Special Issue:
Challenges and Opportunities in Drug Delivery
Andras G. Lacko
Lipoprotein Drug Delivery Research Laboratory, Department of Microbiology, Immunology & Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Nirupama A. Sabnis
Lipoprotein Drug Delivery Research Laboratory, Department of Microbiology, Immunology & Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Dorota Stankowska
Lipoprotein Drug Delivery Research Laboratory, Department of Microbiology, Immunology & Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Akpedje Serena Dossou
Lipoprotein Drug Delivery Research Laboratory, Department of Microbiology, Immunology & Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Rong Ma
Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Ronald Petty
Lipoprotein Drug Delivery Research Laboratory, Department of Microbiology, Immunology & Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; North Texas Research Eye Institute, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA
Rob Dickerman
Texas Brain and Spine Institute Frisco TX, USA
Bruce A. Bunnell
Lipoprotein Drug Delivery Research Laboratory, Department of Microbiology, Immunology & Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Abstract
The primary focus of this review is lipoprotein-based drug carriers, more specifically, high-density lipoprotein (HDL) type nanoparticles (NPs). These nanostructures are discussed regarding their suitability for clinical applications, particularly cancer therapy. Poor solubility and insufficient capability to selectively target malignant tumors represent significant challenges facing many anticancer drugs. Nevertheless, we and others have found that most, if not all, of these difficulties, can be overcome by incorporating drugs into lipoprotein nanocarriers (1). While not a novel approach, as HDL type NPs have been documented to deliver anticancer agents to cancer cells effectively and tumors (2-5), including those that, on their own (without facilitation), exhibited less than desirable therapeutic efficacy (6), due to their desirable features (see below), HDL type drug carriers, at least in our view, hold tremendous promise as facilitators of cancer chemotherapy. One of the key aspects of the HDL-type NP-facilitated drug transport is the receptor-mediated uptake of the payload from the NPs (7,8). Consequently, in this review, major emphasis is placed on monitoring the expression of the scavenger receptor type B1 (SR-B1) as a potentially valuable tool for the pre-treatment selection of patients regarding their suitability for advanced, personalized chemotherapy. The main emphasis in this article is on developing novel cancer therapeutics, while approaches for treating other diseases via lipoprotein nanocarriers are briefly discussed.
Stephen Bevan Shrewsbury, MBChB
Impel Pharmaceuticals Inc., Seattle, WA, USA
Greg Davies, BSc (Hons)
Impel Pharmaceuticals Inc, Seattle, WA, USA
Lisa McConnachie, PhD
Impel Pharmaceuticals Inc, Seattle, WA, USA
John Hoekman, PhD
Impel Pharmaceuticals Inc, Seattle, WA, USA
Abstract
Nasal drug delivery presents a potential opportunity for achieving rapid, extensive drug absorption via a nonoral route by 1) avoiding degradation within the gastrointestinal tract and first-pass metabolism in the liver and 2) facilitating faster onset via rapid absorption into the bloodstream. However, the site of drug deposition within the nasal cavity may impact drug pharmacokinetics. Precision Olfactory Delivery (POD®) by Impel Pharmaceuticals Inc. is a new technology that provides handheld, manually actuated, propellant-powered drug delivery to the upper nasal space for rapid and efficient absorption. Rapid onset of effect can be a major advantage in many clinical applications where quick and effective administration is needed (eg, alleviating agitation in emergency settings or reducing debilitating migraine symptoms). Here, we review the pharmacokinetic profile of INP105, which is being developed to deliver olanzapine (OLZ) by POD to treat agitation in patients with autism. Because formulation can play a large role in the pharmacokinetic profile of a nasally administered drug, we provide a comprehensive review of both published and previously unpublished preclinical data outlining how the INP105 formulation was developed and optimized for study in humans. Multiple formulation carriers and excipients were tested to find a stable INP105 formulation with a desirable nasal absorption profile. Because the nasal architecture in nonhuman primates (NHPs) is similar to humans, the pharmacokinetics and tolerability of an INP105 combination product (NHP-INP105) using a clinical formulation combined with a device specifically designed for NHPs has been investigated in preclinical NHP studies, providing translational data for human studies and the pathway for testing novel products and formulations. The pharmacokinetics and tolerability of INP105 were then evaluated in an early clinical study in humans, demonstrating favorable pharmacokinetic and pharmacodynamic profiles. In this review, we aim to illustrate how delivery of therapeutics to the upper nasal space using POD, such as with agents like INP105, has the potential to optimize nasal delivery and unlock the potential of delivery-limited drugs to provide patients with rapid onset of effect, ease of use, and convenience.
