ABSTRACT
By combining living cells with therapeutics, cell-drug conjugates can potentiate the functions of both components, particularly for applications in drug delivery and therapy. The conjugates can be designed to persist in the bloodstream, undergo chemotaxis, evade surveillance by the immune system, proliferate, or maintain or transform their cellular phenotypes. In this Review, we discuss strategies for the design of cell-drug conjugates with specific functions, the techniques for their preparation, and their applications in the treatment of cancers, autoimmune diseases and other pathologies. We also discuss the translational challenges and opportunities of this class of drug-delivery systems and therapeutics.
ABSTRACT
The development of minimally invasive surgery has greatly advanced precision tumor surgery, but sometime suffers from restricted visualization of the surgical field, especially during the removal of abdominal tumors. A 3-D inspection of tumors could be achieved by intravenously injecting tumor-selective fluorescent probes, whereas most of which are unable to instantly distinguish tumors via in situ spraying, which is urgently needed in the process of surgery in a convenient manner. In this study, this work has designed an injectable and sprayable fluorescent nanoprobe, termed Poly-g-BAT, to realize rapid tumor imaging in freshly dissected human colorectal tumors and animal models. Mechanistically, the incorporation of γ-glutamyl group facilitates the rapid internalization of Poly-g-BAT, and these internalized nanoprobes can be subsequently activated by intracellular NAD(P)H: quinone oxidoreductase-1 to release near-infrared fluorophores. As a result, Poly-g-BAT can achieve a superior tumor-to-normal ratio (TNR) up to 12.3 and enable a fast visualization (3 min after in situ spraying) of tumor boundaries in the xenograft tumor models, Apcmin/+ mice models and fresh human tumor tissues. In addition, Poly-g-BAT is capable of identifying minimal premalignant lesions via intravenous injection.
ABSTRACT
Insulin replacement therapy is indispensable in the treatment of type 1 and advanced type 2 diabetes. However, insulin's clinical application is challenging due to its narrow therapeutic index. To mitigate acute and chronic risks of glucose excursions, glucose-responsive insulin (GRI) has long been pursued for clinical application. By integrating GRI with glucose-sensitive elements, GRI is capable of releasing or activating insulin in response to plasma or interstitial glucose levels without external monitoring, thereby improving glycemic control and reducing hypoglycemic risk. In this Perspective, we first introduce the history of GRI development and then review major glucose-responsive components that can be leveraged to control insulin delivery. Subsequently, we highlight the recent advances in GRI delivery carriers and insulin analogs. Finally, we provide a look to the future and the challenges of clinical application of GRI.
Subject(s)
Blood Glucose , Hypoglycemic Agents , Insulin , Humans , Insulin/metabolism , Insulin/therapeutic use , Hypoglycemic Agents/therapeutic use , Blood Glucose/metabolism , Blood Glucose/drug effects , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 1/drug therapy , AnimalsABSTRACT
Continuous glucose monitoring systems (CGMs) are critical toward closed-loop diabetes management. The field's progress urges next-generation CGMs with enhanced antinoise ability, reliability, and wearability. Here, we propose a coin-sized, fully integrated, and wearable CGM, achieved by holistically synergizing state-of-the-art interdisciplinary technologies of biosensors, minimally invasive tools, and hydrogels. The proposed CGM consists of three major parts: (i) an emerging biochemical signal amplifier, the organic electrochemical transistor (OECT), improving the signal-to-noise ratio (SNR) beyond traditional electrochemical sensors; (ii) a microneedle array to facilitate subcutaneous glucose sampling with minimized pain; and (iii) a soft hydrogel to stabilize the skin-device interface. Compared to conventional CGMs, the OECT-CGM offers a high antinoise ability, tunable sensitivity and resolution, and comfort wearability, enabling personalized glucose sensing for future precision diabetes health care. Last, we discuss how OECT technology can help push the limit of detection of current wearable electrochemical biosensors, especially when operating in complicated conditions.
