Nano/Microrobots Line Up for Gastrointestinal Tract Diseases: Targeted Delivery, Therapy, and Prevention

Nano/microrobots (NMRs) are tiny devices that can convert energy into motion and operate at nano/microscales.54 Especially in biomedical research, NMRs have received much attention over the past twenty years because of their excellent capabilities and great potential in various applications, including on-demand drug delivery, gene and cell transport, and precise microsurgery. Reports published in recent years show that synthetic nano/microrobots have promising potential to function in the gastrointestinal (GI) region, particularly in terms of drug delivery. These tiny robots were able to be designed in such a way that they propel in their surroundings (biological media) with high speed, load cargo (drug) efficiently, transport it safely, and release upon request successfully. Their propulsion, retention, distribution, and toxicity in the GI tract of mice has been evaluated. The results envisage that such nano/microrobots can be further modified and developed as a new-generation treatment of GI tract diseases. In this minireview, we focus on the functionality of micro/nanorobots as a biomedical treatment system for stomach/intestinal diseases. We review the research progress from the first in vivo report in December 2014 to the latest in August 2021. Then, we discuss the treatment difficulties and challenges in vivo application (in general) and possible future development routes.

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Mechanisms and Pharmaceutical Action of Lipid Nanoformulation of Natural Bioactive Compounds as Efficient Delivery Systems in the Therapy of Osteoarthritis

Pharmaceutics ◽

10.3390/pharmaceutics13081108 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1108

Author(s):

Oana Craciunescu ◽

Madalina Icriverzi ◽

Paula Ecaterina Florian ◽

Anca Roseanu ◽

Mihaela Trif

Keyword(s):

Drug Delivery ◽

Bioactive Compounds ◽

Targeted Delivery ◽

Drug Delivery Systems ◽

Delivery Systems ◽

Joint Disease ◽

Duration Of Action ◽

Immune System Activation

Osteoarthritis (OA) is a degenerative joint disease. An objective of the nanomedicine and drug delivery systems field is to design suitable pharmaceutical nanocarriers with controllable properties for drug delivery and site-specific targeting, in order to achieve greater efficacy and minimal toxicity, compared to the conventional drugs. The aim of this review is to present recent data on natural bioactive compounds with anti-inflammatory properties and efficacy in the treatment of OA, their formulation in lipid nanostructured carriers, mainly liposomes, as controlled release systems and the possibility to be intra-articularly (IA) administered. The literature regarding glycosaminoglycans, proteins, polyphenols and their ability to modify the cell response and mechanisms of action in different models of inflammation are reviewed. The advantages and limits of using lipid nanoformulations as drug delivery systems in OA treatment and the suitable route of administration are also discussed. Liposomes containing glycosaminoglycans presented good biocompatibility, lack of immune system activation, targeted delivery of bioactive compounds to the site of action, protection and efficiency of the encapsulated material, and prolonged duration of action, being highly recommended as controlled delivery systems in OA therapy through IA administration. Lipid nanoformulations of polyphenols were tested both in vivo and in vitro models that mimic OA conditions after IA or other routes of administration, recommending their clinical application.

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Single Domain Antibodies as Carriers for Intracellular Drug Delivery: A Proof of Principle Study

Biomolecules ◽

10.3390/biom11070927 ◽

2021 ◽

Vol 11 (7) ◽

pp. 927

Author(s):

Sebas D. Pronk ◽

Erik Schooten ◽

Jurgen Heinen ◽

Esra Helfrich ◽

Sabrina Oliveira ◽

...

Keyword(s):

Drug Delivery ◽

Targeted Delivery ◽

Single Domain ◽

Drug Conjugates ◽

Intracellular Drug Delivery ◽

Internalization Rate ◽

Single Domain Antibodies ◽

Different Characteristics

Antibody-drug conjugates (ADCs) are currently used for the targeted delivery of drugs to diseased cells, but intracellular drug delivery and therefore efficacy may be suboptimal because of the large size, slow internalization and ineffective intracellular trafficking of the antibody. Using a phage display method selecting internalizing phages only, we developed internalizing single domain antibodies (sdAbs) with high binding affinity to rat PDGFRβ, a receptor involved in different types of diseases. We demonstrate that these constructs have different characteristics with respect to internalization rates but all traffic to lysosomes. To compare their efficacy in targeted drug delivery, we conjugated the sdAbs to a cytotoxic drug. The conjugates showed improved cytotoxicity correlating to their internalization speed. The efficacy of the conjugates was inhibited in the presence of vacuolin-1, an inhibitor of lysosomal maturation, suggesting lysosomal trafficking is needed for efficient drug release. In conclusion, sdAb constructs with different internalization rates can be designed against the same target, and sdAbs with a high internalization rate induce more cell killing than sdAbs with a lower internalization rate in vitro. Even though the overall efficacy should also be tested in vivo, sdAbs are particularly interesting formats to be explored to obtain different internalization rates.

