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Background: Based on the concept of "multimodal analgesia", a novel dual drug delivery system was designed to achieve synergistic analgesia between najanajaatra venom protein (αCT) and resveratrol (Res). In order to meet the joint loading of two drugs with different physicochemical properties without affecting each other, an oral Janus nanoparticle (JNP) with a unique cavity structure and synergistic drug delivery was constructed using an improved double emulsion solvent evaporation method, and combined with low-molecular-weight chitosan/sodium alginate and PLGA to achieve its pH-responsive., Results: The synthesized αCT/Res-JNPs are homogeneous in shape, with a two-compartment structure, approximately 230 nm in size, and zeta potential of 23.6 mV. Drug release assayed in vitro show that JNP was stable in simulated gastric juice (pH = 1.2) but was released in phosphate buffer saline (pH = 7.4). After intragastric administration in rats, PK evaluation showed that αCT/Res-JNPs could significantly improve the oral bioavailability, and the simultaneous encapsulation of the two drugs had no significant interaction on PK parameters. An obvious synergistic analgesic effects of αCT/Res-JNPs was confirmed in a spinal cord injury and acute pain model. Confocal laser scanning microscopy and single-pass intestinal perfusion model provided strong evidence that αCT/Res-JNPs could pass through intestinal epithelial cells, and the endocytosis pathway was mainly involved in the mediation and pinocytosis of reticulin. The concentrations of αCT and Res from αCT/Res-JNP in lymphatic transport were only about 8.72% and 6.08% of their blood concentrations at 1 h, respectively, which indicated that lymphatic transport in the form of JNP has limited advantages in improving the oral bioavailability of Res and αCT. Cellular uptake efficiency at 4 h was about 10-15% in Caco-2 cell lines for αCT/Res-JNP, but was reduced to 7% in Caco-2/HT29-MTX co-culture models due to the hindrance by the mucus layers. Approximately 12-17% of αCT/Res-JNP were transported across Caco-2/HT29-MTX/Raji monolayers. The cumulative absorption of JNP in three cell models was higher than that of free drug., Conclusions: This study investigated the contribution of Janus nanoparticles in oral absorption, and provide a new perspective for oral administration and analgesic treatment of dual drug delivery system containing peptide drugs., (© 2021. The Author(s).)

The dispersibility and stability issues of peptide drugs during preparation and storage hinder the widespread adoption of pressurized metered-dose inhaler (pMDI). This study aimed to develop a reverse microemulsion (RM) of exenatide (EXE) pMDI through a liquid-based bottom-up method, thus to overcome the stability issue of peptide drugs encountered in traditional top-down methods, such as milling down and high-pressure homogenization. In this study, Pluronic® L64 (L64) was chosen as a surfactant to prepare the EXE-RM pMDI formulations with the assistance of ethanol. The results showed RM possessed a particle size of 123.80 ± 2.91 nm with 0.121 ± 0.024 PdI and a satisfied fine-particle fraction of 41.30 ± 3.73% measured by a next-generation impactor. In addition, the dispersion stability of RM pMDI was maintained after storage at 4 °C for 50 days. The secondary structure of EXE was maintained during the preparation process. Moreover, the results indicated that L64 was compatible with cells and could improve the penetration of EXE through cell monolayers. Through the liquid-based bottom-up method, EXE-RM pMDI was successfully prepared and exhibited favorable stability and aerodynamic performance. This study offers a preparation strategy to enhance the stability of peptides in pMDIs.

About 25years ago it was demonstrated that certain peptides possess the ability to cross the plasma membrane. This led to the development of cell-penetrating peptides (CPPs) as vectors to mediate the cellular entry of (macro-)molecules that do not show cell entry by themselves. Nonetheless, in spite of an early bloom of promising pre-clinical studies, not a single CPP-based drug has been approved, yet. It is a paradigm in CPP research that the peptides are taken up by virtually all cells. In exploratory research and early preclinical development, this assumption guides the choice of the therapeutic target. However, while this indiscriminatory uptake may be the case for tissue culture experiments, in an organism this is clearly not the case. Biodistribution analyses demonstrate that CPPs only target a very limited number of cells and many tissues are hardly reached at all. Here, we review biodistribution analyses of CPPs and CPP-based drug delivery systems. Based on this analysis we propose a paradigm change towards a more opportunistic approach in CPP research. The application of CPPs should focus on those pathophysiologies for which the relevant target cells have been shown to be reached in vivo., (Copyright © 2017. Published by Elsevier Ltd.)