Subject(s)
Biosensing Techniques , Diabetes Mellitus , Humans , Blood Glucose Self-Monitoring , Blood Glucose , Continuous Glucose Monitoring , Reproducibility of Results , Glucose , Diabetes Mellitus/diagnosisABSTRACT
Toll-like receptor 7/8 agonists, such as imidazoquinolines (IMDQs), are promising for the de novo priming of antitumor immunity. However, their systemic administration is severely limited due to the off-target toxicity. Here, this work describes a sequential drug delivery strategy. The formulation is composed of two sequential modules: a tumor microenvironment remodeling nanocarrier (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4, termed CA4-NPs) and an immunotherapy nanocarrier (apcitide peptide-decorated poly(l-glutamic acid)-graft-IMDQ-N3 conjugate, termed apcitide-PLG-IMDQ-N3). CA4-NPs, as a vascular disrupting agent, are utilized to remodel the tumor microenvironment for enhancing tumor coagulation and hypoxia. Subsequently, the apcitide-PLG-IMDQ-N3 could identify and target tumor coagulation through the binding of surface apcitide peptide to the GPIIb-IIIa on activated platelets. Afterward, IMDQ is activated selectively through the conversion of "-N3" to "-NH2" in the presence of hypoxia. The biodistribution results confirm their high tumor uptake of activated IMDQ (22.66%ID/g). By augmenting the priming and immunologic memory of tumor-specific CD8+ T cells, 4T1 and CT26 tumors with a size of ≈500 mm3 are eradicated without recurrence in mouse models.
Subject(s)
Tumor Microenvironment , Tumor Microenvironment/drug effects , Animals , Mice , Cell Line, Tumor , Polyglutamic Acid/chemistry , Polyglutamic Acid/analogs & derivatives , Nanoparticles/chemistry , Drug Carriers/chemistry , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/administration & dosage , Polyethylene Glycols/chemistry , Tissue Distribution , Drug Delivery Systems , ImmunotherapyABSTRACT
The motor imagery brain-computer interface (MI-BCI) based on electroencephalography (EEG) is a widely used human-machine interface paradigm. However, due to the non-stationarity and individual differences among subjects in EEG signals, the decoding accuracy is limited, affecting the application of the MI-BCI. In this paper, we propose the EISATC-Fusion model for MI EEG decoding, consisting of inception block, multi-head self-attention (MSA), temporal convolutional network (TCN), and layer fusion. Specifically, we design a DS Inception block to extract multi-scale frequency band information. And design a new cnnCosMSA module based on CNN and cos attention to solve the attention collapse and improve the interpretability of the model. The TCN module is improved by the depthwise separable convolution to reduces the parameters of the model. The layer fusion consists of feature fusion and decision fusion, fully utilizing the features output by the model and enhances the robustness of the model. We improve the two-stage training strategy for model training. Early stopping is used to prevent model overfitting, and the accuracy and loss of the validation set are used as indicators for early stopping. The proposed model achieves within-subject classification accuracies of 84.57% and 87.58% on BCI Competition IV Datasets 2a and 2b, respectively. And the model achieves cross-subject classification accuracies of 67.42% and 71.23% (by transfer learning) when training the model with two sessions and one session of Dataset 2a, respectively. The interpretability of the model is demonstrated through weight visualization method.
Subject(s)
Brain-Computer Interfaces , Humans , Electroencephalography , Learning , ImaginationABSTRACT
Copper ions (Cu2+), as a crucial trace element, play a vital role in living organisms. Thus, the detection of Cu2+ is of great significance for disease prevention and diagnosis. Nanochannel devices with an excellent nanoconfinement effect show great potential in recognizing and detecting Cu2+ ions. However, these devices often require complicated modification and treatment, which not only damages the membrane structure, but also induces nonspecific, low-sensitivity and non-repeatable detection. Herein, a 2D MXene-carboxymethyl chitosan (MXene/CMC) freestanding membrane with ordered lamellar channels was developed by a super-assembly strategy. The introduction of CMC provides abundant space charges, improving the nanoconfinement effect of the nanochannel. Importantly, the CMC can chelate with Cu2+ ions, endowing the MXene/CMC with the ability to detect Cu2+. The formation of CMC-Cu2+ complexes decreases the space charges, leading to a discernible variation in the current signal. Therefore, MXene/CMC can achieve highly sensitive and stable Cu2+ detection based on the characteristics of nanochannel composition. The linear response range for Cu2+ detection is 10-9 to 10-5 M with a low detection limit of 0.095 nM. Notably, MXene/CMC was successfully applied for Cu2+ detection in real water and fetal bovine serum samples. This work provides a simple, highly sensitive and stable detection platform based on the properties of the nanochannel composition.