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Multiplexed Non-invasive in vivo Imaging to Assess Metabolism and Receptor Engagement in Tumor Xenografts

10.1101/758383 ◽

2019 ◽

Author(s):

Alena Rudkouskaya ◽

Nattawut Sinsuebphon ◽

Marien Ochoa ◽

Joe E. Mazurkiewicz ◽

Xavier Intes ◽

...

Keyword(s):

Drug Delivery ◽

Targeted Delivery ◽

Near Infrared ◽

Metabolic Response ◽

Imaging Modalities ◽

Wide Field ◽

Receptor Ligand ◽

Non Invasive ◽

Intracellular Drug Delivery

AbstractFollowing an ever-increased focus on personalized medicine, there is a continuing need to develop preclinical molecular imaging modalities to guide the development and optimization of targeted therapies. To date, non-invasive quantitative imaging modalities that can comprehensively assess simultaneous cellular drug delivery efficacy and therapeutic response are lacking. In this regard, Near-Infrared (NIR) Macroscopic Fluorescence Lifetime Förster Resonance Energy Transfer (MFLI-FRET) imaging offers a unique method to robustly quantify receptor-ligand engagement in vivo and subsequent intracellular internalization, which is critical to assess the delivery efficacy of targeted therapeutics. However, implementation of multiplexing optical imaging with FRET in vivo is challenging to achieve due to spectral crowding and cross-contamination. Herein, we report on a strategy that relies on a dark quencher that enables simultaneous assessment of receptor-ligand engagement and tumor metabolism in intact live mice. First, we establish that IRDye QC-1 (QC-1) is an effective NIR dark acceptor for the FRET-induced quenching of donor Alexa Fluor 700 (AF700) using in vitro NIR FLI microscopy and in vivo wide-field MFLI imaging. Second, we report on simultaneous in vivo imaging of the metabolic probe IRDye 800CW 2-deoxyglucose (2-DG) and MFLI-FRET imaging of NIR-labeled transferrin FRET pair (Tf-AF700/Tf-QC-1) uptake in tumors. Such multiplexed imaging revealed an inverse relationship between 2-DG uptake and Tf intracellular delivery, suggesting that 2-DG signal may predict the efficacy of intracellular targeted delivery. Overall, our methodology enables for the first time simultaneous non-invasive monitoring of intracellular drug delivery and metabolic response in preclinical studies.

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Understanding Microdroplet Formations for Biomedical Applications

Volume 15: Processing and Engineering Applications of Novel Materials ◽

10.1115/imece2008-69223 ◽

2008 ◽

Author(s):

Salil Desai ◽

Anthony Moore ◽

Benjamin Harrison ◽

Jagannathan Sankar

Keyword(s):

Drug Delivery ◽

Sodium Chloride ◽

Sodium Alginate ◽

Calcium Chloride ◽

Biomedical Applications ◽

Tissue Scaffolds ◽

Ambient Conditions ◽

On Demand ◽

Drop On Demand

This paper focuses on understanding microdroplet formation of sodium alginate biopolymer at various concentrations utilizing drop-on-demand inkjet technology. We investigate the effect of sodium chloride on the rheology of sodium alginate and derive a correlation between the size of the droplet versus the size of the microcapsules formed. Varying sizes of microcapsules are formed based on different concentrations of calcium chloride solvent. This understanding will give insight for fabricating drug delivery capsules and tissue scaffolds that are subject to extreme ambient conditions when interfaced with in-vivo environments.

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FORMULATION OF NANOPARTICLES OF TELMISARTAN INCORPORATED IN CARBOXYMETHYLCHITOSAN FOR THE BETTER DRUG DELIVERY AND ENHANCED BIOAVAILABILITY

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10i9.19162 ◽

2017 ◽

Vol 10 (9) ◽

pp. 236

Author(s):

Upasana Yadav ◽

Angshuman Ray Chowdhuri ◽

Sumanta Kumar Sahu ◽

Nuzhat Husain ◽

Qamar Rehman

Keyword(s):

