Advanced Therapeutics最新文献

In recent years, the development of electro-responsive nanomaterials has attracted significant attention in the field of cancer therapy. By incorporating these smart nanomaterials into therapeutic approaches, researchers explored many novel strategies to selectively induce cell death in tumor tissues while minimizing damage to healthy cells. This comprehensive review highlights the current state of research on electro-responsive nanomaterials and their ability to manipulate accidental and regulated cell death for effective tumor therapy. The scope includes the biomechanisms of electro-responsive nanotherapeutics inducing tumor cell death and their various detailed applications in cancer treatments. The review is concluded with deliberations on the key challenges and future outlooks of electro-responsive nanotherapeutics for tumor therapy.

A rapid emergence of small interfering ribonucleic acid (siRNA) is witnessed as a powerful tool in gene therapy for suppressing gene expression. Since highly porous metal-organic frameworks (MOFs) are fragile and inefficient with non-specific gene delivery techniques, developing strategies use them to encapsulate unmodified natural siRNA from enzymatic degradation. MOFs with high nucleic acid binding affinity are ideal for encapsulating siRNAs in cancer therapy, bypassing circulation time and non-specificity. To knock down Plk1gene, tumor cell membranes can hide Plk1 siRNA-containing (Zeolitic Imidazolate framework) ZIF-8 nanoparticles. For tumor suppression MOF-promoted lysosome siRNA release, cell membrane coating, and PLK1 silencing are employed. Lysosomes attack cancer by delivering miRNA to targeted cells. Single-stranded miRNA, two-stranded siRNA. Despite their different sources, structures, modes of action, and biological activities, miRNA and siRNA regulate gene expression. SIRNA blocks genes more accurately than miRNA, which regulates larger genes. SiRNA-MOF integration in vitro results in a maximum of 27% consistent gene silencing during endocytic absorption. Cofactor-encapsulated MOF-internalized siRNA kills enzymes. A universal siRNA delivery for a specific genetic sequence with personalized therapeutic potential contrasts with multi-route cancer drugs. SiRNAs cleave long-stranded RNAs coding for specific genes, allowing biocompatible MOFs to encapsulate macromolecules and protect them from injury.

30–55% post-surgical recurrent rate of early and middle stage non-small cell lung cancer (e/mNSCLC) suggests the need of adjuvant therapy. The e/mNSCLC derived organoids (e/mNSCLCOs)-based efficacy evaluation of the proposed regimens may improve clinical benefits for e/mNSCLC patients. The e/mNSCLCOs are established from 33 IA-IIIB resectable non-small cell lung cancer (NSCLC) patients without systemic antitumor therapy via optimized 3D culture, of which six with epidermal growth factor receptor (EGFR) mutation. Immunohistochemical staining is employed to ascertain the maintenance of biomarker expression patterns of e/mNSCLCOs with that of their parental tumors. The e/mNSCLCOs are treated with six conventional anti-NSCLC chemotherapeutic regimens, respectively. Calcein-AM/PI cell viability/cytotoxicity assay and EdU cell proliferation test reveal that the platinum-based chemotherapeutic or mono-chemotherapeutic regimens are generally ineffective to e/mNSCLCOs because of their high IC₅₀ values. Non-platinum gemcitabine combined with vinorelbine achieve better anti-e/mNSCLCOs outcome in terms of suppressed cell proliferation and 51.6–65.8% of intra-organoid cell death. The 6 e/mNSCLCOs with EGFR mutations are sensitive to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in drug selective patterns. The low efficacy of conventional anti-NSCLC drugs to e/mNSCLCOs suggests the necessity to explore alternative approaches for better adjuvant management of e/mNSCLC patients.

Calixarenes are third generation of macrocyclic molecules with excellent biocompatibility currently being researched extensively for their diverse potential as therapeutic candidates and for delivery of drugs and biologics. This review discusses the unique structural features which allow them to selectively bind to a wide variety of guest molecules within their hydrophobic cavity, as well as complex with other molecules on their upper and lower rims to enable their application for encapsulation of drugs for targeted and controlled release, molecular carriers for antigens and nucleic acids, and as biomedical sensors. The calixarenes’ unique host–guest chemistry enables encapsulation of lipophilic drugs in the latter's cavity, while the head groups and side chains on the upper and lower rim can be functionalized readily with various targeting moieties as peptides and biological ligands which specifically recognize and bind to cancer cells via surface receptors. The design of calixarene constructs help incorporation of multiple functionalities into a single platform. This active targeting approach enhances the accumulation of the drug at the tumor site while reducing its distribution in healthy tissues, thereby minimizing side effects. Ongoing research in exploration and optimization of calixarenes for application as targeted drug and gene delivery agents has been discussed.

The design of biologic and synthetic drugs in the pharmaceutical industry is facing three key challenges, namely, ensuring bioavailability, solubility, and stability. Ionic liquids (ILs) and deep eutectic solvents (DESs), classified as designer solvents, have emerged as excellent solvents for improving the permeability and stability of biotherapeutic drugs. Moreover, they have shown remarkable solubilizing effects for synthetic drugs, particularly in solubilizing active pharmaceutical ingredients (API), and are known as eco-friendly solvents. Thus, in this review, the development of designer formulations in pharmaceutical industries is reported, and the underlying strategies for designing the most efficient formulations for both biotherapeutics and synthetic drugs are examined.

