Delivery Vehicles For Therapy Research Articles

Imidazolyl Lipids Enhanced LNP Endosomal Escape for Ferroptosis RNAi Treatment of Cancer.

Treatments for cancer that incorporate small interfering RNA (siRNA) to target iron-dependent ferroptosis are thought to be highly promising. However, creating a reliable and clinically feasible siRNA delivery system continues to be a major obstacle in the field of cancer treatment. Here, three imidazole-based ionizable lipid nanoparticles (LNPs) with pH-sensitive effects are rationally designed and synthesized for siRNA delivery. LNPs formulated with the top-performing lipid (O12-D3-I3) encapsulating FVII siRNA (FVII@O-LNP) elicited greater gene silencing than those with the benchmark Onpattro lipid DLin-MC3-DMA (MC3) due to its stronger endosomal escape. Moreover, Fc-siRNA@O-LNPs encapsulated with ferrocene (Fc) and SLC7A11/Nrf2-targeted siRNA is formulated. The outcomes demonstrate optimal safety profiles and a significant anti-tumor effect by inducing long-lasting and efficient ferroptosis through a synergistic action in vivo. In summary, this work shows that imidazolyl lipid-prepared LNPs are efficient delivery vehicles for cancer therapy and ferroptosis-targeting siRNA administration, both of which have extensive clinical application potential.

Biosynthesis and characterization of curcumin loaded CdO-SiO2@chitosan nanocomposite: Multifunctional agent for enhanced drug delivery vehicles for cancer therapy

Curcumin, a potent and extensively utilized cancer chemotherapeutic agent, faces limitations due to dose-dependent cardiotoxicity as its cumulative side effect. To surmount this challenge, a novel drug delivery system based on the biosynthesis of a cadmium oxide and silicon dioxide nanocomposite (CdO-SiO2-NC) has been developed. In this research, we have successfully synthesized innovative agents designed for an efficient drug delivery system, known as CdO-SiO2@CS-CUR-NC. A comprehensive characterization of this CdO-SiO2@CS-CUR-NC included an evaluation of the composition, chemical structure and morphology. The outcomes of assays focusing on inhibiting bacterial growth demonstrated significant efficacy in curbing bacterial proliferation within the concentration range of 50–100 µg/mL. This inhibitory effect was primarily attributed to the construction of reactive oxygen species (ROS). Furthermore, CdO-SiO2@CS-CUR-NC displayed noteworthy anti-inflammatory properties, evident from an observed to IC50 value of 25.12 µg/mL in human red blood cells. These outcomes suggest the possibility of this nanocomposite being used as an effective anti-inflammatory agent. Additionally, investigations into its cytotoxicity revealed a dose-dependent anti-cancer impact of the CdO-SiO2-NC across a variety of human cancer cell lines. The pronounced cytotoxicity on A549 cancer cells was particularly remarkable, where the IC50 value was measured as 31.10 µg/mL. The versatility of CdO-SiO2@CS-CUR-NC, encompassing antibacterial activity, anti-inflammatory as well as anticancer attributes, presents a auspicious avenue for further exploration. Particularly noteworthy is the potential application of CdO-SiO2@CS-CUR-NC as a novel anticancer agent in the field of lung cancer treatment. This research not only contributes to our comprehension of nanoscale interventions but also propels the potential roles of nanotechnology within the realm of pharmaceuticals.