Electron Microscopy ◽

Drug Delivery ◽

Targeted Delivery ◽

Drug Loading ◽

Water Soluble ◽

Bioavailability Enhancement ◽

Water Soluble Drug ◽

Efficient Option

Objective: In this study, we have made an attempt to the developed formulation of nanoparticles (NPs) of telmisartan (TLM) incorporated in carboxymethyl chitosan (CMCS) for the better drug delivery and enhanced bioavailability.Materials and Methods: The NPs size and morphology were investigated by high-resolution transmission electron microscopy and field emission scanning electron microscopy, respectively. The crystal structures and surface functional groups were analyzed using X-ray diffraction pattern, and Fourier transform infrared spectroscopy, respectively.Results: To increase the solubility of TLM by targeted delivery of the drug through polymeric NPs is an alternative efficient, option for increasing the solubility. TLM nanosuspension powders were successfully formulated for dissolution and bioavailability enhancement of the drug. We focused on evaluating the influence of particle size and crystalline state on the in vitro and in vivo performance of TLM.Conclusion: In summary, we have developed a new approach toward the delivery of poorly water-soluble drug TLM by CMCS NPs. The particles having a good drug loading content and drug encapsulation efficiency. The cytotoxicity of the synthesized NPs is also very less.

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Single-Walled Carbon Nanohorns as Promising Nanotube-Derived Delivery Systems to Treat Cancer

Pharmaceutics ◽

10.3390/pharmaceutics12090850 ◽

2020 ◽

Vol 12 (9) ◽

pp. 850 ◽

Cited By ~ 1

Author(s):

Alazne Moreno-Lanceta ◽

Mireia Medrano-Bosch ◽

Pedro Melgar-Lesmes

Keyword(s):

Drug Delivery ◽

Anticancer Agents ◽

Targeted Delivery ◽

Drug Delivery Systems ◽

Physicochemical Characteristics ◽

Delivery Systems ◽

Preclinical Research ◽

Carbon Nanohorns ◽

Single Walled Carbon

Cancer has become one of the most prevalent diseases worldwide, with increasing incidence in recent years. Current pharmacological strategies are not tissue-specific therapies, which hampers their efficacy and results in toxicity in healthy organs. Carbon-based nanomaterials have emerged as promising nanoplatforms for the development of targeted delivery systems to treat diseased cells. Single-walled carbon nanohorns (SWCNH) are graphene-based horn-shaped nanostructure aggregates with a multitude of versatile features to be considered as suitable nanosystems for targeted drug delivery. They can be easily synthetized and functionalized to acquire the desired physicochemical characteristics, and no toxicological effects have been reported in vivo followed by their administration. This review focuses on the use of SWCNH as drug delivery systems for cancer therapy. Their main applications include their capacity to act as anticancer agents, their use as drug delivery systems for chemotherapeutics, photothermal and photodynamic therapy, gene therapy, and immunosensing. The structure, synthesis, and covalent and non-covalent functionalization of these nanoparticles is also discussed. Although SWCNH are in early preclinical research yet, these nanotube-derived nanostructures demonstrate an interesting versatility pointing them out as promising forthcoming drug delivery systems to target and treat cancer cells.

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Reassessing the Role of Intra-Arterial Drug Delivery for Glioblastoma Multiforme Treatment

Journal of Drug Delivery ◽

10.1155/2015/405735 ◽

2015 ◽

Vol 2015 ◽

pp. 1-15 ◽

Cited By ~ 9

Author(s):

Jason A. Ellis ◽

Matei Banu ◽

Shaolie S. Hossain ◽

Rajinder Singh-Moon ◽

Sean D. Lavine ◽

...

Keyword(s):

Drug Delivery ◽

Targeted Delivery ◽

Optical Measurements ◽

Pharmacological Agents ◽

Cellular Targets ◽

Therapeutic Landscape ◽

Rational Drug

Effective treatment for glioblastoma (GBM) will likely require targeted delivery of several specific pharmacological agents simultaneously. Intra-arterial (IA) delivery is one technique for targeting the tumor site with multiple agents. Although IA chemotherapy for glioblastoma (GBM) has been attempted since the 1950s, the predicted benefits remain unproven in clinical practice. This review focuses on innovative approaches to IA drug delivery in treating GBM. Guided by novel in vitro and in vivo optical measurements, newer pharmacokinetic models promise to better define the complex relationship between background cerebral blood flow and drug injection parameters. Advanced optical technologies and tracers, unique nanoparticles designs, new cellular targets, and rational drug formulations are continuously modifying the therapeutic landscape for GBM. Personalized treatment approaches are emerging; however, such tailored approaches will largely depend on effective drug delivery techniques and on the ability to simultaneously deliver multidrug regimens. These new paradigms for tumor-selective drug delivery herald dramatic improvements in the effectiveness of IA chemotherapy for GBM. Therefore, within this context of so-called “precision medicine,” the role of IA delivery for GBM is thoroughly reassessed.

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Study of the Dynamic Uptake of Free Drug and Nanostructures for Drug Delivery Based on Bioluminescence Measurements

Journal of Nanomaterials ◽

10.1155/2017/8542806 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12

Author(s):

Zhongjian Fang ◽

Houchao Xu ◽

Xiangjun Ji ◽

Congbiao Liu ◽

Kai Wang ◽

...