Subject(s)
Chitosan , Nitrites , Trace Elements , Transition Elements , Copper , Chitosan/chemistry , Ions/chemistryABSTRACT
Advanced chemotherapeutic strategies including prodrug and nanocatalytic medicine have significantly advanced tumor-selective theranostics, but delicate prodrug screening, tedious synthesis, low degradability/biocompatibility of inorganic components, and unsatisfied reaction activity complicate treatment efficacies. Here, the intrinsic anticancer bioactivity of liquid metal nanodroplets (LMNDs) is explored through galvanic replacement. By utilizing a mechano-degradable ligand, the resultant size of the aqueous LMND is unexpectedly controlled as small as ≈20 nm (LMND20). It is demonstrated that LMND20 presents excellent tumor penetration and biocompatibility and activates tumor-selective carrier-to-drug conversion, synchronously depleting Cu2+ ions and producing Ga3+ ions through galvanic replacement. Together with abundant generation of reactive oxygen species, multiple anticancer pathways lead to selective apoptosis and anti-angiogenesis of breast cancer cells. Compared to the preclinical/clinical anticancer drugs of tetrathiomolybdate and Ga(NO3 )3 , LMND20 administration significantly improves the therapeutic efficacy and survival in a BCap-37 xenograft mouse model, yet without obvious side effects.
Subject(s)
Antineoplastic Agents , Neoplasms , Prodrugs , Humans , Animals , Mice , Nanomedicine , Neoplasms/drug therapy , Neoplasms/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Prodrugs/pharmacology , Prodrugs/therapeutic use , Metals , Ions , Cell Line, TumorABSTRACT
Glucose-responsive formulations of insulin can increase its therapeutic index and reduce the burden of its administration. However, it has been difficult to develop single-dosage formulations that can release insulin in both a sustained and glucose-responsive manner. Here we report the development of a subcutaneously injected glucose-responsive formulation that nearly does not trigger the formation of a fibrous capsule and that leads to week-long normoglycaemia and negligible hypoglycaemia in mice and minipigs with type 1 diabetes. The formulation consists of gluconic acid-modified recombinant human insulin binding tightly to poly-L-lysine modified by 4-carboxy-3-fluorophenylboronic acid via glucose-responsive phenylboronic acid-diol complexation and electrostatic attraction. When the insulin complex is exposed to high glucose concentrations, the phenylboronic acid moieties of the polymers bind rapidly to glucose, breaking the complexation and reducing the polymers' positive charge density, which promotes the release of insulin. The therapeutic performance of this long-acting single-dose formulation supports its further evaluation and clinical translational studies.
ABSTRACT
OBJECTIVE: To investigate risk factors of acute cerebrovascular events and effects on the prognosis within 1 year after hip fracture surgery. METHODS: A retrospective analysis was performed on 320 elderly patients with hip fracture treated from July 2017 to December 2020, including 111 males and 209 females, aged from 60 to 101 years old with an average of (79.05±8.48) years old. According to whether acute cerebrovascular events occurred within 1 year after surgery, patients were divided into cerebrovascular events and non-cerebrovascular events group. Clinical data of patients were collected, including age, sex, comorbidities, fracture type, white blood cell count, hemoglobin, albumin, activities of daily living (ADL) score, walking ability, type of anesthesia, type of surgery, and length of hospital stay, Univariate analysis and multivariate Logistic regression were used to analyze the independent risk factors of acute cerebrovascular events within 1 year after hip fracture in elderly patients. ADL, walking ability and mortality were compared between the two groups 1 year after surgery. RESULTS: Acute cerebrovascular events occurred in 38 patients (11.9%) within 1 year after surgery. In the cerebrovascular events group, there were 20 males and 18 females, aged (82.53±7.91) years. In the non-cerebrovascular event group, there were 91 males and 191 females, aged with an average of (78.59±8.46) years old . Univariate analysis showed that acute cerebrovascular events were associated with age (t=2.712, P=0.007), male (χ2=6.129, P=0.013), hypertension (χ2=8.449, P=0.004), arrhythmia (χ2=6.360, P=0.012), stroke history (χ2=34.887, P=0.000), diabetes mellitus (χ2=4.574, P=0.032) and length of hospital stay (t=2.249, P=0.025) were closely related. Multivariate Logistic regression analysis showed age (OR=1.068, P=0.018), male (OR=2.875, P=0.008), arrhythmia (OR=2.722, P=0.017) and stroke history (OR=7.382, P=0.000) was an independent risk factor for acute cerebrovascular events 1 year after surgery. The patients with cerebrovascular events died at 1 year after surgery (11 cases) compared with those without cerebrovascular events (41 cases), and the difference was statistically significant(χ2=5.108, P=0.024). ADL scores of patients with cerebrovascular events at 1 year after operation were (58.70±14.45) points compared with those without cerebrovascular events (67.83±10.45) points, and the difference was statistically significant(t=4.122, P=0.000). Independent walking, assisted walking and bed rest were 3, 17 and 7 cases in cerebrovascular event group, and 54, 174 and 13 cases in non-cerebrovascular event group, respectively;and the difference was statistically significant(χ2=11.030, P=0.003). CONCLUSION: Acute cerebrovascular events were common in elderly patients 1 year after hip fracture. Age, male, arrhythmia and stroke history were independent risk factors for acute stroke. The patients in the cerebrovascular event group had higher mortality and worse self-care ability and walking ability one year after operation.