Parisa Gazerani
Department of Life Sciences and Health, Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway; Department of Health Science and Technology, Faculty of Medicine, Aalborg University, 9260 Gistrup, Denmark
Abstract
Developing drugs for brain disorders poses significant hurdles. These challenges stem from the scarcity of optimal models for preclinical drug testing and the often observed lack of translation from preclinical to human clinical trials. Further complexity arises from the specific targeting required in many brain disorders, with drug delivery often impeded by the necessity to cross the blood-brain barrier (BBB). As such, the search for novel and efficient platforms for preclinical drug development is a vibrant area of research. In acknowledgment of the limitations of animal tests – such as the lack of translation owing to species differences – and in alignment with the principles of reduction, refinement, and replacement (3Rs), the scientific community is moving towards promoting animal-free drug development plans. In this context, human brain organoids are rapidly emerging as potential alternatives to traditional methods. These early-stage in vitro models, mirroring in vivo complexities, hold great promise for preclinical drug testing for brain disorders. Stable organoid phenotypes and the uncovering of disease-specific features could soon elevate them to a valuable strategy in pharmaceutical testing for a range of brain disorders. Recent advancements in assay-ready organoid platforms and microfluidic chips present considerable potential for the application of human brain organoids in drug development. This commentary briefly discusses the generation of human brain organoids and their application in drug development with existing examples, focusing on their potential use in preclinical drug development for migraine, a prevalent, complex, and disabling brain disorder. The associated challenges and opportunities will also be outlined.
Richard Grondin
Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY 40536
Ofelia M. Littrell
Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY 40536
Yi Ai
Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY 40536
Peter Huettl
Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY 40536
Francois Pomerleau
Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY 40536
Jorge E. Quintero
Department of Neurosurgery, University of Kentucky Medical Center, Lexington, KY 40536
Don M. Gash
Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY 40536
Zhiming Zhang
Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY 40536
Greg A. Gerhardt
Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY 40536; Department of Neurosurgery, University of Kentucky Medical Center, Lexington, KY 40536
Abstract
Glial cell line-derived neurotrophic factor (GDNF) remains a promising disease modifying therapeutic agent for the dopamine-containing neurons that are affected in Parkinson’s disease and recent clinical findings show renewed promise for its use in patients with Parkinson’s disease. However, translating this approach from research laboratories to the clinic has been met with obstacles, including insufficient brain biodistribution, immunogenicity, and poor stability of unglycosylated wildtype GDNF produced from bacteria. We have previously reported that continuous infusion of a novel glycosylated mammalian variant of GDNF (GDNFv) has increased biodistribution compared to wildtype GDNF along with increased dopamine turnover in the non-human primate brain. Here, we extend these findings by comparing continuous versus pulsatile intrastriatal infusion of GDNFv in intact rhesus macaques. Intermittent, pulsatile delivery paradigms were explored to possibly enhance drug distribution in the brain while decreasing the total amount of drug and infusion volume needed to achieve target activation. Vehicle or GDNFv was directly administered into the putamen via a pump and catheter system using a constant flow rate or using pulsatile profiles of two patterns: pulsatile infusion of 24-hour duration or 48-hour duration. Study endpoints involved comparisons of brain biodistribution, retrograde transport to nigral neurons and dopamine turnover. Each catheter was placed in or near the center of the putamen as confirmed by post-operative magnetic resonance imaging. Our results support that continuous and pulsatile administration of GDNFv was well tolerated in all animals. In addition, pulsatile delivery of GDNFv demonstrated favorable physiological activity of potential therapeutic value with biodistribution, retrograde transport to nigral cells and significant dopamine turnover modulation comparable or better than that achieved with continuous flow delivery. More importantly, the animals administered GDNFv via pulsatile protocols only received half the total drug amount and half the infused volume used in the continuously-infused animals, while still attaining a similar efficacy in increasing dopamine turnover. These data suggest that pulsatile delivery of trophic factors, such as GDNFv, may be a viable disease altering strategy for patients with Parkinson’s disease by offering a means to reduce the drug amount needed to improve dopamine function while limiting potential therapeutic barriers.
