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International Journal of Nanomedicine 2022The objective of this study was to investigate the antitumor activity, targeting capability, and mechanism of the developed nanodrug consisting of doxorubicin and...
PURPOSE
The objective of this study was to investigate the antitumor activity, targeting capability, and mechanism of the developed nanodrug consisting of doxorubicin and exosome (Exo-Dox) derived from mesenchymal stem cells in vitro and in vivo.
METHODS
The exosomes were isolated with Exosome Isolation Kit, and the Exo-Dox was prepared by mixing exosome with Dox-HCl, desalinizing with triethylamine and then dialyzing against PBS overnight. The exosome and Exo-Dox were examined by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). The antitumor activity, targeting capability, and mechanism of the developed Exo-Dox were evaluated by cell viability assay, histological and immunofluorescence analysis and in vivo imaging system.
RESULTS
NTA results showed the size of the exosomes had increased from 141.6 nm to 178.1 nm after loading with doxorubicin. Compared with free Dox, the Exo-Dox exhibited higher cytotoxicity against osteosarcoma MG63 cells, HOS cells, and 143B cells than free Dox, the half-maximal inhibitory concentrations (IC50) of Dox, Exo-Dox were calculated to be 0.178 and 0.078 μg mL in MG63 cells, 0.294 and 0.109μg mL in HOS cells, 0.315 and 0.123 μg mL in 143B cells, respectively. The in vivo imaging showed that MSC derived Exo could serve as a highly efficient delivery vehicle for targeted drug delivery. The immunohistochemistry and histology analysis indicated that compared with the free Dox group, the Ki67-positive cells and cardiotoxicity in Exo-Dox group were significantly decreased.
CONCLUSION
Our results suggested that MSC-derived Exo could be excellent nanocarriers used to deliver chemotherapeutic drug Dox specifically and efficiently in osteosarcoma, resulting in enhanced toxicity against osteosarcoma and less toxicity in heart tissue. We further demonstrated the targeting capability of Exo was due to the chemotaxis of MSC-derived exosomes to osteosarcoma cells via SDF1-CXCR4 axis.
Topics: Bone Neoplasms; Cell Line, Tumor; Doxorubicin; Excipients; Exosomes; Humans; Mesenchymal Stem Cells; Nanoparticles; Osteosarcoma; Receptors, CXCR4
PubMed: 35959282
DOI: 10.2147/IJN.S372851 -
International Journal of Pharmaceutics Oct 2020A handful of singular structures and laws can be observed in nature. They are not always evident but, once discovered, it seems obvious how to take advantage of them. In... (Review)
Review
A handful of singular structures and laws can be observed in nature. They are not always evident but, once discovered, it seems obvious how to take advantage of them. In chemistry, the discovery of reproducible patterns stimulates the imagination to develop new functional materials and technological or medical applications. Two clear examples are helical structures at different levels in biological polymers as well as ring and spherical structures of different size and composition. Rings are intuitively observed as holes able to thread elongated structures. A large number of real and fictional stories have rings as inanimate protagonists. The design, development or just discovering of a special ring has often been taken as a symbol of power or success. Several examples are the Piscatory Ring wore by the Pope of the Catholic Church, the NBA Championship ring and the One Ring created by the Dark Lord Sauron in the epic story The Lord of the Rings. In this work, we reveal the power of another extremely powerful kind of rings to fight against the pandemic which is currently affecting the whole world. These rings are as small as ~1 nm of diameter and so versatile that they are able to participate in the attack of viruses, and specifically SARS-CoV-2, in a large range of different ways. This includes the encapsulation and transport of specific drugs, as adjuvants to stabilize proteins, vaccines or other molecules involved in the infection, as cholesterol trappers to destabilize the virus envelope, as carriers for RNA therapies, as direct antiviral drugs and even to rescue blood coagulation upon heparin treatment. "One ring to rule them all. One ring to find them. One ring to bring them all and in the darkness bind them." J. R. R. Tolkien.
