferon genes pathway in dendritic cells (DCs), hence potentiating the maturation of DC and the secretion of type I interferon in a synergistic way. Matured DCs undertake the task of tumor antigen presentation as the crosstalk to adaptive immunity. As such, the administration of AuPB@PDA/Mn coupled with NIR-II laser irradiation has eminently augmented the infiltration of CD8+ T cells as well as the development of memory CD8+ T cells in colorectal tumor models, substantiating enhanced immunomodulatory efficacy against primary and recurrent CRC. Our strategy highlights the potency of an integrated NIR-II photothermal and immunoregulatory modality by photo-activate delivery of Mn2+ ions, as a neoadjuvant paradigm for presurgical tumor debulking and against postoperative tumor recurrence.

Construction of Actively Targeted and High Drug Content Polyprodrug Amphiphiles to Perform Synergistic Chemo–Photo-Anti-Tumor Therapy and Immune-Activated Investigation

Chemotherapy is one of the most employed strategies in clinical treatment of cancer, but the low content of drug molecules caused by the inadequate accumulation of drug carriers in the lesion locations has an adverse impact on the therapeutic effect. To solve this issue, a kind of high drug content prodrug monomers with topological structures of AB2 and AB3 were designed and utilized to construct a series of polyprodrug amphiphiles, P[GMA(-l-RGD/-PEG)-CPTn] (n = 2 or 3), with both targeting peptides (l-RGD) and high drug content. Depending on the structure of prodrug monomers, the content of drug molecules could be achieved as high as 60 wt % (n = 2) and 65 wt % (n = 3), respectively. These polyprodrug amphiphiles could self-assemble with photothermal conversion reagents (IR780) in water to form spherical nanoparticles, which could expose original hidden l-RGD through the removal of hydrophilic PEG coronas under the trigger of a tumor microenvironment and thus promote the endocytosis of nanoparticles. Once in the presence of intracellular glutathione (GSH), high content drug molecules could be efficiently released by a cascade amplification reaction to kill cancer cells, this process could be further enhanced by the synergistic effect of local hyperthermia induced by near-infrared light irradiation. The results from in vitro simulation and in vivo mouse solid tumor models showed that these nanoreagents had a highly inhibitory effect on the tumor. Not only that, the immune response after chemical–optical synergistic therapy was also systematically conducted, the results demonstrated that the maturation of dendritic cells and proliferation of T cells could be successfully activated, accompanied by the increase of high mobility group protein B1 and decrease of immunosuppressive regulatory T cells. We believe this proof-of-concept could effectively solve the bottleneck problem in chemotherapy and provide a continuous immune protection to the body after anti-tumor treatment.

Dual-targeting multifunctional hyaluronic acid ligand-capped gold nanorods with enhanced endo-lysosomal escape ability for synergetic photodynamic-photothermal therapy of cancer.

Au nanorods (AuNRs) have attracted considerable interest as drug delivery systems because of their enhanced cell internalization and stronger drug-loading ability. In addition, the incorporation of photodynamic therapy (PDT) and photothermal therapy (PTT) into one nanosystem presents great promise to defect multiple drawbacks in cancer therapy. Herein, we fabricated a multifunctional and dual-targeting nanoplatform based on hyaluronic acid-grafted-(mPEG/triethylenetetramine-conjugated-lipoic acid/tetra(4-carboxyphenyl)porphyrin/folic acid) polymer ligand capped AuNRs (AuNRs@HA-g-(mPEG/Teta-co-(LA/TCPP/FA)) for combined photodynamic-photothermal therapy of cancer. The prepared nanoparticles displayed high TCPP loading capacity and excellent stability in different biological media. Furthermore, AuNRs@HA-g-(mPEG/Teta-co-(LA/TCPP/FA)) not only could produce a localized hyperthermia to conduct PTT, but also generate cytotoxic singlet oxygen (1 O2 ) to perform PDT under laser irradiation. Confocal imaging results disclosed that this nanoparticle endowing the specific function of polymeric ligand could enhance cellular uptake, accelerate endo/lysosomal escape, as well as produce higher reactive oxygen species. Importantly, this combination therapy strategy could also induce higher anticancer potential than PDT or PTT only against MCF-7 tumor cells in vitro. Therefore, this work presented an AuNRs-based therapeutic nanoplatform with great potential in dual-targeting and photo-induced combination therapy of cancer.