Stephen Bevan Shrewsbury
Impel Pharmaceuticals
Abstract
In this imperfect world, given that humans often need to treat or prevent disease by delivering medicine to the target cells earlier and for longer than previously possible, certain optimum requirements should be met. Treatment, or prevention, by a therapeutic molecule should be delivered at the right time, at the right dose, to the right target cell, by the safest, most convenient, inexpensive and effective method of delivery.
Most new drugs go through a phase, usually in early development, when they are administered by intravenous delivery, but many of these products end up being delivered by a different modality later, and locally acting drugs for local disease may benefit from topical administration to the epithelium, or adjacent tissue, of interest. With many of the newer medicines being proteins or peptides, oral delivery is not an option due to their degradation in the gut, so non-oral formulations are becoming even more important.
This editorial highlights some of the challenges facing developers when considering how to deliver their products. It focuses on a new route of administration that recently received approval that may represent an opportunity for non-invasive delivery of acutely needed medications.
Saikat Basu, PhD
Department of Mechanical Engineering, South Dakota State University, Brookings, SD, United States; Department of Otolaryngology / Head and Neck Surgery, University of North Carolina School of Medicine, Chapel Hill, NC, United States
Uzzam Ahmed Khawaja, BS
Department of Mechanical Engineering, South Dakota State University, Brookings, SD, United States
Syed A A Rizvi, PhD
Department of Pharmaceutical Sciences, Hampton University School of Pharmacy, Hampton, VA, United States
Marcos A Sanchez-Gonzalez,, MD, PhD
Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States
Gustavo Ferrer
Abstract
Background: The nasal route of targeted drug administration facilitates medical management of chronic and acute onsets of various respiratory conditions such as rhinitis and sinusitis and during the initial onset phase of severe acute respiratory syndrome coronavirus 2, when the infection is still contained within the upper airway. Nevertheless, patient comfort issues that are often associated with intranasal devise usage can lead to low compliance, thereby compromising treatment efficacy. Hence, there is an urgent need to detect reproducible and user-friendly intranasal drug delivery modalities that may promote adoption compliance and yet be effective at targeted transport of drugs to the infective airway regions.
Methods: In this pilot study, we have collected evaluation feedback from a cohort of 13 healthy volunteers, who used an open-angle swirling effect atomizer to assess two different nasal spray administration techniques (with 0.9% saline solution), namely the vertical placement protocol (or, VP), wherein the nozzle is held vertically upright at a shallow insertion depth of 0.5 cm inside the nasal vestibule; and the shallow angle protocol (or, SA), wherein the spray axis is angled at 45° to the vertical, with a vestibular insertion depth of 1.5 cm. The VP protocol is based on current usage instructions, while the SA protocol is derived from published findings on alternate spray orientations that have been shown to enhance targeted drug delivery at posterior infection sites, e.g., the ostiomeatal complex and the nasopharynx.
Results: All study participants reported that the SA protocol offered a more gentle and soothing delivery experience, with less impact pressure. Additionally, 60% of participants reported that the VP technique caused painful irritation. We also numerically tracked the drug transport processes for the two spray techniques in a computed tomography-based nasal cavity reconstruction; the SA protocol registered a distinct improvement in airway penetration when compared to the VP protocol.
Conclusion: The participant-reported unequivocally favorable experience with the new SA protocol justifies a full-scale clinical study aimed at testing the related medication compliance parameters and the corresponding therapeutic efficacies.