Topics: Betacoronavirus; Blood Coagulation; COVID-19; Coronavirus Infections; Cyclodextrins; Drug Carriers; Drug Stability; Excipients; Nanostructures; Pandemics; Pneumonia, Viral; SARS-CoV-2; Viral Vaccines
PubMed: 32717282
DOI: 10.1016/j.ijpharm.2020.119689 -
International Journal of Pharmaceutics Mar 2019In pharmaceutical technology, lipids and polymers are considered pillar excipients for the fabrication of most dosage forms, irrespective of the administration route.... (Review)
Review
In pharmaceutical technology, lipids and polymers are considered pillar excipients for the fabrication of most dosage forms, irrespective of the administration route. They play various roles ranging from support vehicles to release rate modifiers, stabilizers, solubilizers, permeation enhancers and transfection agents. Focusing on selected applications, which were discussed at the Annual Scientific Meeting of the Gattefossé Foundation 2018, this manuscript recapitulates the fundamental roles of these two important classes of excipients, either employed alone or in combination, and provides insight on their functional properties in various types of drug formulations. Emphasis is placed on oral formulations for the administration of active pharmaceutical ingredients with low aqueous solubilities or poor permeation properties. Additionally, this review article covers the use of lipids and polymers in the design of colloidal injectable delivery systems, and as substrates in additive manufacturing technologies for the production of tailor-made dosage forms.
Topics: Administration, Oral; Animals; Dosage Forms; Drug Carriers; Excipients; Humans; Lipids; Nanoparticles; Polymers; Printing, Three-Dimensional; Technology, Pharmaceutical
PubMed: 30639218
DOI: 10.1016/j.ijpharm.2018.12.080 -
Biomedicine & Pharmacotherapy =... Jul 2023No medical interventions for noise induced hearing loss (NIHL) are approved by the Food and Drug Administration (USA). Here, we evaluate statins in CBA/CaJ mice as...
No medical interventions for noise induced hearing loss (NIHL) are approved by the Food and Drug Administration (USA). Here, we evaluate statins in CBA/CaJ mice as potential drugs for hearing loss. Direct delivery of fluvastatin to the cochlea and oral delivery of lovastatin were evaluated. Baseline hearing was assessed using Auditory Brain Stem Responses (ABRs). For fluvastatin, a cochleostomy was surgically created in the basal turn of the cochlea by a novel, laser-based procedure, through which a catheter attached to a mini-osmotic pump was inserted. The pump was filled with a solution of 50 µM fluvastatin+carrier or with the carrier alone for continuous delivery to the cochlea. Mice were exposed to one octave band noise (8-16 kHz x 2 h x 110 dB SPL). In our past work with guinea pigs, fluvastatin protected in the contralateral cochlea. In this study in CBA/CaJ mice, hearing was also assessed in the contralateral cochlea 1-4 weeks after noise exposure. At two weeks post exposure, ABR thresholds at 4, 8, 12, 16, and 32 kHz were elevated, as expected, in the noise+carrier alone treated mice by approximately 9-, 17-, 41-, 29-, and 34-dB, respectively. Threshold elevations were smaller in mice treated with noise+fluvastatin to about 2-, 6-, 20-,12- and 12-dB respectively. Survival of inner hair cell synapses were not protected by fluvastatin over these frequencies. Lovastatin delivered by gavage showed lower threshold shifts than with carrier alone. These data show that direct and oral statin delivery protects mice against NIHL.
Topics: United States; Mice; Animals; Guinea Pigs; Mice, Inbred CBA; Hearing Loss, Noise-Induced; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Fluvastatin; Lovastatin; Excipients
PubMed: 37435721
DOI: 10.1016/j.biopha.2023.114674 -
Advanced Drug Delivery Reviews Jul 2021Protein therapeutics carry inherent limitations of membrane impermeability and structural instability, despite their predominant role in the modern pharmaceutical... (Review)
Review
Protein therapeutics carry inherent limitations of membrane impermeability and structural instability, despite their predominant role in the modern pharmaceutical market. Effective formulations are needed to overcome physiological and physicochemical barriers, respectively, for improving bioavailability and stability. Knowledge of membrane affinity, cellular internalization, encapsulation, and release of drug-loaded carrier vehicles uncover the structural basis for designing and optimizing biopharmaceuticals with enhanced delivery efficiency and therapeutic efficacy. Understanding stabilizing and destabilizing interactions between protein drugs and formulation excipients provide fundamental mechanisms for ensuring the stability and quality of biological products. This article reviews the molecular studies of biologics using solution and solid-state NMR spectroscopy on structural attributes pivotal to drug delivery and stability. In-depth investigation of the structure-function relationship of drug delivery systems based on cell-penetrating peptides, lipid nanoparticles and polymeric colloidal, and biophysical and biochemical stability of peptide, protein, monoclonal antibody, and vaccine, as the integrative efforts on drug product design, will be elaborated.
