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Central nervous system (CNS) disorders, such as psychiatric disorders, neurodegeneration, chronic pain, stroke, brain tumor, spinal cord injury, and many other CNS diseases, would hugely benefit from specific and potent peptide pharmaceuticals and their low inherent toxicity. The delivery of peptides to the brain is challenging due to their low metabolic stability, which decreases their duration of action, poor penetration of the blood-brain barrier (BBB), and their incompatibility with oral administration, typically resulting in the need for parenteral administration. These challenges limit peptides’ clinical application and explain the interest in alternative routes of peptide administration, particularly nose-to-brain (N-to-B) delivery, which allows protein and peptide drugs to reach the brain noninvasively. N-to-B delivery can be a convenient method for rapidly targeting the CNS, bypassing the BBB, and minimizing systemic exposure; the olfactory and trigeminal nerves provide a unique pathway to the brain and the external environment. This review highlights the intranasal delivery of drugs, focusing on peptide delivery, illustrating various clinical applications, nasal delivery devices, and the scope and limitations of this approach.

Respiratory diseases are among the leading causes of morbidity and mortality worldwide. Innovations in biochemical engineering and understanding of the pathophysiology of respiratory diseases resulted in the development of many therapeutic proteins and peptide drugs with high specificity and potency. Currently, protein and peptide drugs are mostly administered by injections due to their large molecular size, poor oral absorption, and labile physicochemical properties. However, parenteral administration has several limitations such as frequent dosing due to the short half-life of protein and peptide in blood, pain on administration, sterility requirement, and poor patient compliance. Among various noninvasive routes of administrations, the pulmonary route has received a great deal of attention and is a better alternative to deliver protein and peptide drugs for treating respiratory diseases and systemic diseases. Among the various aerosol dosage forms, dry powder inhaler (DPI) systems appear to be promising for inhalation delivery of proteins and peptides due to their improved stability in solid state. This review focuses on the development of DPI formulations of protein and peptide drugs using advanced spray drying. An overview of the challenges in maintaining protein stability during the drying process and stabilizing excipients used in spray drying of proteins and peptide drugs is discussed. Finally, a summary of spray-dried DPI formulations of protein and peptide drugs, their characterization, various DPI devices used to deliver protein and peptide drugs, and current clinical status are discussed.

Coronavirus disease-2019 (COVID-19) is caused by coronavirus-2 (SARS-CoV-2) and has produced a global pandemic. As of 22 June 2021, 178 million people have been affected worldwide, and 3.87 million people have died from COVID-19. According to the Centers for Disease Control and Prevention (CDC) of the United States, COVID-19 virus is primarily transmitted between people through respiratory droplets and contact routes. Since the location of initial infection and disease progression is primarily through the lungs, the inhalation delivery of drugs directly to the lungs may be the most appropriate route of administration for treating COVID-19. This review article aims to present possible inhalation therapeutics and vaccines for the treatment of COVID-19 symptoms. This review covers the comparison between SARS-CoV-2 and other coronaviruses such as SARS-CoV/MERS, inhalation therapeutics for the treatment of COVID-19 symptoms, and vaccines for preventing infection, as well as the current clinical status of inhaled therapeutics and vaccines.

Background Decreased cerebral blood flow and systemic inflammation during heart failure (HF) increase the risk for vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer disease-related dementias (ADRD). We previously demonstrated that PNA5, a novel glycosylated angiotensin 1–7 (Ang-(1–7)) Mas receptor (MasR) agonist peptide, is an effective therapy to rescue cognitive impairment in our preclinical model of VCID. Neurofilament light (NfL) protein concentration is correlated with cognitive impairment and elevated in neurodegenerative diseases, hypoxic brain injury, and cardiac disease. The goal of the present study was to determine (1) if treatment with Ang-(1–7)/MasR agonists can rescue cognitive impairment and decrease VCID-induced increases in NfL levels as compared to HF-saline treated mice and, (2) if NfL levels correlate with measures of cognitive function and brain cytokines in our VCID model. Methods VCID was induced in C57BL/6 male mice via myocardial infarction (MI). At 5 weeks post-MI, mice were treated with daily subcutaneous injections for 24 days, 5 weeks after MI, with PNA5 or angiotensin 1–7 (500 microg/kg/day or 50 microg/kg/day) or saline ( n  = 15/group). Following the 24-day treatment protocol, cognitive function was assessed using the Novel Object Recognition (NOR) test. Cardiac function was measured by echocardiography and plasma concentrations of NfL were quantified using a Quanterix Simoa assay. Brain and circulating cytokine levels were determined with a MILLIPLEX MAP Mouse High Sensitivity Multiplex Immunoassay. Treatment groups were compared via ANOVA, significance was set at p  < 0.05. Results Treatment with Ang-(1–7)/MasR agonists reversed VCID-induced cognitive impairment and significantly decreased NfL levels in our mouse model of VCID as compared to HF-saline treated mice. Further, NfL levels were significantly negatively correlated with cognitive scores and the concentrations of multiple pleiotropic cytokines in the brain. Conclusions These data show that treatment with Ang-(1–7)/MasR agonists rescues cognitive impairment and decreases plasma NfL relative to HF-saline-treated animals in our VCID mouse model. Further, levels of NfL are significantly negatively correlated with cognitive function and with several brain cytokine concentrations. Based on these preclinical findings, we propose that circulating NfL might be a candidate for a prognostic biomarker for VCID and may also serve as a pharmacodynamic/response biomarker for therapeutic target engagement.