Trojan-like doxorubicin and gold nanoparticle entrapped smart nanostructured lipid carriers for breast cancer synergistic chemo/photothermal therapy

Breast cancer is one of the fatal diseases renowned worldwide. Chemotherapy is not sufficient for the treatment of breast cancer in a significant number of cases. In this study, we present the doxorubicin (DOX) and gold nanoparticles (AuNPs) loaded nanostructured lipid carriers (DOX+AuNPs)@NLCs, designed for dual chemo/photothermal therapy. Different geometries of AuNPs (gold nanospheres (AuNSs), gold nanorods (AuNRs), and gold nanocubes (AuNCs)) were also loaded in NLCs to exploit their photothermal heating capacity and to conceptualize the most efficient combination of drug delivery system for combined therapy. The light-triggered on-demand release of DOX from NLCs was examined before and after NIR irradiation (808 nm). The highest heating potential was obtained via AuNRs with ∆T = 22 °C in 5 min with 19.5 µg Au/mg lipid. The cytotoxic effect of these formulations was evaluated on MDA-MB-231 breast cancer cells and the highest growth inhibition (81%) is achieved with (DOX+AuNRs)@NLC under 5 min NIR application. It is found that the geometry directly effects the photothermal capability of AuNPs, a synergistic interaction between cytotoxic action of DOX and local hyperthermia provided by AuNPs can significantly enhance the skills on the irreversible cellular damage and developed state-of-art formulations hold a great potential as a combined-cancer-therapy agent. Thus, this study offers promise for the development of a lipid-based nano-platform that is biocompatible, multifunctional, and can be utilized for combined therapy, with tunable properties.

Mo-based Mo2Ti2C3 MXene as photothermal nanoagents to eradicating methicillin-resistant Staphylococcus aureus with photothermal therapy

Over the last decades, two-dimensional (2D) materials have progressively yielded great outcomes sparking intense research owing to their unique configuration and physicochemical properties. Their current research has effectively been channeled for biomedical purposes. Among them is the largest family, 2D transitional metal carbides (MXenes). In this context, Mo2Ti2C3 (MTC) a form of MXenes with excellent photo-conversion capacity was fabricated and its rising popularity due to its potential for possible treatment of infectious diseases was probed. We demonstrated that MTC MXene's potentiality for the conversion of the photo to heat showed better efficacy in inhibiting the growth of methicillin-resistant Staphylococcus aureus (MRSA). MTC under laser treatment completely killed MRSA, a combined treatment that caused an irreversible antibacterial effect. Also, MTC impeded bacteria-associated infections by completely killing MRSA in an infected wound, preventing tissue proliferation, angiogenesis, and tissue inflammations, demonstrating good biocompatibility, a sure prospect for clinical translation. Furthermore, the collaborative work of the MTC and the local hyperthermia significantly ameliorated MRSA-induced subcutaneous infection and bacterial keratitis, preserving the structural wholeness and transparency of the infected cornea. This study suggests that MTC may serve as a potential platform to augment near-infrared (NIR) therapeutic eradication of bacteria actively and precisely.