Innovative utilization of cell membrane‐coated nanoparticles in precision cancer therapy

AbstractCell membrane‐coated nanoparticles (CMNPs) have recently emerged as a promising platform for cancer therapy. By encapsulating therapeutic agents within a cell membrane‐derived coating, these nanoparticles combine the advantages of synthetic nanoparticles and natural cell membranes. This review provides a comprehensive overview of the recent advancements in utilizing CMNPs as effective drug delivery vehicles for cancer therapy. The synthesis and fabrication methods of CMNPs are comprehensively discussed. Various techniques, such as extrusion, sonication, and self‐assembly, are employed to coat synthetic nanoparticles with cell membranes derived from different cell types. The cell membrane coating enables biocompatibility, reducing the risk of an immune response and enhancing the stability of the nanoparticles in the bloodstream. Moreover, functionalization strategies for CMNPs, primarily chemical modification, genetic engineering, and external stimuli, are highlighted. The presence of specific cell surface markers on the coated membrane allows targeted drug delivery to cancer cells and maximizes therapeutic efficacy. Preclinical studies utilizing CMNPs for cancer therapy demonstrated the successful delivery of various therapeutic agents, such as chemotherapeutic drugs, nucleic acids, and immunotherapeutic agents, using CMNPs. Furthermore, the article explores the future directions and challenges of this technology while offering insights into its clinical potential.

Defined covalent attachment of three cancer drugs to DNA origami increases cytotoxicity at nanomolar concentration

DNA nanostructures have captured great interest as drug delivery vehicles for cancer therapy. Despite rapid progress in the field, some hurdles, such as low cellular uptake, low tissue specificity or ambiguous drug loading, remain unsolved. Herein, well-known antitumor drugs (doxorubicin, auristatin, and floxuridine) were site-specifically incorporated into DNA nanostructures, demonstrating the potential advantages of covalently linking drug molecules via structural staples instead of incorporating the drugs by noncovalent binding interactions. The covalent strategy avoids critical issues such as an unknown number of drug-DNA binding events and premature drug release. Moreover, covalently modified origami offers the possibility of precisely incorporating several synergetic antitumor drugs into the DNA nanostructure at a predefined molar ratio and to control the exact spatial orientation of drugs into DNA origami. Additionally, DNA-based nanoscaffolds have been reported to have a low intracellular uptake. Thus, two cellular uptake enhancing mechanisms were studied: the introduction of folate units covalently linked to DNA origami and the transfection of DNA origami with Lipofectamine. Importantly, both methods increased the internalization of DNA origami into HTB38 and HCC2998 colorectal cancer cells and produced greater cytotoxic activity when the DNA origami incorporated antiproliferative drugs. The results here present a successful and conceptually distinct approach for the development of DNA-based nanostructures as drug delivery vehicles, which can be considered an important step towards the development of highly precise nanomedicines.

Evolving utility of exosomes in pancreatic cancer management.

Despite the development of newer oncological treatment, the survival of patients with pancreatic cancer (PC) remains poor. Recent studies have identified exosomes as essential mediators of intercellular communications and play a vital role in tumor initiation, metastasis and chemoresistance. Thus, the utility of liquid biopsies using exosomes in PC management can be used for early detection, diagnosis, monitoring as well as drug delivery vehicles for cancer therapy. This review summarizes the function, and clinical applications of exosomes in cancers as minimally invasive liquid biomarker in diagnostic, prognostic and therapeutic roles.

An Efficacy and Mechanism Driven Study on the Impact of Hypoxia on Lipid Nanoparticle Mediated mRNA Delivery.

Hypoxia is a common hallmark of human disease that is characterized by abnormally low oxygen levels in the body. While the effects of hypoxia on many small molecule-based drugs are known, its effects on several classes of next-generation medications including messenger RNA therapies warrant further study. Here, we provide an efficacy- and mechanism-driven study that details how hypoxia impacts the cellular response to mRNA therapies delivered using 4 different chemistries of lipid nanoparticles (LNPs, the frontrunner class of drug delivery vehicles for translational mRNA therapy utilized in the Moderna and Pfizer/BioNTech COVID-19 vaccines). Specifically, our work provides a comparative analysis as to how various states of oxygenation impact LNP-delivered mRNA expression, cellular association, endosomal escape, and intracellular ATP concentrations following treatment with 4 different LNPs across 3 different cell lines. In brief, we first identify that hypoxic cells express less LNP-delivered mRNA into protein than normoxic cells. Next, we identify generalizable cellular reoxygenation protocols that can reverse the negative effects that hypoxia imparts on LNP-delivered mRNA expression. Finally, mechanistic studies that utilize fluorescence-activated cell sorting, confocal microscopy, and enzyme inhibition reveal that decreases in mRNA expression correlate with decreases in intracellular ATP (rather than with differences in mRNA LNP uptake pathways). In presenting this data, we hope that our work provides a comprehensive efficacy and mechanism-driven study that explores the impact of differential oxygenation on LNP-delivered mRNA expression while simultaneously establishing fundamental criteria that may one day be useful for the development of mRNA drugs to treat hypoxia-associated disease.