Subject(s)
Hip Fractures , Stroke , Female , Humans , Male , Aged , Middle Aged , Aged, 80 and over , Retrospective Studies , Activities of Daily Living , Risk Factors , Prognosis , Arrhythmias, CardiacABSTRACT
Immune checkpoints play key roles in maintaining self-tolerance. Targeted potentiation of the checkpoint molecule PD-L1 through in situ manipulation offers clinical promise for patients with autoimmune diseases. However, the therapeutic effects of these approaches are often compromised by limited specificity and inadequate expression. Here, we report a two-step dual-anchor coupling strategy for enhanced immobilization of PD-L1 on target endogenous cells by integrating bioorthogonal chemistry and physical insertion of the cell membrane. In both type 1 diabetes and rheumatoid arthritis mouse models, we demonstrate that this approach leads to elevated and sustained conjugation of PD-L1 on target cells, resulting in significant suppression of autoreactive immune cell activation, recruitment of regulatory T cells, and systematic reshaping of the immune environment. Furthermore, it restores glucose homeostasis in type 1 diabetic mice for over 100 days. This specific in situ bioengineering approach potentiates the functions of PD-L1 and represents its translational potential.
Subject(s)
Arthritis, Rheumatoid , Autoimmune Diseases , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 1 , Humans , Mice , Animals , B7-H1 Antigen/metabolism , Autoimmune Diseases/therapy , Diabetes Mellitus, Type 1/therapyABSTRACT
Chemotherapy remains as the first-choice treatment option for triple-negative breast cancer (TNBC). However, the limited tumor penetration and low cellular internalization efficiency of current nanocarrier-based systems impede the access of anticancer drugs to TNBC with dense stroma and thereby greatly restricts clinical therapeutic efficacy, especially for TNBC bone metastasis. In this work, biomimetic head/hollow tail nanorobots were designed through a site-selective superassembly strategy. We show that nanorobots enable efficient remodeling of the dense tumor stromal microenvironments (TSM) for deep tumor penetration. Furthermore, the self-movement ability and spiky head markedly promote interfacial cellular uptake efficacy, transvascular extravasation, and intratumoral penetration. These nanorobots, which integrate deep tumor penetration, active cellular internalization, near-infrared (NIR) light-responsive release, and photothermal therapy capacities into a single nanodevice efficiently suppress tumor growth in a bone metastasis female mouse model of TNBC and also demonstrate potent antitumor efficacy in three different subcutaneous tumor models.
Subject(s)
Hyperthermia, Induced , Nanoparticles , Triple Negative Breast Neoplasms , Animals , Humans , Mice , Female , Triple Negative Breast Neoplasms/therapy , Triple Negative Breast Neoplasms/pathology , Biomimetics , Cell Line, Tumor , Phototherapy , Tumor MicroenvironmentABSTRACT
Frequent insulin injections remain the primary method for controlling the blood glucose level of individuals with diabetes mellitus but are associated with low compliance. Accordingly, oral administration has been identified as a highly desirable alternative due to its non-invasive nature. However, the harsh gastrointestinal environment and physical intestinal barriers pose significant challenges to achieving optimal pharmacological bioavailability of insulin. As a result, researchers have developed a range of materials to improve the efficiency of oral insulin delivery over the past few decades. In this review, we summarize the latest advances in material design that aim to enhance insulin protection, permeability, and glucose-responsive release. We also explore the opportunities and challenges of using these materials for oral insulin delivery.
