A bone-targeting near-infrared luminescence nanocarrier facilitates alpha-ketoglutarate efficacy enhancement for osteoporosis therapy.

Osteoporosis (OP), which largely increases the risk of fractures, is the most common chronic degenerative orthopedic disease in the elderly due to the imbalance of bone homeostasis. Alpha-ketoglutaric acid (AKG), an endogenous metabolic intermediate involved in osteogenesis, plays critical roles in osteogenic differentiation and mineralization and the inhibition of osteoclastogenic differentiation. However, the low bioavailability and poor bone-targeting efficiency of AKG seriously limit its efficacy in OP treatment. In this work, a bone-targeting, near-infrared emissive lanthanide luminescence nanocarrier loaded with AKG (ß-NaYF4:7%Yb, 60%Nd@NaLuF4@mSiO2-EDTA-AKG, abbreviated as LMEK) is developed for the enhancement of AKG efficacy in OP therapy. By utilizing the NIR-II luminescence (>1000 nm) of LMEK, whole-body bone imaging with high spatial resolution is achieved to confirm the bone enrichment of AKG noninvasively in vivo. The results reveal that LMEK exhibits a remarkable OP therapeutic effect in improving the osseointegration of the surrounding bone in the ovariectomized OP mice models, which is validated by the enhanced inhibition of osteoclast through hypoxia-inducible factor-1α suppression and promotion of osteogenic differentiation in osteoblast. Notably, the dose of AKG in LMEK can be reduced to only 0.2 % of the dose when pure AKG is used in therapy, which dramatically improves the bioavailability of AKG and mitigates the metabolism burden. This work provides a strategy to conquer the low utilization of AKG in OP therapy, which not only overcomes the challenges in AKG efficacy for OP treatment but also offers insights into the development and application of other potential drugs for skeletal diseases. STATEMENT OF SIGNIFICANCE: Alpha-ketoglutarate (AKG) is an intermediate within the Krebs cycle, participating in diverse metabolic and cellular processes, showing potential for osteoporosis (OP) therapy. However, AKG's limited bioavailability and inefficient bone-targeting hinder its effectiveness in treating OP. Herein, a near-infrared emissive nanocarrier is developed that precisely targets bones and delivers AKG, bolstering its effectiveness in OP therapy. Thanks to this efficient bone-targeting delivery, the AKG dosage is reduced to 0.2 % of the conventional treatment level. This marks the first utilization of a bone-targeting nanocarrier to amplify AKG's bioavailability and OP therapy efficacy. Furthermore, the mechanism of AKG-loaded nanocarrier regulating the biological behavior of osteoclasts and osteoblasts mediated is tentatively explored.

An erythrocyte membrane-modified biomimetic synergistic nanosystem for cancer anti-vascular therapy and initial efficacy monitoring.

Tumor vascular disruption has become a promising strategy for cancer therapy in recent decades. Nanocomposites loaded with therapeutic materials and drugs are expected to improve the accuracy of anti-vascular therapy and minimize side effects. However, how to prolong blood circulation of therapeutic nanocomposites for enhanced accumulation in tumor vasculature and how to monitor the initial efficacy of anti-vascular therapy for early evaluation of prognosis remain unsolved. Herein, a biomimetic nanosystem consisting of erythrocyte membrane modified nanocomposites (CMNCs) is developed for cooperation to achieve anti-vascular cancer therapy and initial efficacy monitoring. By utilizing poly(lactic-co-glycolic acid) (PLGA) as the interface material, functional nanomaterials and drug molecules are successfully integrated into CMNCs. The long circulation and immune escape features of the erythrocyte membrane facilitate CMNCs loaded with photothermal agents and chemodrugs to be delivered to the tumor region for anti-vascular treatment. Furthermore, the vascular damage-induced haemorrhage and the following coagulation process is labelled by near infrared emissive CMNCs to indicate the initial therapeutic efficacy of the treatment. This work not only points to a biomimetic strategy for conquering the challenges in anti-vascular cancer therapy, but also provides insights into the biological responses of erythrocyte membrane modified nanocomposites to exploit their biomedical applications.

Multi-Channel Lanthanide Nanocomposites for Customized Synergistic Treatment of Orthotopic Multi-Tumor Cases.