Recent Advances in the Lipid Nanoparticle-Mediated Delivery of mRNA Vaccines

Lipid nanoparticles (LNPs) have recently emerged as one of the most advanced technologies for the highly efficient in vivo delivery of exogenous mRNA, particularly for COVID-19 vaccine delivery. LNPs comprise four different lipids: ionizable lipids, helper or neutral lipids, cholesterol, and lipids attached to polyethylene glycol (PEG). In this review, we present recent the advances and insights for the design of LNPs, as well as their composition and properties, with a subsequent discussion on the development of COVID-19 vaccines. In particular, as ionizable lipids are the most critical drivers for complexing the mRNA and in vivo delivery, the role of ionizable lipids in mRNA vaccines is discussed in detail. Furthermore, the use of LNPs as effective delivery vehicles for vaccination, genome editing, and protein replacement therapy is explained. Finally, expert opinion on LNPs for mRNA vaccines is discussed, which may address future challenges in developing mRNA vaccines using highly efficient LNPs based on a novel set of ionizable lipids. Developing highly efficient mRNA delivery systems for vaccines with improved safety against some severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants remains difficult.

Extracellular Vesicles as Drug Targets and Delivery Vehicles for Cancer Therapy.

Extracellular vesicles (EVs) are particles that are released from cells into the extracellular space both under pathological and normal conditions. It is now well established that cancer cells secrete more EVs compared to non-cancerous cells and that, captivatingly, several proteins that are involved in EV biogenesis and secretion are upregulated in various tumours. Recent studies have revealed that EVs facilitate the interaction between cancer cells and their microenvironment and play a substantial role in the growth of tumours. As EVs are involved in several aspects of cancer progression including angiogenesis, organotropism, pre-metastatic niche formation, fostering of metastasis, and chemoresistance, inhibiting the release of EVs from cancer and the surrounding tumour microenvironment cells has been proposed as an ideal strategy to treat cancer and associated paraneoplastic syndromes. Lately, EVs have shown immense benefits in preclinical settings as a novel drug delivery vehicle. This review provides a brief overview of the role of EVs in various hallmarks of cancer, focusing on (i) strategies to treat cancer by therapeutically targeting the release of tumour-derived EVs and (ii) EVs as valuable drug delivery vehicles. Furthermore, we also outline the drawbacks of the existing anti-cancer treatments and the future prospective of EV-based therapeutics.

Hollow Nanooxidase Enhanced Phototherapy Against Solid Tumors.

Although phototherapy has attracted extensive attention in antitumor field in recent years, its therapeutic effect is usually unsatisfactory because of the complexity and variability of the tumor microenvironment (TME). Herein, we report novel CoSn(OH)6@CoOOH hollow carriers with oxidase properties that can enhance phototherapy. Hollow CoSn(OH)6@CoOOH nanocubes (NCs) with a particle size of ∼160 nm were synthesized via a two-step process of coprecipitation and etching. These NCs can react with O2 to generate singlet oxygen without hydrogen peroxide and consume glutathione, and their hollow structure can be utilized to carry drug molecules. After loading indocyanine green (ICG) and 1,2-bis(2-(4,5-dihydro-1H-imidazol-2-yl)propan-2-yl) diazene dihydrochloride (AIPH), the resulting nanosystem (HCIA) exhibited enhanced phototherapy effects through the catalytic activity of oxidase, production of alkyl radicals, and consumption of glutathione. Cell and mouse experiments showed that HCIA combined with near-infrared laser irradiation significantly inhibited the growth of 4T1 tumors. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that PI3K-Akt and MAPK signaling pathways were highly relevant to this therapeutic system. Such hollow NCs with oxidase activity have considerable potential for the design of multifunctional drug delivery vehicles for tumor therapy.

