ABSTRACT
A glucose-responsive insulin delivery system that sustains blood glucose equilibrium for an extended duration can address the low therapeutic window of insulin in diabetes treatment. Herein, insulin is loaded in a water-in-oil-in-water (W1/O/W2) gelled multiple emulsion using poly (4-vinylphenylboronic acid) (PVPBA) homopolymer as an effective emulsifier. The gelled multiple emulsion exhibits a high encapsulation efficiency (99%), enhanced stability and remarkable shear-thinning behavior, making it easy to inject. Under hyperglycemic conditions, the gelled emulsion system instantly binds to glucose molecules and reduces the hydrogen bonds of the PVPBA homopolymer, resulting in insulin release. In a streptozotocin-induced type 1 diabetic mouse model, a single subcutaneous injection of the gelled emulsion rapidly responds to high blood glucose concentration (BGC) and release insulin in a glucose dependent manner, thus prolonging the antihyperglycemic effect compared with free insulin.
ABSTRACT
Kirsten rat sarcoma (KRAS) is the most commonly mutated oncogene in lung cancers. Gene therapy is emerging as a promising cancer treatment modality; however, the systemic administration of gene therapy has been limited by inefficient delivery to the lungs and systemic toxicity. Herein, we report a noninvasive aerosol inhalation nanoparticle (NP) system, termed "siKRAS@GCLPP NPs," to treat KRAS-mutant non-small-cell lung cancer (NSCLC). The self-assembled siKRAS@GCLPP NPs are capable of maintaining structural integrity during nebulization, with preferential distribution within the tumor-bearing lung. Inhalable siKRAS@GCLPP NPs show not only significant tumor-targeting capability but also enhanced antitumor activity in an orthotopic mouse model of human KRAS-mutant NSCLC. The nebulized delivery of siKRAS@GCLPP NPs demonstrates potent knockdown of mutated KRAS in tumor-bearing lungs without causing any observable adverse effects, exhibiting a better biosafety profile than the systemic delivery approach. The results present a promising inhaled gene therapy approach for the treatment of KRAS-mutant NSCLC and other respiratory diseases.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Nanoparticles , Mice , Animals , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , RNA, Small Interfering/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Nanoparticles/chemistry , Mutation , Cell Line, TumorABSTRACT
Gene therapy holds tremendous potential for the treatment of incurable brain diseases including Alzheimer's disease (AD), stroke, glioma, and Parkinson's disease. The main challenge is the lack of effective gene delivery systems traversing the blood-brain barrier (BBB), due to the complex microvessels present in the brain which restrict substances from the circulating blood passing through. Recently, increasing efforts have been made to develop promising gene carriers for brain-related disease therapies. One such development is the self-assembled heavy chain ferritin (HFn) nanoparticles (NPs). HFn NPs have a unique hollow spherical structure that can encapsulate nucleic acid drugs (NADs) and specifically bind to cancer cells and BBB endothelial cells (BBB ECs) via interactions with the transferrin receptor 1 (TfR1) overexpressed on their surfaces, which increases uptake through the BBB. However, the gene-loading capacity of HFn is restricted by its limited interior volume and negatively charged inner surface; therefore, these drawbacks have prompted the demand for strategies to remould the structure of HFn. In this work, we analyzed the three-dimensional (3D) structure of HFn using Chimera software (v 1.14) and developed a class of internally cationic HFn variants (HFn+ NPs) through arginine mutation on the lumenal surface of HFn. These HFn+ NPs presented powerful electrostatic forces in their cavities, and exhibited higher gene encapsulation efficacy than naive HFn. The top-performing candidate, HFn2, effectively delivered siRNA to glioma cells after traversing the BBB and achieved the highest silencing efficacy among HFn+ NPs. Overall, our findings demonstrate that HFn+ NPs obtained by this genetic engineering method provide critical insights into the future development of nucleic acid delivery carriers with BBB-crossing ability.