Simultaneous photothermal ablation of multiple tumors is limited by unpredictable photo-induced apoptosis, caused by individual intratumoral differences. Here, a multi-channel lanthanide nanocomposite was used to achieve tailored synergistic treatment of multiple subcutaneous orthotopic tumors under non-uniform whole-body infrared irradiation prescription. The nanocomposite reduces intratumoral glutathione by simultaneously activating the fluorescence and photothermal channels. The fluorescence provides individual information on different tumors, allowing customized prescriptions to be made. This enables optimal induction of hyperthermia and dosage of chemo drugs, to ensure treatment efficacy, while avoiding overtherapy. With an accessional therapeutic laser system, customized synergistic treatment of subcutaneous orthotopic cancer cases with multiple tumors is possible with both high efficacy and minimized side effects.

EDTA-Modified 17ß-Estradiol-Laden Upconversion Nanocomposite for Bone-Targeted Hormone Replacement Therapy for Osteoporosis.

Hormone therapy (HT) is one of the most effective treatments for osteoporosis. However, the nonselective accumulation of hormone in organs such as breast, heart and uterus other than bones causes serious side effects, which impedes the application of HT. Hence, it is critically important to develop a HT strategy with reduced non-specific enrichment of hormone drugs in non-target tissues and enhanced bone-targeting ability. Methods: Herein, a 17ß-estradiol (E2)-laden mesoporous silica-coated upconversion nanoparticle with a surface modification of ethylenediaminetetraacetic acid (EDTA) (NaLuF4:Yb,Tm@NaLuF4@mSiO2-EDTA-E2, E2-csUCNP@MSN-EDTA) is developed for bone-targeted osteoporosis hormone therapy. EDTA was attached onto the surface of E2 upconversion nanocomposite to enhance its affinity and efficiency targeting bone tissue and cells to optimize hormone replacement therapy for osteoporosis. We characterized the size, cytotoxicity, loading and release efficiency, in situ and ex vivo imaging. Further, in vitro and in vivo osteogenic ability was tested using preosteoblast and ovariectomy mouse model of osteoporosis. Results: The upconversion core of E2-csUCNP@MSN-EDTA nanoparticle serves as an excellent imaging agent for tracking the loaded hormone drug in vivo. The mesoporous silica layer has a high loading efficiency for E2 and provides a relatively long-lasting drug release within 50 h. EDTA anchored on the silica layer endows the nanocomposite with a bone targeting property. The nanocomposite effectively reverses estrogen deficiency-induced osteoporosis and reduces the damage of hormone to the uterus. The bone mineral density in the nanocomposite treatment group is nearly twice that of the ovariectomized (OVX) group. Compared with the E2 group, the uterine weight and luminal epithelial height were significantly lower in the nanocomposite treatment group. Conclusion: This work demonstrated that E2-csUCNP@MSN-EDTA alleviates the side effect of hormone therapy while maintaining its therapeutic efficacy, which has great potential for developing the next generation of methods for osteoporosis treatment.

Upconversion nanocomposite for programming combination cancer therapy by precise control of microscopic temperature.

Combinational administration of chemotherapy (CT) and photothermal therapy (PTT) has been widely used to treat cancer. However, the scheduling of CT and PTT and how it will affect the therapeutic efficacy has not been thoroughly investigated. The challenge is to realize the sequence control of these two therapeutic modes. Herein, we design a temperature sensitive upconversion nanocomposite for CT-PTT combination therapy. By monitoring the microscopic temperature of the nanocomposite with upconversion luminescence, photothermal effect can be adjusted to achieve thermally triggered combination therapy with a sequence of CT, followed by PTT. We find that CT administered before PTT results in better therapeutic effect than other administration sequences when the dosages of chemodrug and heat are kept at the same level. This work proposes a programmed method to arrange the process of combination cancer therapy, which takes full advantage of each therapeutic mode and contributes to the development of new cancer therapy strategies.

Temperature-feedback upconversion nanocomposite for accurate photothermal therapy at facile temperature.