A comparative study on micelles, liposomes and solid lipid nanoparticles for paclitaxel delivery

The purpose of this work was to compare the in vitro and in vivo characteristics of LDV-targeted lipid-based micelles, liposomes and solid lipid nanoparticles (SLN) to provide further insights into their therapeutic potential for clinical development. Micelles, liposomes and SLN were prepared using LDV peptide amphiphiles and palmitic acid-derived lipids using solvent evaporation, thin-film hydration and microfluidic mixing respectively. Nanocarriers were characterized for their physicochemical properties, paclitaxel loading efficiency, in vitro release behavior, stability in biological media as well as in vivo antitumor efficacy in melanoma xenograft model. TEM and DLS results confirmed the presence of paclitaxel-loaded nanosized micelles (6 to 12 nm), liposomes (123.31 ± 5.87 nm) and SLN (80.53 ± 5.37 nm). SLN demonstrated the slowest paclitaxel release rate and the highest stability in biological media compared to micelles and liposomes. Paclitaxel-loaded SLN demonstrated a statistically significant delay in tumor growth compared to mice treated with paclitaxel-loaded liposomes and paclitaxel-loaded micelles (p < 0.05). The results obtained in this study indicate the potential of SLN as drug delivery vehicles for anticancer therapy.

Porphyrin Centered Paclitaxel Tetrameric Prodrug Nanoassemblies as Tumor-Selective Theranostics for Synergized Breast Cancer Therapy.

Although having undergone decades of development, nanoparticulate drug delivery vehicles for efficient cancer therapy remain a challenge, confined by low drug loading, instability, and poor cancer tissue selectivity. A self-assembled prodrug, the combination of prodrug strategy and the self-assembly merits, represents a special chemical entity which spontaneously organizes into supramolecular composites with defined architecture, therefore also providing a strategy to develop new medications. Paclitaxel (PTX) is still among the most generally prescribed chemotherapeutics in oncology but is restricted by poor solubility. Although photodynamic therapy, with its noninvasive features and barely developed drug resistance, signifies an alternative tool to suppress life-threatening cancer, sole use hardly fulfills its potential. To this end, a reduction-activatable heterotetrameric prodrug with the photosensitizer is synthesized, then formulated into self-assembled nanoparticles (NPs) for tumor imaging and combined chemo- and photodynamic therapy. Coating the NPs with amphiphilic polymer distearylphosphatidylethanolamine-polyethylene glycol-arginine-glycine-aspartate (DSPE-PEG-RGD) offers high stability and enables cancer tissue targeting. The as-prepared NPs enlighten disease cells and reveal more potent cytotoxicity comparing to PTX and the photosensitizer alone. Furthermore, the NPs selectively accumulates into tumors and synergistically inhibits tumor proliferation with reduced side effects in mice.

Microfluidic Preparation of Gelatin Methacryloyl Microgels as Local Drug Delivery Vehicles for Hearing Loss Therapy.

