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.

ABSTRACT Introduction Intravenous nanocrystals (INCs) have shown intrinsic advantages in antitumor applications, particularly their properties of high drug loading, low toxicity, and controllable size. Therefore, it has a very bright application prospect as a drug delivery system. Areas covered The ideal formulation design principles, fabrication, solidification, in vivo fate of INCs, the applications in drug delivery system (DDS) and the novel applications are covered in this review. Expert opinion It is vital to select a suitable formulation and fabrication method to produce a stable and sterile INCs. Besides, the type of stabilizers and physical characteristics can also influence the in vivo fate of INCs, which is worthy of further studying. Based on wide researches about applications of INCs in cancer, biomimetic INCs are concerned increasingly for its favorable compatibility. The output of these studies suggested that INCs-based drug delivery could be a novel strategy for addressing the delivery of the drug that faces solubility, bioavailability, and toxicity problems.

ABSTRACT Introduction Oral cavity drug and vaccine delivery has the potential for local targeting, dose reduction, minimization of systemic side effects, and generation of mucosal immunity. To overcome current limitations of delivery into the oral cavity mucosa, microneedles (MNs) have emerged as a promising technology. Areas covered We reviewed the literature on MN application in the oral cavity, including in vitro studies, in vivo animal studies, and human clinical trials. Expert opinion MNs are sufficiently robust to cross the oral cavity epithelium and nearly painless when applied to different parts of the human oral mucosa including the lip, cheek, tongue, and palate. In recent years, MNs have been evaluated for different applications, including vaccination, topical anesthetic delivery, and treatment of local oral pathologies such as oral lesions or carcinomas. MNs are attractive because they have the potential to produce a better treatment outcome with reduced side effects. Over the coming years, we project a significant increase in research related to the development of MNs for use in dentistry and other medical conditions of the mouth.

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.

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.

ABSTRACT Introduction Oral delivery is the most commonly used route of drug administration owing to good patient compliance. However, the gastrointestinal (GI) tract contains multiple physiological barriers that limit the absorption efficiency of conventional passive delivery systems resulting in a low drug concentration reaching the diseased sites. Micro/nanorobots can convert energy to self-propulsive force, providing a novel platform to actively overcome GI tract barriers for noninvasive drug delivery and treatment. Areas covered In this review, we first describe the microenvironments and barriers in the different compartments of the GI tract. Afterward, the applications of micro/nanorobots to overcome GI tract barriers for active drug delivery are highlighted and discussed. Finally, we summarize and discuss the challenges and future prospects of micro/nanorobots for further clinical applications. Expert opinion Micro/nanorobots with the ability to autonomously propel themselves and to load, transport, and release payloads on demand are ideal carriers for active oral drug delivery. Although there are many challenges to be addressed, micro/nanorobots have great potential to introduce a new era of drug delivery for precision therapy.

ABSTRACT Introduction Self-triggered micro/milli devices (STMDs), which are artificial devices capable of responding to the surrounding environment and transferring external energy into kinetic energy thus realizing autonomous movement, have come to the forefront as a powerful tool in cargo delivery via gastrointestinal tract. Urgent needs have been raised to overview the development of this area. Areas covered We summarize the advancement of designing STMDs for delivery via gastrointestinal tract. We first give a brief overview on the opportunities and challenges of delivery via gastrointestinal tract involving gastric barriers and intestinal barriers. Then, emphasis is laid on the design and applications of STMDs for delivery via gastrointestinal tract. We focus on their morphological characteristics and function design, expounding their working mechanisms in the complex gastrointestinal tract. Expert opinion Although with much progress in STMDs, there is still a huge gap between laboratory researches and clinical applications due to some limitations including latent digestive burden, sophisticated fabrication, unstable delivery and so on. We give a discussion on the potential, challenges and prospects of developing STMDs for delivery via gastrointestinal tract.

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.

ABSTRACT Introduction Glaucoma is the leading cause of irreversible blindness worldwide. Schlemm’s canal surgery using an iTrack flexible microcatheter has become popular because of its high quality-of-life issues and the growing demand for less invasive but effective procedures. The unique design of the microcatheter makes it a multimodal tool, which can be used not only in the field of antiglaucoma surgery but also as a drug delivery system to treat various conditions. Areas covered This review presents an update on the selected aspects of a drug delivery system using the iTrack microcatheter, including glaucoma gene therapy and posterior-segment diseases, both in animal models and human patients. The authors also report the case of a patient with branch retinal vein occlusion treated with suprachoroidal bevacizumab in the submacular region administered with the iTrack catheter. Expert opinion The findings presented in this study may indicate that the application of a microcatheter in open-angle glaucoma gene therapy is reasonable and can be combined with full or partial surgical canaloplasty procedures. Translation of this potential into a treatment modality would require overcoming multiple barriers.

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.