Aim: It was the aim of this study to evaluate the mucus permeating properties of self-emulsifying drug delivery systems (SEDDS) exhibiting different size and zeta potential., Methods: Various SEDDS were prepared and characterized regarding droplet size, zeta potential and stability. Desmopressin was incorporated as model peptide drug and log P (SEDDS/water) was determined. Thereafter, mucus permeation studies with freshly isolated porcine mucus via Transwell method were performed. Moreover, the impact of water movement on mucus permeation of SEDDS was investigated. Different types of nanocarriers including nanoparticles and liposomes served as references., Results: SEDDS exhibited an initial droplet size of 25.0 ± 2.2, 49.5 ± 4.6, 123.5 ± 12.1, 226.2 ± 93.4 and 502.9 ± 93.7 nm and a zeta potential of +24.4 ± 4.6, +10.6 ± 2.0, 0.2 ± 3.8, -8.2 ± 3.4 and -35.1 ± 2.7 mV. Log P was in the range of 1.29-2.09 and mucus permeation studies with these SEDDS revealed a clear correlation between droplet size and permeation rate. The smaller SEDDS were, the higher their mucus permeating properties were. Negatively charged SEDDS demonstrated a higher permeation rate than positively charged SEDDS. In comparison to liposomes and solid nanocarriers SEDDS exhibited up to 5-fold higher mucus permeating properties., Conclusion: Small droplet size and negative zeta potential of SEDDS could be identified as key parameters for their mucus permeating properties., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Peptides have gained tremendous popularity as biological therapeutic agents in recent years due to their favourable specificity, diversity of targets, well-established screening methods, ease of production, and lower cost. However, their poor physiological and storage stability, pharmacokinetics, and fast clearance have limited their clinical translation. Novel nanocarrier-based strategies have shown promise in overcoming these issues. In this direction, porous silicon (pSi) and mesoporous silica nanoparticles (MSNs) have been widely explored as potential carriers for the delivery of peptide therapeutics. These materials possess several advantages, including large surface areas, tunable pore sizes, and adjustable pore architectures, which make them attractive carriers for peptide delivery systems. In this review, we cover pSi and MSNs as drug carriers focusing on their use in peptide delivery. The review provides a brief overview of their fabrication, surface modification, and interesting properties that make them ideal peptide drug carriers. The review provides a systematic account of various studies that have utilised these unique porous carriers for peptide delivery describing significant in vitro and in vivo results. We have also provided a critical comparison of the two carriers in terms of their physicochemical properties and short-term and long-term biocompatibility. Lastly, we have concluded the review with our opinion of this field and identified key areas for future research for clinical translation of pSi and MSN-based peptide therapeutic formulations. [ABSTRACT FROM AUTHOR]

Diabetes is a global disease that can lead to a range of complications. Currently, the treatment of type 2 diabetes focuses on oral hypoglycemic drugs and insulin analogues. Studies have shown that drugs such as oral metformin are useful in the treatment of diabetes but can limit the liver's ability to release sugar. The development of glucose-lowering peptides has provided new options for the treatment of type 2 diabetes. Peptide drugs have low oral utilization due to their easy degradation, short half-life, and difficulty passing through the intestinal mucosa. Therefore, improving the oral utilization of peptide drugs remains an urgent problem. This paper reviews the research progress of peptide drugs in the treatment of diabetes mellitus and proposes that different types of nano-formulation carriers, such as liposomes, self-emulsifying drug delivery systems, and polymer particles, should be combined with peptide drugs for oral administration to improve their absorption in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

The development of peptide drugs has made tremendous progress in the past few decades because of the advancements in modification chemistry and analytical technologies. The novel‐designed peptide drugs have been modified through various biochemical methods with improved diagnostic, therapeutic, and drug‐delivery strategies. Researchers found it a helping hand to overcome the inherent limitations of peptides and bring continued advancements in their applications. Furthermore, the emergence of peptide‐drug conjugates (PDCs)—utilizes target‐oriented peptide moieties as a vehicle for cytotoxic payloads via conjugation with cleavable chemical agents, resulting in the key foundation of the new era of targeted peptide drugs. This review summarizes the various classifications of peptide drugs, suitable chemical modification strategies to improve the ADME (adsorption, distribution, metabolism, and excretion) features of peptide drugs, and recent (2015–early 2024) progress/achievements in peptide‐based drug delivery systems as well as their fruitful implication in preclinical and clinical studies. Furthermore, we also summarized the brief description of other types of PDCs, including peptide‐MOF conjugates and peptide‐UCNP conjugates. The principal aim is to provide scattered and diversified knowledge in one place and to help researchers understand the pinching knots in the science of PDC development and progress toward a bright future of novel peptide drugs. [ABSTRACT FROM AUTHOR]