Local drug delivery has become an effective method for disease therapy in fine organs including ears, eyes, and noses. However, the multiple anatomical and physiological barriers, unique clearance pathways, and sensitive perceptions characterizing these organs have led to suboptimal drug delivery efficiency. Here, we developed dexamethasone sodium phosphate-encapsulated gelatin methacryloyl (Dexsp@GelMA) microgel particles, with finely tunable size through well-designed microfluidics, as otic drug delivery vehicles for hearing loss therapy. The release kinetics, encapsulation efficiency, drug loading efficiency, and cytotoxicity of the GelMA microgels with different degrees of methacryloyl substitution were comprehensively studied to optimize the microgel formulation. Compared to bulk hydrogels, Dexsp@GelMA microgels of certain sizes hardly cause air-conducted hearing loss in vivo. Besides, strong adhesion of the microgels on the round window membrane was demonstrated. Moreover, the Dexsp@GelMA microgels, via intratympanic administration, could ameliorate acoustic noise-induced hearing loss and attenuate hair cell loss and synaptic ribbons damage more effectively than Dexsp alone. Our results strongly support the adhesive and intricate microfluidic-derived GelMA microgels as ideal intratympanic delivery vehicles for inner ear disease therapies, which provides new inspiration for microfluidics in drug delivery to the fine organs.

Advances in aptamer-based drug delivery vehicles for cancer therapy.

Overall, aptamers are special classes of nucleic acid-based macromolecules that are beginning to investigate because of their capability of avidity binding to a specific target for clinical use. Taking advantage of target-specific medicine led to more effective therapeutic and limitation of side effects of drugs. Herein, we discuss several aptamers and their binding capability and capacity for selecting tumor biomarkers and usage of them as targeting ligands for the functionalization of nanomaterials. We review recent applications based on aptamers and several nanoparticles to rise efficacy and develop carrier systems such as graphene oxide, folic acid, gold, mesopores silica, and various polymers and copolymer, polyethylene glycol, cyclodextrin, chitosan. The nanocarriers have been characterized by particle size, zeta potential, aptamer conjugation, and drug encapsulation efficiency. Hydrodynamic diameter and Zeta potential can used in order to monitor aptamers' crosslinking, in-vitro drug release, intracellular delivery of nanocarriers, and cellular cytotoxicity assay. Also, they are studied for cellular uptake and internalization to types of cancer cell lines such as colorectal, breast, prostate, leukemia and etc. The results are investigated in in-vivo cytotoxicity assay and cell viability assay. Targeted cancer therapy seems a good and promising strategy to overcome the systemic toxicity of chemotherapy.

Simulation study on the physicochemical properties of Fe3O4 nanoparticles as drug delivery vehicles for dopamine replacement therapy of Parkinson’s disease

A simulation study to investigate the physicochemical properties of Fe3O4 nanoparticles as a drug delivery vehicle for dopamine replacement therapy is done. Albumin is added as an additional permeation enabling molecule to successfully cross the blood-brain-barrier. Both PEGylated and non-PEGylated systems are investigated to report on the post-synthesis stability of these systems and discover pathways for NP hydrodynamic size tunability without compromising the NP stability. This is done for nanoparticle sizes varying from 1.0 to 7.0 nm and within a molecular dynamics study with a Monte Carlo simulated annealing scheme. Bonding modes are investigated with reference to chemisorption and physisorption in the context of bond strength (binding energy) as a function of the molecule (drug) loading on different sized nanoparticles.

Advances in the Synthesis and Application of Magnetic Ferrite Nanoparticles for Cancer Therapy.

Cancer is among the leading causes of mortality globally, with nearly 10 million deaths in 2020. The emergence of nanotechnology has revolutionised treatment strategies in medicine, with rigorous research focusing on designing multi-functional nanoparticles (NPs) that are biocompatible, non-toxic, and target-specific. Iron-oxide-based NPs have been successfully employed in theranostics as imaging agents and drug delivery vehicles for anti-cancer treatment. Substituted iron-oxides (MFe2O4) have emerged as potential nanocarriers due to their unique and attractive properties such as size and magnetic tunability, ease of synthesis, and manipulatable properties. Current research explores their potential use in hyperthermia and as drug delivery vehicles for cancer therapy. Significantly, there are considerations in applying iron-oxide-based NPs for enhanced biocompatibility, biodegradability, colloidal stability, lowered toxicity, and more efficient and targeted delivery. This review covers iron-oxide-based NPs in cancer therapy, focusing on recent research advances in the use of ferrites. Methods for the synthesis of cubic spinel ferrites and the requirements for their considerations as potential nanocarriers in cancer therapy are discussed. The review highlights surface modifications, where functionalisation with specific biomolecules can deliver better efficiency. Finally, the challenges and solutions for the use of ferrites in cancer therapy are summarised.