Brian Kawahara
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA
Pradip K. Mascharak
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA
Abstract
Drug resistance to conventional chemotherapeutics is a great impediment to cancer therapy. A major part of this problem arises from rapid metabolism of the drugs by cytochrome P450 class of enzymes before they reach their targets or at the target itself. Inhibition of such enzymatic deactivation of the drugs could offer partial rescue and make chemotherapy more effective. Site specific delivery of exogenous carbon monoxide has been shown to inhibit cytochrome P450 enzymes and resurrect sensitivity to chemotherapeutics already available in the market. Successful design for application of such CO delivery will thus be extremely desirable to patients particularly in poor countries where the antibody-based or nanodrug therapies, discovered recently, are too expensive for the general population. The potential of such carbon monoxide-induced cytochrome P450 inhibition to improve drug sensitization to conventional chemotherapeutics in breast cancer therapy has been discussed in this account.
Larry L Mweetwa
Department of Pharmacy, Boitekanelo College, Plot 5824 Masetlheng Rd, Gaborone 00000, Botswana
Tiro Mampane
Department of Pharmacy, Boitekanelo College, Plot 5824 Masetlheng Rd, Gaborone 00000, Botswana
Thatoyaone J Kenaope
Department of Pharmacy, Boitekanelo College, Plot 5824 Masetlheng Rd, Gaborone 00000, Botswana
Bonang Mosala
Department of Pharmacy, Boitekanelo College, Plot 5824 Masetlheng Rd, Gaborone 00000, Botswana
Kenneth Pule
Department of Pharmacy, Boitekanelo College, Plot 5824 Masetlheng Rd, Gaborone 00000, Botswana
Gerald Juma Obure
Department of Pharmacy, Boitekanelo College, Plot 5824 Masetlheng Rd, Gaborone 00000, Botswana
Getrude Mothibe
Department of Pharmacy, Boitekanelo College, Plot 5824 Masetlheng Rd, Gaborone 00000, Botswana
Abstract
Nanobiotechnology is a multi-strategic approach that engineers biological components (atoms and molecules) at the nanoscales. The concept was introduced as an effective alternative with drug delivery and targeting properties. Nanobiotechnology has several applications in cancerous disease, autoimmune, inflammation, infectious, and viral diseases, and for the management of COVID-19. Nanoparticles have biomimetic properties, encapsulation, and safety formulation of drugs, and all these properties give them an advantage over conventional drug strategies. Nanobiotechnology research is currently progressive and needs extensive exploration and understanding for its potential use in future innovations. The present review studied the concept of nanobiotechnology, its origin, mechanism of drug delivery and targeting, applications, and future perspective in pharmacology and innovation to decipher its role in future advanced research.
Kauther I. Layas
Libyan Oxygen Medical Centre, Tripoli, Libya
Prabal K. Chatterjee
Centre for Precision Health and Translational Medicine, School of applied Sciences, University of Brighton, Lewes Road, Brighton, BN2 4GJ, UK
Ananth S. Pannala
Centre for Precision Health and Translational Medicine, School of applied Sciences, University of Brighton, Lewes Road, Brighton, BN2 4GJ, UK
Abstract
Acute kidney injury is characterized by abrupt failure of kidney function, sometimes leading to chronic kidney disease, and is associated with significant morbidity and mortality. However, there is no clear effective therapeutic solution and treatment is mainly based on either alleviation or removal of the possible cause and/or renal replacement therapy. Oxidative stress has been indicated as one of the main pathophysiological pathways in the development of acute kidney injury. Various treatments including antioxidants, inflammatory mediators and genetic modifiers have been proposed to for the treatment of this condition. Epidemiological studies show lower incidence of kidney failure with higher consumption of antioxidants. However, the data is inconclusive due to their physicochemical properties, bioavailability or toxicity. Novel drug delivery systems such as liposomes and nanoparticles have been proposed to overcome the pharmacodynamic and pharmacokinetic barriers. This review provides a brief introduction to acute kidney injury and the different factors involved in its pathology, focusing on oxidative stress. It also covers details of antioxidant use as preventive and/or treatment option. It will summarise their limitations as free drugs and the possible improvement in their bioavailability by two main novel drug delivery systems: liposomes and polymeric nanoparticles. Other therapies such as inflammatory mediators and genetic modifiers are also discussed briefly.