In situ depot gel is a type of polymeric long-acting injectable (pLAI) drug delivery system; compared to microsphere technology, its preparation process is simpler and more conducive to industrialization. To ensure the chemical stability of peptide ACTY116, we avoided the use of harsh conditions such as high temperatures, high shear mixing, or homogenization; maintaining a water-free and oxygen-free environment was also critical to prevent hydrolysis and oxidation. Molecular dynamics (MDs) simulations were employed to assess the stability mechanism between ACTY116 and the pLAI system. The initial structure of ACTY116 with an alpha helix conformation was constructed using SYBYL-X, and the copolymer PLGA was generated by AMBER 16; results showed that PLGA-based in situ depot gel improved conformational stability of ACTY116 through hydrogen bonds formed between peptide ACTY116 and the components of the pLAI formulation, while PLGA (Poly(DL-lactide-co-glycolide)) also created steric hindrance and shielding effects to prevent conformational changes. As a result, the chemical and conformational stability and in vivo long-acting characteristics of ACTY116 ensure its enhanced efficacy. In summary, we successfully achieved our objective of developing a highly stable peptide-loaded long-acting injectable (LAI) in situ depot gel formulation that is stable for at least 3 months under harsh conditions (40 °C, above body temperature), elucidating the underlying stabilisation mechanism, and the high stability of the ACTY116 pLAI formulation creates favourable conditions for its in vivo pharmacological activity lasting for weeks or even months. [ABSTRACT FROM AUTHOR]

Purpose: Proteins and peptides have secured a place as excellent therapeutic moieties on account of their high selectivity and efficacy. However due to oral absorption limitations, current formulations are mostly delivered parenterally. Oral delivery of peptides and proteins (PPs) can be considered the need of the hour due to the immense benefits of this route. This review aims to critically examine and summarize the innovations and mechanisms involved in oral delivery of peptide and protein drugs. Methods: Comprehensive literature search was undertaken, spanning the early development to the current state of the art, using online search tools (PubMed, Google Scholar, ScienceDirect and Scopus). Results: Research in oral delivery of proteins and peptides has a rich history and the development of biologics has encouraged additional research effort in recent decades. Enzyme hydrolysis and inadequate permeation into intestinal mucosa are the major causes that result in limited oral absorption of biologics. Pharmaceutical and technological strategies including use of absorption enhancers, enzyme inhibition, chemical modification (PEGylation, pro-drug approach, peptidomimetics, glycosylation), particulate delivery (polymeric nanoparticles, liposomes, micelles, microspheres), site-specific delivery in the gastrointestinal tract (GIT), membrane transporters, novel approaches (self-nanoemulsifying drug delivery systems, Eligen technology, Peptelligence, self-assembling bubble carrier approach, luminal unfolding microneedle injector, microneedles) and lymphatic targeting, are discussed. Limitations of these strategies and possible innovations for improving oral bioavailability of protein and peptide drugs are discussed. Conclusion: This review underlines the application of oral route for peptide and protein delivery, which can direct the formulation scientist for better exploitation of this route. [ABSTRACT FROM AUTHOR]

Nanocarriers provide a number of undeniable advantages that could improve the bioavailability of active agents for human, animal, and plant cells. In this study, we compared hybrid nanoparticles (HNPs) consisting of a calcium phosphate core coated with chitosan with unmixed calcium phosphate (CaP) and chitosan nanoparticles (CSNPs) as carriers of a model substrate, enalaprilat. This tripeptide analog is an inhibitor of angiotensin-converting enzyme and was chosen by its ability to lower intraocular pressure (IOP). In particular, we evaluated the physicochemical characteristics of the particles using dynamic light scattering (DLS) and scanning electron microscopy (SEM) and analyzed their ability to incorporate and release enalaprilat. HNPs exhibited the highest drug loading capacity and both HNPs and CSNPs demonstrated slow drug release. The comparison of the physiological effects of enalaprilat-loaded CaP particles, HNPs, and CSNPs in terms of their impact on IOP in rabbits revealed a clear advantage of hybrid nanoparticles over both inorganic and chitosan nanoparticles. These results could have important mechanistic implications for developing nano-based delivery systems for other medical, veterinary, and agricultural applications. [ABSTRACT FROM AUTHOR]