Subject(s)
Glioma , Nanoparticles , Animals , Apoferritins/pharmacology , Blood-Brain Barrier/metabolism , Drug Delivery Systems , Endothelial Cells/metabolism , Glioma/drug therapy , Mice , Nanoparticles/therapeutic use , RNA, Small Interfering/metabolismABSTRACT
Abstract The modern process of new drug discovery and development is an exciting, yet a challenging, endeavor. Although it can result in significant financial income and meet the medical needs of patients, it ultimately may result in failure. To achieve a fast and successful new product discovery and development process, natural products which are evolutionarily optimized as drug-like molecules have gained great attention as better potential sources of new chemical entities. Historically, plant species containing berberine are used in various traditional phytotherapy. However, despite the various therapeutic effects it exerts, berberine is not yet developed into a drug product. Addressing the barriers that hinder its successful development and the efforts made to overcome them is thus crucial. The toxicological and pharmacokinetic properties of berberine are the main barriers towards its development into a marketed drug product. It has low aqueous solubility, poor absorption, fast metabolism, and wide tissue distribution which lead to low bioavailability limiting its clinical application. Synthetic berberine derivatives with improved properties are suggested as better alternatives for further development and future therapeutic application. Hence, this paper summarizes the preclinical research studies conducted in the last decade to reveal the therapeutic potential of synthetic berberine derivatives for the treatment of various diseases and hence achieve successful berberine-based drug development in the future. To exploit the value of natural products as a source of leads for the development of effective drugs, collaboration among the different discovery and development scientists is essential.
ABSTRACT
Osteoarthritis (OA), a chronic and degenerative joint disease, remains a challenge in treatment due to the lack of disease-modifying therapies. As a promising therapeutic agent, adipose-derived stem cells (ADSCs) have an effective anti-inflammatory and chondroprotective paracrine effect that can be enhanced by genetic modification. Unfortunately, direct cell delivery without matrix support often results in poor viability of therapeutic cells. Herein, a hydrogel implant approach that enabled intra-articular delivery of gene-engineered ADSCs was developed for improved therapeutic outcomes in a surgically induced rat OA model. An injectable extracellular matrix (ECM)-mimicking hydrogel was prepared as the carrier for cell delivery, providing a favorable microenvironment for ADSC spreading and proliferation. The ECM-mimicking hydrogel could reduce cell death during and post injection. Additionally, ADSCs were genetically modified to overexpress transforming growth factor-ß1 (TGF-ß1), one of the paracrine factors that exert an anti-inflammatory and pro-anabolic effect. The gene-engineered ADSCs overexpressing TGF-ß1 (T-ADSCs) had an enhanced paracrine effect on OA-like chondrocytes, which effectively decreased the expression of tumor necrosis factor-alpha and increased the expression of collagen II and aggrecan. In a surgically induced rat OA model, intra-articular injection of the T-ADSC-loaded hydrogel markedly reduced cartilage degeneration, joint inflammation, and the loss of the subchondral bone. Taken together, this study provides a potential biomaterial strategy for enhanced OA treatment by delivering the gene-engineered ADSCs within an ECM-mimicking hydrogel.
Subject(s)
Hydrogels , Osteoarthritis , Adipocytes , Adipose Tissue , Animals , Osteoarthritis/therapy , Rats , Stem CellsABSTRACT
Prolonged, intense inflammation and excessive oxidative stress hinder diabetic wounds from healing normally, leading to disorders downstream including the postponement of re-epithelialization and extracellular matrix (ECM) formation. Herein, we report a hyaluronic acid (HA) and chitosan based hydrogel (OHA-CMC) with inherent antibacterial and hemostatic activities fabricated via Schiff base reaction. By encapsulating nanotechnologically-modified curcumin (CNP) and epidermal growth factor (EGF) into the hydrogel, OHA-CMC/CNP/EGF exhibited extraordinary antioxidant, anti-inflammatory, and migration-promoting effects in vitro. Meanwhile, OHA-CMC/CNP/EGF presented on-demand drug release in synchrony with the phases of the wound healing process. Specifically, curcumin was rapidly and constantly released to alleviate inflammation and oxidative stress in the early phase of wound healing, while a more gradual and sustained release of EGF supported late proliferation and ECM remodeling. In a diabetic full-thickness skin defect model, OHA-CMC/CNP/EGF dramatically improved wound healing with ideal re-epithelialization, granulation tissue formation, and skin appendage regeneration, highlighting the enormous therapeutic potential this biomaterial holds as a diabetic wound dressing.