Minesh Patel
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Eric Conte
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Nan Luo
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Virali Patel
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Ashley Varela Martinez
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Hae Chan Kim
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Naga Goli
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Robert B. Campbell
Department of Pharmaceutical Sciences, MCPHS University Worcester, MA 01608, USA; Professor of Pharmaceutics, MCPHS University, Department of Pharmaceutical Sciences, 19 Foster Street, Worcester, MA 01608, USA
Abstract
Retinoblastoma is the most common type of eye cancer in infants and children. Probability of saving vision and survival depends upon two main factors: progression of the disease from unilateral to bilateral and severity of the disease. In order to effectively treat retinoblastoma and retain vision, it is crucial to focus treatment options on reducing toxicity and nonspecific targeting while enhancing drug delivery, cellular uptake, and accumulation of chemotherapeutic agents to their specific target sites. Rapid elimination from blood circulation is the greatest obstacle that conventional chemotherapeutic agents face on journey to their target sites. Target specific nanoparticles have proven to be a useful tool in efforts to overcome challenges typically encountered by targeting strategies. Development of nanoparticles loaded with chemotherapeutic agents can allow for more selective tumor targeting, extended drug circulation times, and reduced drug-associated toxicity. Nanoparticles can significantly improve the treatment efficacy in retinoblastoma. The purpose of this review is to discuss the important characteristics and differences of nano delivery systems used against cellular and in vivo models of retinoblastoma, particularly as they relate to the popular Y79 retinoblastoma cell line.
Remy André-Jean
Mobile Hepatits Team, Perpignan Hospital, Perpignan, France
Bouchkira Hakim
Mobile Hepatits Team, Perpignan Hospital, Perpignan, France
Happiette Arnaud
Mobile Hepatits Team, Perpignan Hospital, Perpignan, France
Hervet Jeremy
Mobile Hepatits Team, Perpignan Hospital, Perpignan, France
Roy Berengere
Mobile Hepatits Team, Perpignan Hospital, Perpignan, France
Wenger Hugues
Mobile Hepatits Team, Perpignan Hospital, Perpignan, France
Abstract
Introduction and objective: HCV treatment for all was effective in France since 2017. HCV testing, diagnosis and treatment of drugs users and precarious people remain low. Lost follow-up was too important since several stages are necessary. Pangenotypic direct antiviral agents were available. Point-of-care HCV RNA testing offers advantage over antibody testing, enabling diagnosis of active infection with real time measure in a single visit. It is missing link between HCV RDT, liver fibrosis evaluation by FIBROSCAN and treatment. Validated Xpert HCV Viral Load assay CEPHEID, fast training technique, allow developing projects of diagnosis to treatment session. Our objective was to evaluate test to cure session allowing the access in 5 hours to an antiviral treatment to vulnerable and precarious populations (drug users, migrants, psychiatric patients).
Materials and methods: Eligible patients had to have known positive serology or risk behavior, an unknown or unchecked viral load after antiviral treatment; 5 to 7 patients were recruited per each session by social or nursing interview. Between 9 am and 2 pm these patients had access to measure of the hepatic fibrosis by FIBROSCAN, HCV viral load in real time by CEPHEID Xpert HCV Viral load finger-stick samples, social interview, shared educational evaluation, collective workshops, especially harm reduction, depiction of results by hepatologist and prescription of DAA (sofosbuvir velpastasvir combination) allowed delivery of 1st month of treatment. Specific social and nursing follow-up was made during and after treatment. Compliance and sustained virological rate were determinate at week 12.
Results: From October 2019 to December 2021, 223 sessions were realized on 27 sites: 9 drug units, one prison, 17 social units; 1602 patients with drug using history were screened; 427 patients had HCV positive serology and 24 patients did not come; 403 FIBROSCAN measures and 403 measures of viral load in real time were realized. Mean value of liver stiffness was 8.2 and 29% of patients were F3 or F4: 229 patients were HCV RNA positive (56.8%), 57 declared knew their HCV status; 228 treatments began same day, only 1 was delayed due to default social rights; 120 patients had a negative viral load spontaneously and 54 following prior treatment; 399 social interviews and 405 collective workshops were realized. On 31st January 2022, 207 antiviral treatments were completed and 199 patients were cured; 12 patients interrupted treatment; 3 patients relapsed and 5 reinfections; 89% of patients were satisfied with this program.
