Oral ingestion remains as the most convenient route of administration for the application of pharmaceuticals since it is non-invasive and does not require trained personnel to administer the drugs. ...Despite significant progress in novel oral drug delivery platforms over the past few decades, the oral delivery of macromolecules (particularly for peptides and proteins) is one of the major challenges faced by the biopharmaceutical industry. This is even more important since a large number of biologic drugs have been available in the past decade which typically require intravenous administration. Recently, silica nanoparticles have emerged as multifunctional, biocompatible and biodegradable inorganic nanocarriers with enormous potential as an oral drug delivery platform for various therapeutics including macromolecules. Their unique structural composition facilitates the loading of large therapeutic payloads at desired loading capacities for a controlled and site-specific oral delivery. Here, we review first the physiological challenges for oral delivery of peptides and proteins. Next, we discuss silica-based functional materials for oral delivery of macromolecules and highlight their evolving role not only as an encapsulant but as a permeation enhancer as well. Lastly, we also discuss potential strategies for future translation of these novel materials to the clinic.
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Nanoemulsion dosage form serves as a vehicle for the delivery of active pharmaceutical ingredients and has attracted great attention in drug delivery and pharmacotherapy. In particular, nanoemulsions ...act as an excellent vehicle for poorly aqueous soluble drugs, which are otherwise difficult to formulate in conventional dosage forms. Nanoemulsions are submicron emulsions composed of generally regarded as safe grade excipients. Particle size at the nanoscale and larger surface area lead to some very interesting physical properties that can be exploited to overcome anatomical and physiological barriers associated in drug delivery to the complex diseases such as cancer. Along these lines, nanoemulsions have been engineered with specific attributes such as size, surface charge, prolonged blood circulation, target specific binding ability, and imaging capability. These attributes can be tuned to assist in delivering drug/imaging agents to the specific site of interest, based on active and passive targeting mechanisms. This review focuses on the current state of nanoemulsions in the translational research and its role in targeted cancer therapy. In addition, the production, physico-chemical characterization, and regulatory aspects of nanoemulsion are addressed.
Therapies targeting epigenetic changes for cancer treatment are in Phase I/II trials; however, all of these target only nuclear DNA. Emerging evidence suggests presence of methylation marks on ...mitochondrial DNA (mtDNA); but their contribution in cancer is unidentified. Expression of genes encoded on mtDNA are altered in cancer cells, along with increased glycolytic flux. Such glycolytic flux and elevated reactive oxygen species is supported by increased antioxidant; glutathione. MicroRNA-34a can translocate to mitochondria, mediate downstream apoptotic effects of tumor suppressor P53, and inhibit the antioxidant response element Nrf-2, resulting in depleted glutathione levels. Based on such strong rationale, we encapsulated microRNA-34a in our well-established Hyaluronic-Acid nanoparticles and delivered to cisplatin-sensitive and cisplatin-resistant A549-lung adenocarcinoma cells. Successful delivery and uptake in cells resulted in altered ATP levels, decreased glycolytic flux, Nrf-2 and glutathione levels, ultimately resulting in caspase-3 activation and apoptosis. Most important were the concurrent underlying molecular changes in epigenetic status of D-loop on the mtDNA and transcription of mtDNA-encoded genes. Although preliminary, we provide a novel therapeutic approach in form of altered mitochondrial bioenergetics and redox status of cancer cells with underlying changes in epigenetic status of mtDNA that can subsequently results in induction of cancer cell apoptosis.
PIK75 is a specific inhibitor of the p110 α isoform of phosphatidylinositol-3-kinase, an enzyme which is upregulated in several human cancers. However its poor water solubility and stability has ...limited its pre-clinical development.
In our current work we developed and evaluated PIK75 nanosuspension prepared using high pressure homogenization technique. The nanosuspension was characterized for various properties such as size, surface charge and saturation solubility. The saturation solubility processing techniques were critically evaluated to optimize sample processing conditions. In vitro studies were conducted to determine the stability of the formulation and in vivo studies were carried out to understand the pharmacokinetic and tissue distribution properties of the nanosuspension.
The nanosuspension exhibited an 11-fold improvement in saturation solubility with drug recovery greater than 90% for 6h in the nanosuspension system and in human plasma. In vivo studies indicated that both PIK75 suspension and nanosuspension showed a similar plasma pharmacokinetic profile however tissue distribution studies indicated lower PIK75 levels in the kidney post nanosuspension administration.
The results of this study showed that PIK75 could be formulated as a nanosuspension to improve saturation solubility, enhance stability in plasma and minimize exposure to drug metabolizing tissues.
BACKGROUND Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) ...antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under “sub-immunogenic” conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273 (CII) and NF-κB inhibitor 1,25-dihydroxycholecalciferol.METHODS A double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71–specific (Cit-Vim–specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate.RESULTS DEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim–specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181–treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim–specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181.CONCLUSION The safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA.TRIAL REGISTRATION Anzctr.org.au identifier ACTRN12617001482358, updated September 8, 2022.FUNDING Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 777357), supported by European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations; Arthritis Queensland; National Health and Medical Research Council (NHMRC) Senior Research Fellowship; and NHMRC grant 2008287.