ABSTRACT
Cardiovascular diseases (CVDs) remain one of the major causes of mortality worldwide. In response to this and other worldwide health epidemics, nanomedicine has emerged as a rapidly evolving discipline that involves the development of innovative nanomaterials and nanotechnologies and their applications in therapy and diagnosis. Nanomedicine presents unique advantages over conventional medicines due to the superior properties intrinsic to nanoscopic therapies. Once used mainly for cancer therapies, recently, tremendous progress has been made in nanomedicine that has led to an overall improvement in the treatment and diagnosis of CVDs. This review elucidates the pathophysiology and potential targets of atherosclerosis and associated ischemic diseases. It may be fruitful to pursue future work in the nanomedicine-mediated treatment of CVDs based on these targets. A comprehensive overview is then provided featuring the latest preclinical and clinical outcomes in cardiovascular imaging, biomarker detection, tissue engineering, and nanoscale delivery, with specific emphasis on nanoparticles, nanostructured scaffolds, and nanosensors. Finally, the challenges and opportunities regarding the future development and clinical translation of nanomedicine in related fields are discussed. Overall, this review aims to provide a deep and thorough understanding of the design, application, and future development of nanomedicine for atherosclerosis and related ischemic diseases.
Subject(s)
Atherosclerosis , Nanoparticles , Atherosclerosis/drug therapy , Atherosclerosis/therapy , Drug Delivery Systems , Humans , Nanomedicine , Nanoparticles/therapeutic use , NanotechnologyABSTRACT
Macrophages are attractive therapeutic targets due to their contributions to many pathological processes including cancers, atherosclerosis, obesity, diabetes and other inflammatory diseases. Macrophage-targeted gene therapy is an effective strategy for regulating macrophage function at the site of inflammation to treat related diseases. However, macrophages are recognized as difficult to transfect cells and non-specific delivery would inevitably cause unwanted systemic side effects. Herein, we prepared a series of macrophage-targeted nanoparticles (NPs) using cationic lipid-like compound G0-C14 and different carbohydrates-modified poly(lactide-co-glycolide) (PLGA) or poly(lactide-coglycolide)-b-poly(ethylene glycol) (PLGA-PEG) for gene delivery by a robust self-assembly method. The yielded NPs were decorated with carbohydrate-based targeting moieties including mannose, galactose, dextran, and a mixture of mannose and galactose. EGFP messenger RNA (mRNA) and GFP plasmid DNA (pDNA) were used as reporter genes to evaluate NP-mediated gene transfection in macrophages. Experimental results of macrophage phagocytosis demonstrated that more carbohydrate-decorated NPs were endocytosed by Raw 264.7 cells than the ones without carbohydrate modification. Mannose-decorated NPs showed better targeting ability to macrophages than NPs decorated with galactose only and a blended mixture of mannose and galactose. It is worth noting that polysaccharide dextran-modified NPs also exhibited evident targeting effects. CCK-8 assay revealed that no cytotoxicity was observed for all tested NP concentrations up to 2.8 mg/mL. The carbohydrate-decorated polymer/G0-C14 exhibited strong entrapment of mRNA and pDNA with an encapsulation efficiency of above 95%. The targeted NPs significantly improved cellular internalization and transfection efficiency in macrophages, depending on the type and content of the carbohydrate moieties presented on the NP surface. Interestingly, dextran-decorated NPs showing higher endocytosis at various concentrations in macrophages also demonstrated more efficient mRNA transfection, suggesting that the NP-mediated mRNA transfection efficiency was consistent with the endocytosis results.