Caco-2 cell monolayers are widely employed as an in vitro model of the intestinal barrier, capable of accurately predicting the absorption of conventional small-molecule drugs. However, this model may not be applicable to all drugs, and the accuracy of absorption prediction is typically poor for high molecular weight drugs. Recently, human induced pluripotent stem (iPS) cell-derived small intestinal epithelial cells (hiPSC-SIECs), exhibiting properties similar to those of the small intestine when compared with Caco-2 cells, have been developed and are considered a novel candidate model for in vitro evaluation of intestinal drug permeability. Therefore, we evaluated the utility of human hiPSC-SIECs as a new in vitro model to predict the intestinal absorption of middle-molecular weight drugs and peptide drugs. Firstly, we showed that the hiPSC-SIEC monolayer allowed faster transport of peptide drugs (insulin and glucagon-like peptide-1) than the Caco- 2 cell monolayer. Second, we revealed that hiPSC-SIECs require divalent cations (Mg2+ and Ca2+) to maintain barrier integrity. Third, we demonstrated that experimental conditions established for Caco-2 cells are not persistently applicable to hiPSC-SICEs when analyzing absorption enhancers. Comprehensively clarifying the features of hiPSC-SICEs is essential to establish a new in vitro evaluation model. [ABSTRACT FROM AUTHOR]

Although polyethylene glycol (PEG), or "PEGylation" has become a widely applied approach for improving the efficiency of drug delivery, the immunogenicity and non-biodegradability of this synthetic polymer have prompted an evident need for alternatives. To overcome these caveats and to mimic PEG -or other natural or synthetic polymers- for the purpose of drug half-life extension, unstructured polypeptides are designed. Due to their tunable length, biodegradability, low immunogenicity and easy production, unstructured polypeptides have the potential to replace PEG as the preferred technology for therapeutic protein/peptide delivery. This review provides an overview of the evolution of unstructured polypeptides, starting from natural polypeptides to engineered polypeptides and discusses their characteristics. Then, it is described that unstructured polypeptides have been successfully applied to numerous drugs, including peptides, proteins, antibody fragments, and nanocarriers, for half-life extension. Innovative applications of unstructured peptides as releasable masks, multimolecular adaptors and intracellular delivery carriers are also discussed. Finally, challenges and future perspectives of this promising field are briefly presented. Polypeptide fusion technology simulating PEGylation has become an important topic for the development of long-circulating peptide or protein drugs without reduced activity, complex processes, and kidney injury caused by PEG modification. Here we provide a detailed and in-depth review of the recent advances in unstructured polypeptides. In addition to the application of enhanced pharmacokinetic performance, emphasis is placed on polypeptides as scaffolders for the delivery of multiple drugs, and on the preparation of reasonably designed polypeptides to manipulate the performance of proteins and peptides. This review will provide insight into future application of polypeptides in peptide or protein drug development and the design of novel functional polypeptides. [Display omitted] [ABSTRACT FROM AUTHOR]

In recent years, natural polyelectrolyte complex chitosan/poly-γ-glutamic acid (CS/γ-PGA) has emerged as a promising nanocarrier delivery system for drug delivery due to its non-toxic and easily degradable properties. However, tightly bound CS/γ-PGA complexes often lead to lower encapsulation efficiency of peptide drugs without coordination of metal ions. In this investigation, we find that procyanidin (PC), as a cross-linking agent, is able to combine with CS and insulin through hydrogen bonding, which significantly improve encapsulation efficiency of insulin up to 90% in CS/γ-PGA/PC complex nanoparticles (CNPs). The results of this study demonstrate that CNPs release insulin in a pH-dependent approach and greatly reduce its enzymatic degradation in vitro. The transepithelial permeability of the CNPs is 8.1-fold higher than that of native insulin via both endocytosis and paracellular passways. Further pharmacokinetic studies reveal an oral pharmacological availability of 9.81 ± 1.32% in type I diabetic rats after intragastric administration of freeze-dried CNPs which loaded in enteric-coated capsules. In consequence, CNPs not only improve oral bioavailability of insulin but also are a promising delivery platform for insulin or other peptide/protein drugs. [ABSTRACT FROM AUTHOR]