Microfluidic fabricated bisdemethoxycurcumin thermosensitive liposome with enhanced antitumor effect

Bisdemethoxycurcumin (BDMC) is the main active ingredient that is isolated from Zingiberaceae plants, wherein it has excellent anti-tumor effects. However, insolubility in water limits its clinical application. Herein, we reported a microfluidic chip device that can load BDMC into the lipid bilayer to form BDMC thermosensitive liposome (BDMC TSL). The natural active ingredient glycyrrhizin was selected as the surfactant to improve solubility of BDMC. Particles of BDMC TSL had small size, homogenous size distribution, and enhanced cultimulative release in vitro. The anti-tumor effect of BDMC TSL on human hepatocellular carcinomas was investigated via 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, live/dead staining, and flowcytometry. These results showed that the formulated liposome had a strong cancer cell inhibitory, and presented a dose-dependent inhibitory effect on migration. Further mechanistic studies showed that BDMC TSL combined with mild local hyperthermia could significantly upregulate B cell lymphoma 2 associated X protein levels and decrease B cell lymphoma 2 protein levels, thereby inducing cell apoptosis. The BDMC TSL that was fabricated via microfluidic device were decomposed under mild local hyperthermia, which could beneficially enhance the anti-tumor effect of raw insoluble materials and promote translation of liposome.

Near-Infrared Light-Mediated Cyclodextrin Metal-Organic Frameworks for Synergistic Antibacterial and Anti-Biofilm Therapies.

Bacterial infections pose a significant threat to global public health; therefore, the development of novel therapeutics is urgently needed. Herein, a controllable antibacterial nanoplatform utilizing cyclodextrin metal-organic frameworks (CD-MOFs) as a template to synthesize ultrafine silver nanoparticles (Ag NPs) in their porous structure is constructed. Subsequently, polydopamine (PDA) is encapsulated on the CD-MOFs' surface via dopamine polymerization to enhance the water stability and enable hyperthermia capacity. The resulting Ag@MOF@PDA generates localized hyperthermia and gradually releases Ag+ to achieve long-term photothermal-chemical bactericidal capability. The release rate of Ag+ can be accelerated by NIR-mediated heating in a controllable manner, quickly reaching the effective concentration and reducing the frequency of medication to avoid potential toxicity. In vitro experiments demonstrate that the combined antibacterial strategy can not only effectively kill both gram-negative and gram-positive bacteria, but also directly eradicate mature biofilms. In vivo results confirm that both bacterial- and biofilm-infected wounds treated with a combination of Ag@MOF@PDA and laser exhibit satisfactory recovery with minimal toxicity, displaying a superior therapeutic effect compared to other groups. Together, the results warrant that the Ag@MOF@PDA realizes synergistic antibacterial capacity and controllable release of Ag+ to combat bacterial and biofilm infections, providing a potential antibiotic-free alternative in the "post-antibiotic era."

A Novel Patient-Personalized Nanovector Based on Homotypic Recognition and Magnetic Hyperthermia for an Efficient Treatment of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the deadliest brain tumor, characterized by an extreme genotypic and phenotypic variability, besides a high infiltrative nature in healthy tissues. Apart from very invasive surgical procedures, to date, there are no effective treatments, and life expectancy is very limited. In this work, an innovative therapeutic approach based on lipid-based magnetic nanovectors is proposed, owning a dual therapeutic function: chemotherapy, thanks to an antineoplastic drug (regorafenib) loaded in the core, and localized magnetic hyperthermia, thanks to the presence of iron oxide nanoparticles, remotely activated by an alternating magnetic field. The drug is selected based on ad hoc patient-specific screenings; moreover, the nanovector is decorated with cell membranes derived from patients' cells, aiming at increasing homotypic and personalized targeting. It is demonstrated that this functionalization not only enhances the selectivity of the nanovectors toward patient-derived GBM cells, but also their blood-brain barrier in vitro crossing ability. The localized magnetic hyperthermia induces both thermal and oxidative intracellular stress that lead to lysosomal membrane permeabilization and to the release of proteolytic enzymes into the cytosol. Collected results show that hyperthermia and chemotherapy work in synergy to reduce GBM cell invasion properties, to induce intracellular damage and, eventually, to prompt cellular death.