Subject(s)
Nanoparticles , Carbohydrates , Genetic Therapy , Macrophages , Polyethylene GlycolsABSTRACT
The hydrophobicity of bioactive molecules poses a considerable problem in the pharmaceutical and the food industry. Using food-based protein nanocarriers is one promising way to deliver hydrophobic molecules. These types of protein possess many functional properties such as surface activity, water-binding capacity, emulsification, foaming, gelation, and antioxidant activity, as well as their incorporation in the food industry as ingredients. Besides, they express low toxicity, are less expensive compared to synthetic polymers, and are biodegradable. This review aims to give a brief overview of the recent studies done using food proteins as colloidal delivery systems for hydrophobic and poorly soluble compounds.
Subject(s)
Dietary Proteins/administration & dosage , Dietary Proteins/chemistry , Drug Delivery Systems/methods , Hydrophobic and Hydrophilic Interactions/drug effects , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Animals , Drug Delivery Systems/trends , Gels , Humans , Polymers/administration & dosage , Polymers/chemistry , Solubility , WaterABSTRACT
Glaucoma is considered a leading cause of blindness with the human eye being one of the body's most delicate organs. Ocular diseases encompass diverse diseases affecting the anterior and posterior ocular sections, respectively. The human eye's peculiar and exclusive anatomy and physiology continue to pose a significant obstacle to researchers and pharmacologists in the provision of efficient drug delivery. Though several traditional invasive and noninvasive eye therapies exist, including implants, eye drops, and injections, there are still significant complications that arise which may either be their low bioavailability or the grave ocular adverse effects experienced thereafter. On the other hand, new nanoscience technology and nanotechnology serve as a novel approach in ocular disease treatment. In order to interact specifically with ocular tissues and overcome ocular challenges, numerous active molecules have been modified to react with nanocarriers. In the general population of glaucoma patients, disease growth and advancement cannot be contained by decreasing intraocular pressure (IOP), hence a spiking in future research for novel drug delivery systems and target therapeutics. This review focuses on nanotechnology and its therapeutic and diagnostic prospects in ophthalmology, specifically glaucoma. Nanotechnology and nanomedicine history, the human eye anatomy, research frontiers in nanomedicine and nanotechnology, its imaging modal quality, diagnostic and surgical approach, and its possible application in glaucoma will all be further explored below. Particular focus will be on the efficiency and safety of this new therapy and its advances.
Subject(s)
Glaucoma/drug therapy , Intraocular Pressure/drug effects , Nanomedicine/methods , Animals , Biological Availability , Drug Delivery Systems/methods , Drug Implants/adverse effects , Drug Implants/chemistry , Drug Liberation/genetics , Humans , Intraocular Pressure/physiology , Mice , Rabbits , Tomography, Optical Coherence , Trabecular Meshwork/cytology , Trabecular Meshwork/drug effects , Trabecular Meshwork/transplantationABSTRACT
Cisplatin cis-(diammine)dichloridoplatinum(II) (CDDP) is the first platinum-based complex approved by the food and drug administration (FDA) of the United States (US). Cisplatin is the first line chemotherapeutic agent used alone or combined with radiations or other anti-cancer agents for a broad range of cancers such as lung, head and neck. Aroplatin™, Lipoplatin™ and SPI-077 are PEGylated liposome-based nano-formulations that are still under clinical trials. They have many limitations, for example, poor aqueous solubility, drug resistance and toxicities, which can be overcome by encapsulating the cisplatin in Nemours nanocarriers. The extensive literature from different electronic databases covers the different nano-delivery systems that are developed for cisplatin. This review critically emphasizes on the recent advancement, development, innovations and updated literature reported for different carrier systems for CDDP.