Topics: Animals; Biological Availability; Biological Products; Drug Carriers; Drug Delivery Systems; Drug Design; Drug Stability; Excipients; Humans; Magnetic Resonance Spectroscopy; Proteins
PubMed: 33609600
DOI: 10.1016/j.addr.2021.02.007 -
Acta Poloniae Pharmaceutica 2011Interest in use of the polysaccharide chitosan as a pharmaceutical excipient by different dose routes and for a number of applications is not new but it still does not... (Review)
Review
Interest in use of the polysaccharide chitosan as a pharmaceutical excipient by different dose routes and for a number of applications is not new but it still does not appear to be present in any marketed drugs. Also a novel excipient in a new formulation requires a lot of safety consideration. Published literature showed that chitosan has low oral toxicity and prior human exposure has occurred through use in dietary supplements and food additive, medical device and cosmetic applications. Although systemic exposure to chitosan may be limited, this needs a more careful assessment of its safety as a parenteral excipient. Chitosan has local biological activity in the form of hemostatic action, facilitates platelet adhesion, cholesterol lowering and weight management. Chitosan has become an upcoming research area as a novel excipient in controlled drug delivery, which necessitates us to get an overall information about it.
Topics: Animals; Chemistry, Pharmaceutical; Chitosan; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Excipients; Humans
PubMed: 21928704
DOI: No ID Found -
Pharmaceutics Dec 2022Liposomes can increase plasma half-life, enhance targeting, and diminish the side-effects of loaded drugs. On the downside, physical and chemical instabilities of...
UNLABELLED
Liposomes can increase plasma half-life, enhance targeting, and diminish the side-effects of loaded drugs. On the downside, physical and chemical instabilities of dispersions often result in a reduced lifespan, which limits their availability on the market. Solid formulations obtained by freeze-drying can immobilize vesicles and provide extended shelf life. For both processes, the choice of excipients and process parameters are crucial to protect the carrier layers against tension caused by freezing and/or dehydration. The aim of this work is to evaluate the influence of freezing and drying parameters, besides excipient choice, to obtain solid long-circulating and fusogenic liposomes (LCFL-PTX/DXR) co-encapsulating paclitaxel (PTX) and doxorubicin (DXR) at a synergistic ratio (1:10).
METHODS
LCFL-PTX/DXR was evaluated by freeze-drying microscopy (glass transition, Tg'), differential scanning calorimetry (collapse temperature, Tc), freeze-thawing and freeze-drying processes. Freeze-dried samples were evaluated by thermogravimetry (residual moisture) and the resuspended liposomes were characterized in terms of size, polydispersity index (PI), zeta potential (ZP), and drug content. Liposomes morphology was evaluated by cryomicroscopy.
RESULTS
Trehalose protected PTX cargo upon freeze-thawing and more than 80% of the original DXR retention. The formulations with trehalose resulted in a cake with 5-7% of moisture content (200-240 nm); 44-60% of PTX retention, and 25-35% of DXR retention, with the variations caused by cryoprotector concentration and process changes.
CONCLUSIONS
Trehalose protected liposome integrity, maintaining PTX retention and most of DXR upon freeze-thawing. Freeze-drying reduced the retention of both drugs inside all liposomes, whereas formulation with trehalose presented minor losses. Therefore, this frozen formulation is an alternative product option, with no need for manipulation before use.