ABSTRACT
Diabetes mellitus is a serious threat to human life and health. The α-glucosidase and protein tyrosine phosphatase 1B (PTP1B) were important targets for the treatment of type 2 diabetes mellitus. In this paper, euparin, a natural product from Eupatorium chinense possessed extensive pharmacological activities, was selected as the lead compound. It was derived into chalcone compounds with high efficiency, and the inhibitory activities of these 30 products on α-glucosidase and PTP1B were tested. The results showed that compounds 12 and 15 had good inhibitory activities against both enzymes. The IC50 value of 12 to inhibit α-glucosidase and PTP1B was 39.77 and 39.31 µM, and the IC50 value of 15 to inhibit α-glucosidase and PTP1B was 9.02 and 3.47 µM, respectively. In addition, molecular docking results showed that compounds 12 and 15 exhibited good binding affinities toward both α -glucosidase and PTP1B with negative binding energies. The results of the present study demonstrate that compounds 12 and 15 might be beneficial in the treatment of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2 , Glycoside Hydrolase Inhibitors , Humans , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Diabetes Mellitus, Type 2/drug therapy , alpha-Glucosidases/metabolism , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Molecular Docking SimulationABSTRACT
Microneedles (MNs) have become versatile platforms for minimally invasive transdermal drug delivery devices. However, there are concerns about MN-induced skin infections with long-term transdermal administration. Using the Langmuir-Blodgett (LB) technique, a simple method for depositing antibacterial nanoparticles of various shapes, sizes, and compositions onto MNs is developed. This strategy has merits over conventional dip coating techniques, including controlled coating layers, uniform and high coverage, and a straightforward fabrication process. This provides MNs with a fast-acting and long-lasting antibacterial effect. This study demonstrates that antibacterial MNs achieve superior bacterial elimination in vitro and in vivo without sacrificing payload capacity, drug release, or mechanical strength. It is believed that such a functional nanoparticle coating technique offers a platform for the expansion of MNs function, especially in long-term transdermal drug delivery fields.
Subject(s)
Drug Delivery Systems , Needles , Administration, Cutaneous , Drug Delivery Systems/methods , Skin , Anti-Bacterial Agents/pharmacologyABSTRACT
Pulmonary arterial hypertension (PAH) is considered the third most common cardiovascular disease after coronary heart disease and hypertension. The diagnosis of PAH is mainly based on the comprehensive judgment of computed tomography and other medical image examinations. Medical image processing based on deep learning has achieved significant success. However, the data belongs to the patient's privacy; therefore, the medical institutions as data custodians have the responsibility to protect the security of their data privacy. This situation makes medical institutions face a dilemma when building data-driven deep learning-assisted medical diagnosis methods. On the one hand, they need to pursue more high-quality data based on Big Data architecture for deep learning; on the other hand, they need to protect patient privacy to avoid data leakage. In response to the above challenges, we propose a hierarchical hybrid automatic segmentation model for pulmonary blood vessels based on local learning and federated learning approaches for segmenting the pulmonary blood vessels. The experiments prove the proposal could automatically segment the vessels from the original CT. It also indicates that the model based on a federated learning approach can achieve impressive performance under the premise of protecting data privacy for Big Data.
ABSTRACT
Boron neutron capture therapy (BNCT) was clinically approved in 2020 and exhibits remarkable tumour rejection in preclinical and clinical studies. It is binary radiotherapy that may selectively deposit two deadly high-energy particles (4He and 7Li) within a cancer cell. As a radiotherapy induced by localized nuclear reaction, few studies have reported its abscopal anti-tumour effect, which has limited its further clinical applications. Here, we engineer a neutron-activated boron capsule that synergizes BNCT and controlled immune adjuvants release to provoke a potent anti-tumour immune response. This study demonstrates that boron neutron capture nuclear reaction forms considerable defects in boron capsule that augments the drug release. The following single-cell sequencing unveils the fact and mechanism that BNCT heats anti-tumour immunity. In female mice tumour models, BNCT and the controlled drug release triggered by localized nuclear reaction causes nearly complete regression of both primary and distant tumour grafts.
Subject(s)
Boron Neutron Capture Therapy , Neoplasms , Male , Female , Animals , Mice , Boron/therapeutic use , Neoplasms/drug therapy , Immunotherapy , Neutrons , Boron Compounds/therapeutic useABSTRACT
Lipid nanoparticle-based drug delivery systems have a profound clinical impact on nucleic acid-based therapy and vaccination. Recombinant human insulin, a negatively-charged biomolecule like mRNA, may also be delivered by rationally-designed positively-charged lipid nanoparticles with glucose-sensing elements and be released in a glucose-responsive manner. Herein, we have designed phenylboronic acid-based quaternary amine-type cationic lipids that can self-assemble into spherical lipid nanoparticles in an aqueous solution. Upon mixing insulin and the lipid nanoparticles, a heterostructured insulin complex is formed immediately arising from the electrostatic attraction. In a hyperglycemia-relevant glucose solution, lipid nanoparticles become less positively charged over time, leading to reduced attraction and subsequent insulin release. Compared with native insulin, this lipid nanoparticle-based glucose-responsive insulin shows prolonged blood glucose regulation ability and blood glucose-triggered insulin release in a typeâ 1 diabetic mouse model.