Subject(s)
Cisplatin/chemistry , Drug Carriers/chemistry , Nanomedicine/methods , Nanostructures/chemistry , Neoplasms/drug therapy , Animals , Cisplatin/therapeutic use , HumansABSTRACT
Carbon dots are a carbonaceous nanomaterial that were discovered accidentally and are now drawing significant attention as a new quantum-sized fluorescent nanoparticle. Carbon dots are biocompatible, non-toxic, photostable, and easily functionalized with good photoluminescence and water solubility. Due to these unique properties, they are used broadly in live cell imaging, catalysis, electronics, biosensing, power, targeted drug delivery, and other biomedical applications. Here, we review the recent development of carbon dots in nanomedicine from their use in drug carriers to imaging agents to multifunctional theranostic systems. Finally, we discuss the challenges and views on next-generation carbon dot-based theranostics for clinical applications.
Subject(s)
Carbon/therapeutic use , Nanostructures/therapeutic use , Theranostic Nanomedicine , Animals , Biomarkers/metabolism , Cell Membrane/metabolism , Cytoplasm/metabolism , Diagnostic Imaging , Humans , Neoplasms/diagnosis , Neoplasms/therapyABSTRACT
Mesoporous silica nanomaterials (MSNs) have made remarkable achievements and are being thought of by researchers as materials that can be used to effect great change in cancer therapies, gene delivery, and drug delivery because of their optically transparent properties, flexible size, functional surface, low toxicity profile, and very good drug loading competence. Mesoporous silica nanoparticles (MSNPs) show a very high loading capacity for therapeutic agents. It is well known that cancer is one of the most severe known medical conditions, characterized by cells that grow and spread rapidly. Thus, curtailing cancer is one of the greatest current challenges for scientists. Nanotechnology is an evolving field of study, encompassing medicine, engineering, and science, and it has evolved over the years with respect to cancer therapy. This review outlines the applications of mesoporous nanomaterials in the field of cancer theranostics, as well as drug and gene delivery. MSNs employed as therapeutic agents, as well as their importance and future prospects in the ensuing generation of cancer theranostics and drug and therapeutic gene delivery, are discussed herein. Thus, the use of mesoporous silica nanomaterials can be seen as using one stone to kill three birds.
ABSTRACT
Hydrogels evolved as an outstanding carrier material for local and controlled drug delivery that tend to overcome the shortcomings of old conventional dosage forms for small drugs (NSAIDS) and large peptides and proteins. The aqueous swellable and crosslinked polymeric network structure of hydrogels is composed of various natural, synthetic and semisynthetic biodegradable polymers. Hydrogels have remarkable properties of functionality, reversibility, sterilizability, and biocompatibility. All these dynamic properties of hydrogels have increased the interest in their use as a carrier for peptides and proteins to be released slowly in a sustained manner. Peptide and proteins are remarkable therapeutic agents in today's world that allow the treatment of severe, chronic and life-threatening diseases, such as diabetes, rheumatoid arthritis, hepatitis. Despite few limitations, hydrogels provide fine tuning of proteins and peptides delivery with enormous impact in clinical medicine. Novels drug delivery systems composed of smart peptides and molecules have the ability to drive self-assembly and form hydrogels at physiological pH. These hydrogels are significantly important for biological and medical fields. The primary objective of this article is to review current issues concerned with the therapeutic peptides and proteins and impact of remarkable properties of hydrogels on these therapeutic agents. Different routes for pharmaceutical peptides and proteins and superiority over other drugs candidates are presented. Recent advances based on various approaches like self-assembly of peptides and small molecules to form novel hydrogels are also discussed. The article will also review the literature concerning the classification of hydrogels on a different basis, polymers used, "release mechanisms" their physical and chemical characteristics and diverse applications.