Conclusions: Despite 3 months interruption by COVID 19 pandemic lockdown and sanitary restrictions, 94% of positive participants were linked to care and cure with this mobile clinic model, by screening and RNA real time measure in unity of place adapted to precarious public, patients distant from system of care had access immediately to treatment.
Christian Elmshaeuser
Stem Cell Therapy Division, Institute of Medical Microbiology, University of Giessen, Giessen Germany & International Senior Professional Institute (ISPI) e.V. Giessen, Germany. 2Biochemistry Institute, University of Giessen, Giessen, Germany.
Ina Zoeller
Stem Cell Therapy Division, Institute of Medical Microbiology, University of Giessen, Giessen Germany & International Senior Professional Institute (ISPI) e.V. Giessen, Germany. 2Biochemistry Institute, University of Giessen, Giessen, Germany.
Darisuren Anhlan
Biochemistry Institute, University of Giessen, Giessen, Germany.
Ewald Beck
Biochemistry Institute, University of Giessen, Giessen, Germany.
Bruno Peault
INSERM U506, Groupe Hospitalier Paul Brousse, Villejuif Cedex, France & Orthopaedic Hospital Research Center and Broad Stem Cell Research Center, David Geffen School of Medicine, University of California, Los Angeles, LA, United States & MRC Centre Institute for Regenerative Medicine and Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
Olivier Tabary
Sorbonne Université, INSERM UMR S 938, Centre de Recherche Saint Antoine (CRSA), Paris, France.
Una Chen
Stem Cell Therapy Division, Institute of Medical Microbiology, University of Giessen, Giessen Germany & International Senior Professional Institute (ISPI) e.V. Giessen, Germany. ; 5Research Experience of Stem Cells in Europe Society (RESCUES) e.V., Giessen, Germany.
Abstract
Background-Purpose of this study: Tissue-specific stem cell lines are useful tools for cell biology studies. Information on respiratory tissue cell lines is limited. A doxycycline-regulated epithelial precursor cell line was established from the lung tissue of a tTAxSV40 Tag double transgenic mouse. In this study, we have characterized this cell line in vitro & in vivo, and found to mimic a rare subpopulation of club- and pneumocyte type II-dual cells.
Methods: It was partially characterized using cell viability and death assays, H3-thymidine incorporation assay, chloride efflux assay, Western blotting of proteins secreted, RT-PCR assays for RNA isolated. In addition, immune–deficient SCID mice were used as hosts for implantation of this precursor cell line, and feed with/without doxycycline containing water. Immunofluorescent typing using different antibodies were used to characterize the implanted lung.
Results: This cell line was found to mimic a rare subpopulation of club- and pneumocyte type II- dual cells with multiple phenotypes. Cell growth was doxycycline-regulated and observed only when doxycycline was omitted from the medium or present at concentrations up to 1 µg/ml, higher concentrations were inhibitory. ACT+ ciliated cells were found upon implantation into immune-deficient mice, in addition. Cell growth was doxycycline-regulated in vitro. When transplanted subcutaneously into immune–deficient mice, these cells migrated to the lung to form organized chimeric structures of donor and host origins, with club cells in the terminal bronchioles, ACT+ ciliated cells along the epithelial lining, and pneumocyte type II-cells in the alveolar interstices. No such homing of donor cells to the lung was observed when the implanted mice were fed doxycycline-containing water.
Discussions-Conclusions: This lung stem cell line might be able to provide us with an insight into the differentiation pathway of lung epithelial cells as well as with some understanding of the nature of air trophic-pulmonary epithelial cells. The results of this study underline the possibility of a future application for somatic (stem / precursor) cells in tissue replacement and tissue engineering of the damaged lung. Its ability to secrete and deliver soluble protein, might be a potential novel way for drug delivery. In addition, stem cells are thought to proliferate and differentiate in response to a deficiency or as a result of injury. Successful migration to the target organ and subsequent maturation of these precursors could be attributed to a requirement of lung stem cells to search for an aerated environment. Our findings challenge some current concepts of stem cell biology.This lung stem cell line may become a rich source of cells for tissue engineering and cell-based therapy for lung injury. The route and protocol established for cell introduction into the lung may provide a novel alternative to delivery of soluble protein substances through the airways. This lung stem cell line
Dr. U. Ubaidulla
Associate professor, Department of Pharmaceutics, Cresent School of Pharmacy, B.S. Abdur Rahman Cresent Institute of Science and Technology, India.
