Protein and peptide therapeutics require parenteral administration, which can be a deterrent to medication adherence. For this reason, there have been extensive efforts to develop alternative delivery strategies, particularly for peptides such as insulin that are used to treat endocrine disorders. Oral delivery is especially desirable, but it faces substantial barriers related to the structural organization and physiological function of the gastrointestinal tract. This article highlights strategies designed to overcome these barriers, including permeation enhancers, inhibitors of gut enzymes, and mucus-penetrating and cell-penetrating peptides. It then focuses on the experience with oral peptides that have reached clinical trials, including insulin, calcitonin, parathyroid hormone and vasopressin, with an emphasis on the advances that have recently led to the landmark approval of an oral formulation of the glucagon-like peptide 1 receptor agonist semaglutide for the treatment of type 2 diabetes.

Advances in oral peptide therapeutics.

Nanoparticles (NPs) and submicron particles are increasingly used as carriers for delivering therapeutic compounds to cells. Their entry into the cell represents the initial step in this delivery process, being most of the nanoparticles taken up by endocytosis, although other mechanisms can contribute to the uptake. To increase the delivery efficiency of therapeutic compounds by NPs and submicron particles is very relevant to understand the mechanisms involved in the uptake process. This review covers the proposed pathways involved in the cellular uptake of different NPs and submicron particles types as well as the role that some of the physicochemical nanoparticle characteristics play in the uptake pathway preferentially used by the nanoparticles to gain access and deliver their cargo inside the cell.

https://www.mdpi.com/1999-4923/12/4/371/pdf

Endocytosis: The Nanoparticle and Submicron Nanocompounds Gateway into the Cell

Starting with the enhanced permeability and retention (EPR) effect discovery, nanomedicine has gained a crucial role in cancer treatment. The advances in the field have led to the approval of nanodrugs with improved safety profile and still inspire the ongoing investigations. However, several restrictions, such as high manufacturing costs, technical challenges, and effectiveness below expectations, raised skeptical opinions within the scientific community about the clinical relevance of nanomedicine. In this review, we aim to give an overall vision of the current hurdles encountered by nanotherapeutics along with their design, development, and translation, and we offer a prospective view on possible strategies to overcome such limitations.

Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope.

Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches.

The treatment of central nervous system (CNS) disorders always remains a challenge for the researchers. The presence of various physiological barriers, primarily the blood-brain barrier (BBB) limits the accessibility of the brain and hinders the efficacy of various drug therapies. Hence, drug targeting to the brain, particularly to the diseased cells by circumventing the physiological barriers is essential to develop a promising therapy for the treatment of brain disorders. Presently, the investigations emphasize the role of different nanocarrier systems or surface modified target specific novel carrier system to improve the efficiency and reduce the side effects of the brain therapeutics. Such approaches supposed to circumvent the BBB or have the ability to cross the barrier function and thus increases the drug concentration in the brain. Although the efficacy of novel carrier system depends upon various physiological factors like active efflux transport, protein corona of the brain, stability, and toxicity of the nanocarrier, physicochemical properties, patient-related factors and many more. Hence, to develop a promising carrier system, it is essential to understand the physiology of the brain and BBB and also the other associated factors. Along with this, some alternative route like direct nose-to-brain drug delivery can also offer a better means to access the brain without exposure of the BBB. In this review, we have discussed the role of various physiological barriers including the BBB and blood-cerebrospinal fluid barrier (BCSFB) on the drug therapy and the mechanism of drug transport across the BBB. Further, we discussed different novel strategies for brain targeting of drug including, polymeric nanoparticles, lipidic nanoparticles, inorganic nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, quantum dots, etc. along with the intranasal drug delivery to the brain. We have also illustrated various factors affecting the drug targeting efficiency of the developed novel carrier system.

/pdf/recent-expansions-of-novel-strategies-towards-the-drug-3ystdb5kib.pdf

Recent expansions of novel strategies towards the drug targeting into the brain.

Glioblastoma is the most common malignant brain tumor Efficient delivery of drugs targeting glioblastomas remains a challenge Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified po

Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting.

The oral absorption of exenatide, a drug for type 2 diabetes treatment, can be improved by using nanoparticles (NPs) for its delivery. To improve the mucus penetration and intestinal absorption of exenatide, we designed a block copolymer, CSKSSDYQC-dextran-poly(lactic-co-glycolic acid) (CSK-DEX-PLGA), and used it for the preparation of exenatide-loaded NPs. The functionalized exenatide-loaded NPs composed of CSK-DEX-PLGA were able to target intestinal epithelial cells and reduce the mucus-blocking effect of the intestine. Moreover, the CSK modification of DEX-PLGA was found to significantly promote the absorption efficiency of NPs in the small intestine based on in vitro ligation of the intestinal rings and an examination of different intestinal absorption sites. Compared to DEX-PLGA-NPs (DPs), the absorption of CSK-DEX-PLGA-NPs (CDPs) was increased in the villi, allowing the drug to act on gobletlike Caco-2 cells through clathrin-, caveolin-, and gap-mediated endocytosis. Furthermore, the enhanced transport ability of CDPs was observed in a study on Caco-2/HT-29-MTX cocultured cells. CDPs exhibited a prolonged hypoglycemic response with a relative bioavailability of 9.2% in diabetic rats after oral administration. In conclusion, CDPs can target small intestinal goblet cells and have a beneficial effect on the oral administration of macromolecular peptides as a nanometer-sized carrier.

Mingyu Zhao

Papers

Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting.

Synthesis of CSK-DEX-PLGA Nanoparticles for the Oral Delivery of Exenatide to Improve Its Mucus Penetration and Intestinal Absorption