Enfuvirtide (T-20) is a synthetic peptide fusion inhibitor for the human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS). However, the peptide nature limits a wider application of T-20 with subcutaneous injection (Fuzeon) the only available formulation. In this groundbreaking study, it is sought to overcome this limitation by employing poly lactic-co-glycolic acid (PLGA) and alginate to create novel oral delivery systems for T-20. Remarkably, this investigation marks the first instance of assessing the efficacy of oral delivery systems in mice. Notably, both the PLGA and alginate formulations exhibit the capability to sustain T-20 release, maintaining detectable levels in the bloodstream of mice for over 24 h after a single dose. By venturing into the realm of oral T-20 delivery, this study opens avenues for the prospective development of oral formulations of T-20, potentially leading to their evaluation in clinical trials.

Mild cognitive impairment (MCI) is recognized as a predementia syndrome caused by multiple etiologies and nonmemory symptoms in MCI have recently gained increasing attention. However, the pattern of Aβ deposition and the effect of APOE (apolipoprotein E, APOE) ε4 on cognitive impairment in amnestic MCI (aMCI) and nonamnestic MCI (naMCI) patients has not been demonstrated. In this work, the amyloid-β (Aβ) load by [¹⁸F]florbetapir PET imaging and cognitive performance is compared by comprehensive neuropsychological scales in participants with different MCI types or different APOE ε4 carriage status. According to the Aβ positivity and results of voxel-wise analysis, higher Aβ loads are observed in aMCI patients than naMCI patients, especially aMCI patients with APOE ε4. Additionally, it is observed that memory domain Z scores show a strong negative correlation with global florbetapir SUVR in the aMCI group (r = – 0.352, p < 0.001) but not in the naMCI group (r = –0.016, p = 0.924). Moreover, this correlation is independent of APOE e4 carriage status. This study aims to identify high-risk groups at an early stage of AD(Alzheimer's Disease, AD) through cognitive performance and APOE ε4 carrier status, which can be important for guiding clinical intervention trials.

Liposomal J-Aggregates of Indocyanine Green (L-JA) can serve as a biocompatible and biodegradable nanoparticle for photoacoustic imaging (PAI) and photothermal therapy (PTT). When compared to monomeric indocyanine green (IcG), L-JA is characterized by longer circulation, improved photostability, elevated absorption at longer wavelengths, and increased photoacoustic signal generation. However, the documented methods for the production of L-JA vary widely. An approach to efficiently form IcG J-aggregates (IcG-JA) directly in liposomes at elevated temperatures is developed. Aggregating within fully formed liposomes ensures particle uniformity and allows for control of J-aggregate size. L-JA has unique properties compared to IcG. L-JA provides significant contrast enhancement in photoacoustic images for up to 24 h after injection, while IcG and unencapsulated IcG-JA are cleared within an hour. L-JA allows for more accurate photoacoustic-based blood oxygen saturation (sO₂) estimation and particle tracking compared to IcG. Furthermore, photothermal heating of L-JA with an 852 nm laser is demonstrated to be more effective at lower laser powers than conventional 808 nm lasers for the first time. The presented technique offers an avenue for formulating a multi-faceted contrast agent for photoacoustic imaging and photothermal therapy that offers significant advantages over other conventional agents.

The current search for more effective and milder cancer treatments has led to the development of a wide variety of multifunctional nanoplatforms that are designed to both diagnose and treat cancer. In this study, the optimization of the synthesis of theranostic materials based on mesoporous silica nanoparticles (MSNs) functionalized with different cytotoxic (organotin(IV) compounds), imaging (fluorescein and/or indocyanine green), and targeting agents of interest, such as albumin (HA), is achieved by using different strategies. These systems shows good cytotoxic capacity against triple negative breast cancer (TNBC) cells (MDA-MB-231) in MTT (dimethylthiazolyl-diphenyl-tetrazolium bromide) assays and confocal analysis shows that the incorporation of HA as a potential active targeting molecule may enhance the cellular uptake of the nanomaterial, and thus, increasing its therapeutic potential. The analysis of the results and the effect of the imaging, targeting, and cytotoxic fragments should allow a more in-depth study of these materials in other in vitro and/or in vivo models.

Suppression of the polarization of M1 macrophages is crucial for promoting diabetic wound healing. Hypahorine (HYP), a small molecule alkaloid compound with anti-inflammatory properties, is encapsulated in liposome nanospheres (HYP-INPS) using a one-step ultrasound method and applied to treat open wounds in diabetic rats. Transmission electron microscopy (TEM) revealed that HYP-INPS nanoparticles are spherical and coated with a lipid layer. ZetaPALS analysis demonstrated that HYP-INPS has a potential of -15.67 ± 2.58 mV and a size of 212.87 ± 13.34 nm. In vitro, confocal microscopy revealed the cellular uptake of HYP-INPS in macrophages. Flow cytometry showed that HYP-INPS inhibited the polarization of bone marrow-derived macrophages (BMDMs) to the M1 phenotype. In vivo, HYP-INPS promoted diabetic wound healing by improving the inflammatory microenvironment within wounds. Immunofluorescence revealed that HYP-INPS up-regulated the expression of M2 macrophages and down-regulated the expression of M1 macrophages at the wound site. Transcriptome sequencing showed that HYP-INPS treatment specifically up-regulated ASB10 expression in LPS-induced RAW264.7 cells. Loss-of-function or gain-of-function experiments confirmed the regulatory role of ASB10 in M1 macrophage polarization. Therefore, HYP-INPS targeted ASB10 is concluded to accelerate wound healing in diabetes by inhibiting the polarization of M1 macrophages and improving the inflammatory microenvironment. This newly developed HYP-INPS system holds promise as a potential treatment for diabetic wounds.