PubMed: 36678715
DOI: 10.3390/pharmaceutics15010086 -
Molecules (Basel, Switzerland) Jun 2021Pluronic polymers (pluronics) are a unique class of synthetic triblock copolymers containing hydrophobic polypropylene oxide (PPO) and hydrophilic polyethylene oxide... (Review)
Review
Pluronic polymers (pluronics) are a unique class of synthetic triblock copolymers containing hydrophobic polypropylene oxide (PPO) and hydrophilic polyethylene oxide (PEO) arranged in the PEO-PPO-PEO manner. Due to their excellent biocompatibility and amphiphilic properties, pluronics are an ideal and promising biological material, which is widely used in drug delivery, disease diagnosis, and treatment, among other applications. Through self-assembly or in combination with other materials, pluronics can form nano carriers with different morphologies, representing a kind of multifunctional pharmaceutical excipients. In recent years, the utilization of pluronic-based multi-functional drug carriers in tumor treatment has become widespread, and various responsive drug carriers are designed according to the characteristics of the tumor microenvironment, resulting in major progress in tumor therapy. This review introduces the specific role of pluronic-based polymer drug delivery systems in tumor therapy, focusing on their physical and chemical properties as well as the design aspects of pluronic polymers. Finally, using newer literature reports, this review provides insights into the future potential and challenges posed by different pluronic-based polymer drug delivery systems in tumor therapy.
Topics: Drug Carriers; Drug Delivery Systems; Humans; Hydrophobic and Hydrophilic Interactions; Neoplasms; Poloxamer; Polyethylene Glycols; Polymers; Polypropylenes; Propylene Glycols; Tumor Microenvironment
PubMed: 34204668
DOI: 10.3390/molecules26123610 -
International Journal of Pharmaceutics Sep 2020How prevalent are peptide therapeutic products? How innovative are the formulations used to deliver peptides? This review provides a critical analysis of therapeutic... (Review)
Review
How prevalent are peptide therapeutic products? How innovative are the formulations used to deliver peptides? This review provides a critical analysis of therapeutic peptide products and the formulations approved by the United States Food and Drug administration (FDA), the European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). This review also provides an in-depth analysis of dosage forms and administration routes for delivering peptide therapeutics, including injectables, oral dosage forms, and other routes of administration. We discuss the function of excipients in parenteral formulations in detail, since most peptide therapeutics are parenterally administered. We provide case studies of alternate delivery routes and dosage forms. Based on our analysis, therapeutic peptides administered as injectables remain the most commonly used dosage forms, particularly in the form of subcutaneous, intravenous, or intramuscular injections. In addition, therapeutic peptides are formulated to achieve prolonged release, often through the use of polymer carriers. The limited number of oral therapeutic peptide products and their poor absorption and subsequent low bioavailability indicate a need for new technologies to broaden the formulation design space. Therapeutic peptide products may also be delivered through other administration routes, including intranasal, implant, and sublingual routes. Therefore, an in-depth understanding of how therapeutic peptides are now formulated and administered is essential to improve peptide delivery, improve patient compliance, and reduce the healthcare burden for these crucial therapeutic agents.
Topics: Administration, Intranasal; Administration, Oral; Drug Delivery Systems; Excipients; Humans; Peptides; United States
PubMed: 32622810
DOI: 10.1016/j.ijpharm.2020.119491 -
Lignin as a Natural Carrier for the Efficient Delivery of Bioactive Compounds: From Waste to Health.Molecules (Basel, Switzerland) Jun 2022Lignin is a fascinating aromatic biopolymer with high valorization potentiality. Besides its extensive value in the biorefinery context, as a renewable source of... (Review)
Review
Lignin is a fascinating aromatic biopolymer with high valorization potentiality. Besides its extensive value in the biorefinery context, as a renewable source of aromatics lignin is currently under evaluation for its huge potential in biomedical applications. Besides the specific antioxidant and antimicrobial activities of lignin, that depend on its source and isolation procedure, remarkable progress has been made, over the last five years, in the isolation, functionalization and modification of lignin and lignin-derived compounds to use as carriers for biologically active substances. The aim of this review is to summarize the current state of the art in the field of lignin-based carrier systems, highlighting the most important results. Furthermore, the possibilities and constraints related to the physico-chemical properties of the lignin source will be reviewed herein as well as the modifications and processing required to make lignin suitable for the loading and release of active compounds.
Topics: Antioxidants; Excipients; Lignin
PubMed: 35684534
DOI: 10.3390/molecules27113598