Photothermal therapy (PTT) at present, following the temperature definition for conventional thermal therapy, usually keeps the temperature of lesions at 42-45 °C or even higher. Such high temperature kills cancer cells but also increases the damage of normal tissues near lesions through heat conduction and thus brings about more side effects and inhibits therapeutic accuracy. Here we use temperature-feedback upconversion nanoparticle combined with photothermal material for real-time monitoring of microscopic temperature in PTT. We observe that microscopic temperature of photothermal material upon illumination is high enough to kill cancer cells when the temperature of lesions is still low enough to prevent damage to normal tissue. On the basis of the above phenomenon, we further realize high spatial resolution photothermal ablation of labelled tumour with minimal damage to normal tissues in vivo. Our work points to a method for investigating photothermal properties at nanoscale, and for the development of new generation of PTT strategy.

Core-shell lanthanide upconversion nanophosphors as four-modal probes for tumor angiogenesis imaging.

Multimodality imaging overcomes the shortage and incorporates the advantages of different imaging tools. Lanthanide-based nanoprobes are unique and have rich optical, magnetic, radioactive, and X-ray attenuation properties; however, simple doping of different lanthanide cations into one host can result in a material with multifunction but not the optimized properties. In this study, using NaLuF4:Yb,Tm as the core and 4 nm of (153)Sm(3+)-doped NaGdF4 (half-life of (153)Sm = 46.3 h) as the shell, we developed a lanthanide-based core-shell nanocomposite as an optimized multimodal imaging probe with enhanced imaging ability. The lifetime of upconversion luminescence (UCL) at 800 nm and relaxation rate (1/T1) were at 1044 µs and 18.15 s(-1)·mM(-1), respectively; however, no significant decrease in the attenuation coefficient was observed, which preserved the excellent X-ray imaging ability. The nanomaterial NaLuF4:Yb,Tm@NaGdF4((153)Sm) was confirmed to be effective and applicable for UCL imaging, X-ray computed tomography (CT), magnetic resonance imaging, and single-photon emission computed tomography (SPECT) in vivo. Furthermore, the NaLuF4:Yb,Tm@NaGdF4((153)Sm) nanoparticles were applied in tumor angiogenesis analysis by combining multimodality imaging of CT, SPECT, and confocal UCL imaging, which shows its value of multifunctional nanoparticles NaLuF4:Yb,Tm@NaGdF4((153)Sm) in tumor angiogenesis imaging.

NIR photothermal therapy using polyaniline nanoparticles.

Developing a biocompatible and efficient photothermal coupling agent with appropriate size is a prerequisite for the development of near-infrared (NIR) light-induced photothermal therapy (PTT). In the present study, polyaniline nanoparticles (PANPs) with a size of 48.5 ± 1.5 nm were fabricated and exhibited excellent dispersibility in water by a hydrothermal method and further surface functionalization by capping with F127. The developed F127-modified PANPs (F-PANPs) had a high molar extinction coefficient of 8.95 × 10(8) m(-1) cm(-1), and high NIR photothermal conversion efficiency of 48.5%. Furthermore, combined with NIR irradiation at 808 nm and injection of F-PANP samples, in vivo photothermal ablation of tumor with excellent treatment efficacy was achieved. In vitro transmission electron microscopy (TEM) images of cells, methyl thiazolyl tetrazolium (MTT) assay, histology, and hematology studies revealed that the F-PANPs exhibit low toxicity to living systems. Therefore, F-PANPs could be used as PTT agents for ablating cancer, and the concept of developing polyaniline-based nanoparticles can serve as a platform technology for the next generation of in vivo PTT agents.

Hollow silica nanoparticles loaded with hydrophobic phthalocyanine for near-infrared photodynamic and photothermal combination therapy.

Owing to the convenience and minimal invasiveness, phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is emerging as a powerful technique for cancer treatment. To date, however, few examples of combination PDT and PTT have been reported. Phthalocyanine (Pc) is a class of traditional photosensitizer for PDT, but its bioapplication is limited by high hydrophobicity. In this present study, hollow silica nanospheres (HSNs) were employed to endow the hydrophobic phthalocyanine with water-dispersity, and the as-prepared hollow silica nanoparticles loaded with hydrophobic phthalocyanine (Pc@HSNs) exhibits highly efficient dual PDT and PTT effects. In vitro and in vivo experimental results clearly indicated that the dual phototherapeutic effect of Pc@HSNs can kill cancer cells or eradicate tumor tissues. This multifunctional nanomedicine may be useful for PTT/PDT treatment of cancer.