Engineered exosome as targeted lncRNA MEG3 delivery vehicles for osteosarcoma therapy

Exosomes as nanosized membrane vesicles, could targeted deliver therapeutic agents by modification with target ligands. Exosome-derived non-coding RNAs play a vital role in the development of tumors. Previous evidences reveal that long non-coding RNA maternally expressed gene 3 (lncRNA MEG3) has anti-tumor properties. Whereas, the inhibitory effects of exosome-derived lncRNA MEG3 in osteosarcoma (OS) remain largely unknown. In this study, we utilize the engineering technology to combine exosome and lncRNA for tumor-targeting therapy of OS. We elucidated the anti-OS effects of lncRNA MEG3, and then prepared the c(RGDyK)-modified and MEG3-loaded exosomes (cRGD-Exo-MEG3). The engineered exosomes cRGD-Exo-MEG3 could deliver more efficiently to OS cells both in vitro and in vivo. In this way, cRGD-Exo-MEG3 facilitate the anti-OS effects of MEG3 significantly, with the help of enhanced tumor-targeting therapy. This study elucidates that engineered exosomes as targeted lncRNA MEG3 delivery vehicles have potentially therapeutic effects for OS.

Simulation Study on the Physicochemical Properties of Fe3o4 Nanoparticles as Drug Delivery Vehicles for Dopamine Replacement Therapy of Parkinson's Disease

Simulation Study on the Physicochemical Properties of Fe3o4 Nanoparticles as Drug Delivery Vehicles for Dopamine Replacement Therapy of Parkinson's Disease

Nonviral siRNA delivery systems for pancreatic cancer therapy.

The serious drawbacks of the conventional treatment of pancreatic ductal adenocarcinoma (PDAC) such as nonspecific toxicity and high resistance to chemo and radiation therapy, have prompted the development and application of countless small interfering RNA (siRNA)-based therapeutics. Recent advances in drug delivery systems hold great promise for improving siRNA-based therapeutics and developing a new class of drugs, known as nano-siRNA drugs. However, many fundamental questions, regarding toxicity, immunostimulation, and poor knowledge of nano-bio interactions, need to be addressed before clinical translation. In this review, we provide recent achievements in the design and development of various nonviral delivery vehicles for pancreatic cancer therapy. More importantly, codelivery of conventional anticancer drugs with siRNA as a new revolutionary pancreatic cancer combinational therapy is completely discussed.

Mesenchymal Stem Cells-Derived Exosomes as Dexamethasone Delivery Vehicles for Autoimmune Hepatitis Therapy.

Exosomes (Exos) are nanosized vesicles (around 100 nm) that recently serve as a promising drug carrier with high biocompatibility and low immunogenicity. Previous studies showed that Exos secreted from mesenchymal stem cells (MSCs) provide protection for concanavalin A (Con A)-induced liver injury. In this study, the protective effect of Exos is confirmed, and dexamethasone (DEX)-incorporated Exos named Exo@DEX are prepared. It is then investigated whether Exo@DEX can function more efficiently compared to free drugs and naive Exos in a Con A-induced autoimmune hepatitis (AIH) mouse model. The results show that Exo@DEX efficiently improves the accumulation of DEX in AIH in the liver. These data suggest that Exo@DEX is a promising drug carrier for AIH and could have applications in other diseases.

Recent Targeted of siRNA Delivery Vehicles for Cancer Therapy

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