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Nose to brain delivery of naringin-loaded chitosan nanoparticles for potential use in oxaliplatin-induced chemobrain in rats: Impact on oxidative stress, cGAS/STING and HMGB1/RAGE/TLR2/MYD88 inflammatory axes

ABSTRACT Objectives Oxaliplatininduces chemobrain in cancer patients/survivors. Nutraceuticalnaringin has antioxidant and anti-inflammatory properties with low oralbioavailability. Our aim was to formulate naringin in chitosan nanoparticles fornose to brain delivery and assess its neuroprotective effect against oxaliplatin-inducedchemobrain in rats. Methods Naringinchitosan nanoparticles were prepared by ionic gelation. Rats were administeredoral naringin (80 mg/kg), intranasal naringin (0.3 mg/kg) or intranasal naringin-loadedchitosan nanoparticles (0.3 mg/kg). Naringin’s neuroprotective efficacy wasassessed based on behavioral tests, histopathology, and measuring oxidativestress and inflammatory markers. Results Selectednanoparticles formulation showed drug loading of 5%, size of 150 nm and werecationic. Intranasal naringin administration enhanced memory function,inhibited hippocampal acetylcholinesterase activity, and corrected oxaliplatin-inducedhistological changes. Moreover, it reduced malondialdehyde and elevated reducedglutathione hippocampal levels. Furthermore, it decreased levels of inflammatorymarkers: NF-kB and TNF-α by 1.25-fold.Upstream to this inflammatory status, intranasal naringin downregulated thehippocampal protein levels of two pathways: cGAS/STINGand HMGB1/RAGE/TLR2/MYD88. Conclusion Intranasalnaringin-loaded chitosan nanoparticles showed superior amelioration ofoxaliplatin-induced chemobrain in rats at a dose 267-fold lower to thatadministered orally. The potential involvement of cGAS/STINGand HMGB1/RAGE/TLR2/MYD88 pathways in the mechanistic process of eitheroxaliplatin-induced chemobrain or naringin-mediated neuroprotection was evidenced.

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The crossroad of nanovesicles and oral delivery of insulin

ABSTRACT Introduction Diabetes mellitus is one of the challenging health problems worldwide. Multiple daily subcutaneous injection of insulin causes poor compliance in patients. Development of efficient oral formulations to improve the quality of life of such patients has been an important goal in pharmaceutical industry. However, due to serious issues such as low bioavailability and instability, it has not been achieved yet. Areas covered Due to functional properties of the vesicles and the fact that hepatic directed vesicles of insulin could reach the clinical phases, we focused on three main vesicular delivery systems for oral delivery of insulin; liposomes, niosomes and polymersomes. Recent papers were thoroughly discussed to provide a broad overview of such oral delivery systems. Expert opinion Although conventional liposomes are instable in the presence of bile salts, their further modifications such as surface coating could increase their stability in the GI tract. Bilosomes showed good flexibility and stability in GI fluids. Also, niosomes were stable but they could not induce significant hypoglycemia in animal studies. Although polymersomes were effective, they are expensive and there are some issues about their safety and industrial scale up. Also, we believe that other modifications such as addition of a targeting agent, or surface coating of the vesicles could significantly increase the bioavailability of insulin-loaded vesicles.

Challenges and opportunities in delivering oral peptides and proteins

ABSTRACT Introduction Rapid advances in bioengineering enable the use of complex proteins as therapeutic agents to treat diseases. Compared with conventional small molecule drugs, proteins have multiple advantages, including high bioactivity and specificity with low toxicity. Developing oral dosage forms with active proteins is a route to improve patient compliance and significantly reduce production costs. However, the gastrointestinal environment remains a challenge to this delivery path due to enzymatic degradation, low permeability, and weak absorption, leading to reduced delivery efficiency and poor clinical outcomes. Areas covered This review describes the barriers to oral delivery of peptides and complex proteins, current oral delivery strategies utilized and the opportunities and challenges ahead to try and circumvent these barriers. Oral protein drugs on the market and clinical trials provide insights and approaches for advancing delivery strategies. Expert opinion Although most current studies on oral protein delivery rely on in vitro and in vivo animal data, the safety and limitations of the approach in humans remain uncertain. The shortage of clinical data limits the development of new or alternative strategies. Therefore, designing appropriate oral delivery strategies remains a significant challenge and requires new ideas, innovative design strategies and novel model systems.

Current status of porous coordination networks (PCNs) derived porphyrin spacers for cancer therapy

ABSTRACT Introduction Porous coordination networks (PCNs) have been widely used in large number of applications such as light harvesting, catalysis, and biomedical applications. Inserting porphyrins into PCNs scaffolds can alleviate the solubility and chemical stability problems associated with porphyrin ligands and add functionality to PCNs. The discovery that some PCNs materials have photosensitizer and acoustic sensitizer properties has attracted significant attention in the field of biomedicine, particularly in cancer therapy. This article describes the latest applications of the porphyrin ligand-based family of PCNs in cancer chemodynamic therapy (CDT), photodynamic therapy (PDT), sonodynamic therapy (SDT), photothermal therapy (PTT), and combination therapies and offers some observations and reflections on them. Areas covered This article discusses the use of the PCN family of MOFs in cancer treatment, specifically focusing on chemodynamic therapy, sonodynamic therapy, photodynamic therapy, photothermal therapy, and combination therapy. Expert opinion Although a large number of PCNs have been developed for use in novel cancer therapeutic approaches, further improvements are needed to advance the use of PCNs in the clinic. For example, the main mechanism of action of PCNs against cancer and the metabolic processes in organisms, and how to construct PCNs that maintain good stability in the complex environment of organisms.

Receptor-mediated transcytosis of macromolecules across the blood–brain barrier

ABSTRACT Introduction The blood–brain barrier (BBB) restricts brain access of virtually all macromolecules. Receptor-mediated transcytosis (RMT) is one strategy toward their brain delivery. In this strategy, targeting ligands conjugated to therapeutic payload or decorating particles containing the payload interact with targets on brain capillary endothelial cells (BCEC), triggering internalization, trafficking, and release from BCEC. Areas covered RMT at the BBB has leveraged multiple formats of macromolecules and large particles. Interactions between those and BCEC have been studied primarily using antibodies, with findings applicable to the design of larger particles. BBB-penetrant constructs have also been identified in screening campaigns and directed evolution, and subsequently found to interact with RMT targets. In addition, BCEC targeted by constructs incorporating genomic payload can be made to produce therapeutic proteins. Expert opinion While targeting may not be strictly necessary to reach a therapeutic effect for all macromolecules, it can improve a molecule’s BBB transport, exposing it to the entire brain parenchyma and enhancing its effect. Constructs with better BCEC transcytosis may be designed rationally, leveraging knowledge about BCEC trafficking, and found in screening campaigns, where this knowledge can reduce the search space and improve iterative refinement. Identification of new targets may also help generate BBB-crossing constructs.