The search for efficacious treatment of neurodegenerative and progressive neuroinflammatory diseases continues, as current therapies are unable to halt or reverse disease progression. PACAP represents one potential therapeutic that provides neuroprotection effects on neurons, and also modulates inflammatory responses and circulation within the brain. However, PACAP is a relatively long peptide hormone that is not trivial to synthesize. Based on previous observations that the shortened isoform PACAP1–23 is capable of inducing neuroprotection in vitro, we were inspired to synthesize shortened glycopeptide analogues of PACAP1–23. Herein, we report the synthesis and in vitro characterization of glycosylated PACAP1–23 analogues that interact strongly with the PAC1 and VPAC1 receptors, while showing reduced activity at the VPAC2 receptor.

Heart failure (HF) causes decreased brain perfusion in older adults, and increased brain and systemic inflammation increases the risk of cognitive impairment and Alzheimer’s disease (AD). Glycosylated Ang-(1-7) MasR agonists (PNA5) has shown improved bioavailability, stability, and brain penetration compared to Ang-(1-7) native peptide. Despite promising results and numerous potential applications, clinical applications of PNA5 glycopeptide are limited by its short half-life, and frequent injections are required to ensure adequate treatment for cognitive impairment. Therefore, sustained-release injectable formulations of PNA5 glycopeptide are needed to improve its bioavailability, protect the peptide from degradation, and provide sustained drug release over a prolonged time to reduce injection administration frequency. Two types of poly(D,L-lactic-co-glycolic acid) (PLGA) were used in the synthesis to produce nanoparticles (≈0.769–0.35 µm) and microparticles (≈3.7–2.4 µm) loaded with PNA5 (ester and acid-end capped). Comprehensive physicochemical characterization including scanning electron microscopy, thermal analysis, molecular fingerprinting spectroscopy, particle sizing, drug loading, encapsulation efficiency, and in vitro drug release were conducted. The data shows that despite the differences in the size of the particles, sustained release of PNA5 was successfully achieved using PLGA R503H polymer with high drug loading (% DL) and high encapsulation efficiency (% EE) of >8% and >40%, respectively. While using the ester-end PLGA, NPs showed poor sustained release as after 72 h, nearly 100% of the peptide was released. Also, lower % EE and % DL values were observed (10.8 and 3.4, respectively). This is the first systematic and comprehensive study to report on the successful design, particle synthesis, physicochemical characterization, and in vitro glycopeptide drug release of PNA5 in PLGA nanoparticles and microparticles.

The purpose of this study was to formulate Lactomorphin (MMP2200) in its pure state as spray-dried(SD) powders, and with the excipient Trehalose as co-spray-dried(co-SD) powders; for intranasal and deep lung administration with Dry Powder Inhalers (DPI). Lactomorphin is a glycopeptide which was developed for the control of moderate to severe pain. Particles were rationally designed and produced by advanced spray drying particle engineering in a closed mode from a dilute organic solution. Comprehensive physicochemical characterization using different analytical techniques was carried out to analyze the particle size, particle morphology, particle surface morphology, solid-state transitions, crystallinity/non-crystallinity, and residual water content. The particle chemical composition was confirmed using attenuated total reflectance-Fourier-transform infrared (ATR-FTIR), and Confocal Raman Microscopy (CRM) confirmed the particles’ chemical homogeneity. The solubility and Partition coefficient (LogP) of Lactomorphin were determined by the analytical and computational methodology and revealed the hydrophilicity of Lactomorphin. A thermal degradation study was performed by exposing samples of solid-state Lactomorphin to a high temperature (62 °C) combined with zero relative humidity (RH) and to a high temperature (62 °C) combined with a high RH (75%) to evaluate the stability of Lactomorphin under these two different conditions. The solid-state processed particles exhibited excellent aerosol dispersion performance with an FDA-approved human DPI device to reach lower airways. The cell viability resazurin assay showed that Lactomorphin is safe up to 1000 μg/mL on nasal epithelium cells, lung cells, endothelial, and astrocyte brain cells.