Dr. Sandhiya V
Associate professor, Department of Pharmaceutics, Faculty of Pharmacy, Sree Balaji Medical College and Hospital Campus, BIHER, Chennai-44
Dr. T. Purushoth Prabhu
Professor and Head, Department of pharmacognosy, C.L.Baid metha college of pharmacy, thoraipakkam, Chennai-97
Dr. N. Deepa
Dean, Department of pharmacognosy, Faculty of Pharmacy, Sree Balaji Medical College and hospital campus, BIHER, Chennai-44
Dr. Arulprakasam K C
Professor, JKKMMRF’s Annai JKK Sampoorani Ammal College of Pharmacy, Komarapalayam, India.
Senthilkumar Balakrishnan
Professor, JKKMMRF’s Annai JKK Sampoorani Ammal College of Pharmacy, Komarapalayam, India.
Velayutham Suresh
Professor, JKKMMRF’s Annai JKK Sampoorani Ammal College of Pharmacy, Komarapalayam, India.
Abstract
The urgent need for a novel way to replicate human drug reactions in preclinical research has motivated the development of organ-on-a-chip (OoC) systems. These difficulties are not recognized during preclinical trials, owing to ineffective screening technologies that mimic the complexities of human tissues and provide quick, accurate screening readouts. Microfluidics and microfabrication are powerful methods for creating numerous systems with high spatiotemporal precision to simulate in vivo microenvironments for drug delivery, discovery, development, and screening. This method might be used to investigate cell responses to pharmacological and mechanical stimuli in a more physiologically effective way. In this paper, we examine current achievements in OoC with an emphasis on biomimicry, functionality, and characteristics, as well as multi-organ platforms that attempt to replicate the essential aspects of integrated human physiology. Finally, we explore future prospects and limits that must be addressed in order to get OoC systems closer to clinical translation.
William Kirkpatrick Reid, MD
Independent Researcher
Abstract
Three neurodegenerative disorders- Alzheimer’s dementia (ALZ), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS)- share a common feature in their pathogenesis: evidence of mitochondrial dysfunction and reactive oxygen stress. Their pathologic classifications are based on the findings at autopsy based on patterns of protein aggregates in neurons and glial cells. This pathology supports the concept that neurotoxins are a major factor in the etiology of these disorders. There is value in exploring the similarities in the pathogenesis of ALS, Parkinson Disease and Alzheimer Dementia based on non-genetic etiologies.
The nose to olfactory pathway feeds sensory input from the nasal cavity to the olfactory bulb and the entorhinal lobe. Another component of these pathways involves two branches of the trigeminal nerve with sensory input to the pons and midbrain. A key factor is their capacity to bypass the blood-brain barrier (BBB). The protection of the brain by the BBB diminishes with age and can be lost with damage from insults as with viral infections. The olfactory nerve is the only cranial nerve with direct exposure to the ambient environment and has a high rate of turnover of sensory receptors
The nasal cavity is being studied for drug delivery and can be used to deliver medications into the central nervous system (CNS. The nose-to-brain pathway may represent a critical avenue of exposure to oxidative neurotoxins. Neurotoxic mycotoxins are a major risk to humans. Neurotoxins may be amplified by the nose-to-brain pathway. The pathology shows similarities to prion disease. These neurotoxins are highly fat-soluble and tend to accumulate in mitochondria and synaptic vesicles. Neurotoxins in synaptic vesicles can migrate from neuron to neuron.
There is evidence of chronic fungal infections in ALS patients that secret neurotoxic and immunotoxic mycotoxins leading to progressive immune suppression. The nose-to-olfactory pathway may amplify neurotoxins levels in the brain. If Parkinson Disease and ALZ are due to systemic poisonings, the source of neurotoxins may be episodic and lead to autoimmune disease.