Keyword(s):

Drug Delivery ◽

Drug Carriers ◽

Multicellular Tumor Spheroid ◽

The Past ◽

Loading Methods ◽

Model Drug ◽

Novel Drug ◽

Liposomal Drugs ◽

Great Growth

The past two decades have witnessed the great growth of the development of novel drug carriers. However, the releasing dynamics of drug from drug carriers in vivo and the interactions between cells and drug carriers remain unclear. In this paper, liposomes were prepared to encapsulate D-luciferin, which was the substrate of luciferase and served as a model drug. Based on the theoretical calculation of active loading, methods of preparation for liposomes were optimized. Only when D-luciferin was released from liposomes or taken in by the cells could bioluminescence be produced under the catalysis of luciferase. Models of multicellular tumor spheroid (MCTS) were built with 4T1-luc cells that expressed luciferase stably. The kinetic processes of uptake and distribution of free drugs and liposomal drugs were determined with models of cell suspension, monolayer cells, MCTS, and tumor-bearing nude mice. The technology platform has been demonstrated to be effective for the study of the distribution and kinetic profiles of various liposomes as drug delivery systems.

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Targeted Delivery of Narrow-Spectrum Protein Antibiotics to the Lower Gastrointestinal Tract in a Murine Model of Escherichia coli Colonization

Frontiers in Microbiology ◽

10.3389/fmicb.2021.670535 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nuria Carpena ◽

Kerry Richards ◽

Teresita D. J. Bello Gonzalez ◽

Alberto Bravo-Blas ◽

Nicholas G. Housden ◽

...

Keyword(s):

Escherichia Coli ◽

Drug Delivery ◽

Controlled Release ◽

Animal Models ◽

Targeted Delivery ◽

Intestinal Colonization ◽

Ph Responsive ◽

Human Gut ◽

E Coli

Bacteriocins are narrow-spectrum protein antibiotics that could potentially be used to engineer the human gut microbiota. However, technologies for targeted delivery of proteins to the lower gastrointestinal (GI) tract in preclinical animal models are currently lacking. In this work, we have developed methods for the microencapsulation of Escherichia coli targeting bacteriocins, colicin E9 and Ia, in a pH responsive formulation to allow their targeted delivery and controlled release in an in vivo murine model of E. coli colonization. Membrane emulsification was used to produce a water-in-oil emulsion with the water-soluble polymer subsequently cross-linked to produce hydrogel microcapsules. The microcapsule fabrication process allowed control of the size of the drug delivery system and a near 100% yield of the encapsulated therapeutic cargo. pH-triggered release of the encapsulated colicins was achieved using a widely available pH-responsive anionic copolymer in combination with alginate biopolymers. In vivo experiments using a murine E. coli intestinal colonization model demonstrated that oral delivery of the encapsulated colicins resulted in a significant decrease in intestinal colonization and reduction in E. coli shedding in the feces of the animals. Employing controlled release drug delivery systems such as that described here is essential to enable delivery of new protein therapeutics or other biological interventions for testing within small animal models of infection. Such approaches may have considerable value for the future development of strategies to engineer the human gut microbiota, which is central to health and disease.

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S,S-Tetrazine-Based Hydrogels with Visible Light Cleavable Properties for On-Demand Anticancer Drug Delivery

Research ◽

10.34133/2020/6563091 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Changping Wang ◽

Chongyi Liu ◽

Qiyao Wei ◽

Lei Yang ◽

Peng Yang ◽

...

Keyword(s):

Drug Delivery ◽

Drug Release ◽

Visible Light ◽

Cell Fate ◽

Degradation Kinetics ◽

Green Light ◽

Anticancer Drug Delivery ◽

On Demand ◽

Facile Fabrication

Photocleavable hydrogels are of great importance in the field of controlled drug delivery, stem cell fate regulation, surface patterning, and intelligent devices. However, the development of novel photocleavable gel systems by visible light is usually met with challenges such as the lack of efficient and tunable photocleavable groups and reactions. Herein, we reported the facile fabrication of a new type of photocleavable hydrogels by the direct gelation of 4-arm thiol-terminated polyethylene glycol with 3,6-dichloro-1,2,4,5-tetrazine via the formation of S,S-tetrazine linkages. The prepared hydrogels underwent efficient degradation upon irradiation by ultraviolet or green light, and the degradation kinetics could be significantly promoted by hydrogen peroxide. Correspondingly, the hydrogels loaded with calcium peroxide microparticles or glucose oxidase/catalase enzymes enabled the precise and efficient in vivo photocontrol of gel degradation and drug release for cancer treatment. This work offers a promising and facile strategy towards the fabrication of visible light cleavable hydrogels with tunable and on-demand drug release properties.

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