In recent years, mitochondrial medicine has emerged as a new discipline resting at the intersection of mitochondrial biology, pathology, and pharmaceutics. The central role of mitochondria in ...critical cellular processes such as metabolism and apoptosis has placed mitochondria at the forefront of cell science. Advances in mitochondrial biology have revealed that these organelles continually undergo fusion and fission while functioning independently and in complex cellular networks, establishing direct membrane contacts with each other and with other organelles. Understanding the diverse cellular functions of mitochondria has contributed to understanding mitochondrial dysfunction in disease states. Polyplasmy and heteroplasmy contribute to mitochondrial phenotypes and associated dysfunction. Residing at the center of cell biology, cellular functions, and disease pathology and being laden with receptors and targets, mitochondria are beacons for pharmaceutical modification. This review presents the current state of mitochondrial medicine with a focus on mitochondrial function, dysfunction, and common disease; mitochondrial receptors, targets, and substrates; and mitochondrial drug design and drug delivery with a focus on the application of nanotechnology to mitochondrial medicine. Mitochondrial medicine is at the precipice of clinical translation; the objective of this review is to aid in the advancement of mitochondrial medicine from infancy to application.
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Inflammation is an immune response that marks several pathophysiological conditions in our body. Though adaptive immune cells play a major role in the progression of the disease, components of innate ...immune system, mainly monocytes and macrophages play the central role in onset of inflammation. Tissue-associated macrophages are widely distributed in the body showing tremendous anatomical and functional diversity and are actively involved in maintaining the homeostasis. They exhibit different phenotypes depending on their residing tissue microenvironment and the two major functional phenotypes are classically activated M1 phenotype showing pro-inflammatory characteristics and alternatively activated M2 phenotype demonstrating anti-inflammatory nature. Several cytokines, chemokines and other regulatory mediators delicately govern the balance of the two phenotypes in a tissue. This balance, however, is subverted during infection, injury or autoimmune response leading to increased population of M1 phenotype and subsequent chronic inflammatory disease states. This review underlines the role of macrophages in inflammatory diseases with an insight into potential molecular targets for nucleic acid therapy. Finally, some recent nanotechnology-based approaches to devise macrophage-specific targeted therapy have been highlighted.
Dapivirine, formerly known as TMC 120, is a poorly-water soluble anti-HIV drug, currently being developed as a vaginal microbicide. The clinical use of this drug has been limited due to its poor ...solubility. The aim of this study was to design solid dispersion systems of Dapivirine to improve its solubility. Solid dispersions were prepared by solvent and fusion methods. Dapivirine release from the solid dispersion system was determined by conducting in-vitro dissolution studies. The physicochemical characteristics of the drug and its formulation were studied using Differential Scanning Calorimetry (DSC), powder X-ray Diffraction (XRD), Fourier-transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). A significant improvement in drug dissolution rate was observed with the solid dispersion systems. XRD, SEM and DSC results indicated the transformation of pure Dapivirine which exists in crystalline form into an amorphous form in selected solid dispersion formulations. FTIR and HPLC analysis confirmed the absence of drug-excipient interactions. Solid dispersion systems can be used to improve the dissolution rate of Dapivirine. This improvement could be attributed to the reduction or absence of drug crystallinity, existence of drug particles in an amorphous form and improved wettability of the drug.
Anticancer agents continue to be a preferred therapeutic option for several malignancies. Despite their effectiveness, oncologists are continually looking for tumor-specific anticancer agents to ...prevent adverse effects in patients. Targeting of imaging agents to cancerous tissue is another area that is enthusiastically explored to circumvent some of the drawbacks that current imaging agents possess, including the inability to target small tumor cells, inadequate imaging period, and the risk of renal damage. Formulation scientists have explored nanotechnology-based delivery systems for targeting anticancer agents and tumor-imaging agents to cancer tissue. Targeting with nanotechnology-based delivery systems has been investigated by both passive and active mechanisms with significant clinical success. This review presents a discussion on targeting strategies used for the delivery of nanoparticles by passive and active mechanisms, focusing more specifically on active targeting of nanoparticles using albumin, folic acid, transferrin, and aptamers as targeting ligands.
Mutations in KRAS and p53 signaling pathways contribute to loss of responsiveness to current therapies and a decreased survival in lung cancer. In this study, we have investigated the delivery and ...transfection of wild-type (wt-) p53 and microRNA-125b (miR-125b) expressing plasmid DNA, in SK-LU-1 human lung adenocarcinoma cells as well as in KrasG12D/p53fl/fl (KP) genetically engineered mouse model of lung cancer. Systemic plasmid DNA delivery with dual CD44/EGFR-targeted hyaluronic acid (HA)-based nanoparticles (NPs) resulted in a 2- to 20-fold increase in wt-p53 and miR-125b gene expression in SK-LU-1 cells. This resulted in enhanced apoptotic activity as seen with increased APAF-1 and caspase-3 gene expression. Similarly, in vivo evaluations in KP mouse model indicated successful CD44/EGFR-targeted delivery. Tumor growth inhibition and apoptotic induction were also observed with (wt-p53+miR125b) combination therapy in KP tumor model. Lastly, J774.A1 murine macrophages co-cultured with transfected SK-LU-1 cells showed a 14- to 35-fold increase in the iNOS-Arg-1 ratio, supportive of previous results demonstrating a role of miR-125b in macrophage repolarization. Overall, these results show tremendous promise of wt-p53 and miR-125b gene therapy using dual CD44/EGFR-targeting HA NP vector for effective treatment of lung cancer.
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