Ischemic heart disease, typically caused by myocardial infarction (MI), is the leading cause of death. Ischemic reperfusion (IR) injury following MI is multifaceted, driven by reactive oxidative species (ROS), calcium overload, and inflammatory responses. Because our novel glycopeptide derivative of Angiotensin-(1-7), PNA5, has an improved half-life, decreases circulating inflammatory cytokines, and inhibits endothelial ROS production, we predict that PNA5 will attenuate IR sequelae post-IR. Three-month-old C57Bl/6J male mice were subjected to IR and treated subcutaneously, with PNA5 (100 µg/kg/day,  = 14) or saline (  = 12) starting immediately after reperfusion and continued daily for 8 weeks. Echocardiograms were taken 2, 5, and 8 weeks post-IR in B-mode using the Vevo 2100 High-Resolution Imaging System (Visual Sonics, Canada). Data were analyzed using Vevo 2100® analytic software. The hearts of the mice were stained for infarct size using 2-3-4-triphenyltetrazolium chloride, fibrosis using Picrosirius Red, and inflammation via immunofluorescence for TNFα. Conventional transthoracic echocardiography showed early improvement in ejection fraction by 5 weeks post-IR. Using speckle echocardiography, we demonstrated that PNA5 treatment improved the parameters of strain and dyssynchrony in regional and temporal domains. Global longitudinal strain (GLS) and left ventricular dyssynchrony showed continued dysfunction in untreated animals post-IR, whereas measures of ejection fraction did not. Along with reduced infarct size, PNA5 treatment improved cardiac remodeling, evidenced by reduced scarring within the midapical regions of the heart compared with untreated animals. These data suggest that PNA5 treatments improve heart outcomes post-IR and could potentially be a therapeutic for IR injury; measures of GLS and dyssynchrony may provide more relevant insight into the protective effects of PNA5.

The peptide hormone Angiotensin (1—7), Ang (1—7) or (Asp-Arg-Val-Tyr-Ile-His-Pro), is an essential component of the renin–angiotensin system (RAS) peripherally and is an agonist of the Mas receptor centrally. Activation of this receptor in the CNS stimulates various biological activities that make the Ang (1—7)/MAS axis a novel therapeutic approach for the treatment of many diseases. The related O-linked glycopeptide, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-β-D-Glc)-amide (PNA5), is a biousian revision of the native peptide hormone Ang (1—7) and shows enhanced stability in vivo and greater levels of brain penetration. We have synthesized the native Ang (1—7) peptide and the glycopeptide, PNA5, and have formulated them for targeted respiratory delivery as inhalable dry powders. Solid phase peptide synthesis (SPPS) successfully produced Ang (1—7) and PNA5. Measurements of solubility and lipophilicity of raw Ang (1—7) and raw PNA5 using experimental and computational approaches confirmed that both the peptide and glycopeptide have high-water solubility and are amphipathic. Advanced organic solution spray drying was used to engineer the particles and produce spray-dried powders (SD) of both the peptide and the glycopeptide, as well as co-spray-dried powders (co-SD) with the non-reducing sugar and pharmaceutical excipient, trehalose. The native peptide, glycopeptide, SD, and co-SD powders were comprehensively characterized, and exhibited distinct glass transitions (Tg) consistent with the amorphous glassy state formation with Tgs that are compatible with use in vivo. The homogeneous particles displayed small sizes in the nanometer size range and low residual water content in the solid-state. Excellent aerosol dispersion performance with a human DPI device was demonstrated. In vitro human cell viability assays showed that Ang (1—7) and PNA5 are biocompatible and safe for different human respiratory and brain cells.

The sphingosine-1-phosphate receptor 1 (S1P1), originally the endothelial differentiation gene 1 receptor (EDG-1), is one of five G protein–coupled receptors (GPCRs) S1P1–5 that bind to and are activated by sphingosine-1-phosphate (S1P). The lipid S1P is an intermediate in sphingolipid homeostasis, and S1P1 is a major medical target for immune system modulation; agonism of the receptor produces a myriad of biological responses, including endothelial cell barrier integrity, chemotaxis, lymphocyte trafficking/targeting, angiogenesis, as well as regulation of the cardiovascular system. Use of in silico docking simulations on the crystal structure of S1P1 allows for pinpointing the residues within the receptor’s active site that actively contribute to the binding of S1P, and point to how these specific interactions can be exploited to design more effective synthetic analogs to specifically target S1P1 in the presence of the closely related receptors S1P2, S1P3, S1P4, and S1P5. We examined the binding properties of the endogenous substrate as well as a selection of synthetic sphingosine-derived S1P1 modulators of S1P1 with in silico docking simulations using the software package Molecular Operating Environment® (MOE®). The modeling studies reveal the relevance of phosphorylation, i.e., the presence of a phosphate or phosphonate moiety within the substrate for successful binding to occur, and indicate which residues are responsible for S1P1 binding of the most prominent sphingosine-1-phosphate receptor (S1PR) modulators, including fingolimod and its structural relatives. Furthermore, trends in steric preferences as for the binding of enantiomers to S1P1 could be observed, facilitating future design of receptor-specific substrates to precisely target the active site of S1P1.