In the evolving landscape of cancer treatment, therapeutic peptides are assuming to play an increasingly vital role. Although the number of peptide drugs available for clinical cancer treatment is currently limited, extensive preclinical research is underway, presenting a promising trajectory for the future. The collaborative efforts of natural anti-cancer peptides (ACPs) and synthetic ACPs, propelled by advancements in molecular biology and peptide chemistry, are steering remarkable progress in this domain. We explores the intricate mechanisms underlying the anti-cancer effects of these peptides. The exploration of innovative strategies, including cancer immunotherapy and advanced drug delivery systems, is likely to contribute to the increasing presenceuse of peptide drugs in clinical cancer care. Furthermore, we delve into the potential implications and challenges associated with this anticipated shift, emphasizing the need for continued research and development to unlock the full therapeutic potential of peptide drugs in cancer treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Recently, two oral-administered peptide pharmaceuticals, semaglutide and octreotide, have been developed and are considered as a breakthrough in peptide and protein drug delivery system development. In 2019, the Food and Drug Administration (FDA) approved an oral dosage form of semaglutide developed by Novo Nordisk (Rybelsus®) for the treatment of type 2 diabetes. Subsequently, the octreotide capsule (Mycapssa®), developed through Chiasma's Transient Permeation Enhancer (TPE) technology, also received FDA approval in 2020 for the treatment of acromegaly. These two oral peptide products have been a significant success; however, a major obstacle to their oral delivery remains the poor permeability of peptides through the intestinal epithelium. Therefore, gastrointestinal permeation enhancers are of great relevance for the development of subsequent oral peptide products. Sodium salcaprozate (SNAC) and sodium caprylate (C8) have been used as gastrointestinal permeation enhancers for semaglutide and octreotide, respectively. Herein, we briefly review two approved products, Rybelsus® and Mycapssa®, and discuss the permeation properties of SNAC and medium chain fatty acids, sodium caprate (C10) and C8, focusing on Eligen technology using SNAC, TPE technology using C8, and gastrointestinal permeation enhancement technology (GIPET) using C10. [ABSTRACT FROM AUTHOR]

We investigated the anti-cancer properties of gold nanoparticles loaded TNF- and CALNN peptides, which we proposed as a potential drug delivery system using in vitro and in vivo models. The binding of GNPs-TNF- and GNPs-TNF-CALNN was characterized using a UV, ELISA and SEM analysis. The outcomes demonstrated that a novel drug delivery system had an anti-proliferative activity against breast cancer cell lines through a mechanism of apoptosis induction. In vivo model involved studying the cytotoxic influence of a drug delivery system GNPs, GNPs-TNF-α and GNPs-TNF-α-CALNN when applied to the transplanted AN-3 cell line. tumor sections were examined using microarray. In-vivo studies demonstrated that GNPs alone had less of a growth inhibitory effect on tumors implanted in mice when compared to GNPs-TNF – CALNN combined therapy. The cytotoxic assay showed that GNPs, GNPs-TNF-α and GNPs-TNF-α-CALNN exhibit selective toxicity towards cancer cells, inducing cell apoptosis through activation of caspase-3 and 7, p53 protein. [ABSTRACT FROM AUTHOR]

Drug delivery systems (DDS) for oral delivery of peptide drugs contain excipients that facilitate and enhance absorption. However, little knowledge exists on how DDS excipients such as permeation enhancers interact with the gastrointestinal mucus barrier. This study aimed to investigate interactions of the permeation enhancer sodium 8-[(2-hydroxybenzoyl)amino]octanoate (SNAC) with ex vivo porcine intestinal mucus (PIM), ex vivo porcine gastric mucus (PGM), as well as with in vitro biosimilar mucus (BM) by profiling their physical and barrier properties upon exposure to SNAC. Bulk mucus permeability studies using the peptides cyclosporine A and vancomycin, ovalbumin as a model protein, as well as fluorescein-isothiocyanate dextrans (FDs) of different molecular weights and different surface charges were conducted in parallel to mucus retention force studies using a texture analyzer, rheological studies, cryo-scanning electron microscopy (cryo-SEM), and single particle tracking of fluorescence-labelled nanoparticles to investigate the effects of the SNAC-mucus interaction. The exposure of SNAC to PIM increased the mucus retention force, storage modulus, viscosity, increased nanoparticle confinement within PIM as well as decreased the permeation of cyclosporine A and ovalbumin through PIM. Surprisingly, the viscosity of PGM and the permeation of cyclosporine A and ovalbumin through PGM was unaffected by the presence of SNAC, thus the effect of SNAC depended on the regional site that mucus was collected from. In the absence of SNAC, the permeation of different molecular weight and differently charged FDs through PIM was comparable to that through BM. However, while bulk permeation of neither of the FDs through PIM was affected by SNAC, the presence of SNAC decreased the permeation of FD4 and increased the permeation of FD150 kDa through BM. Additionally, and in contrast to observations in PIM, nanoparticle confinement within BM remained unaffected by the presence of SNAC. In conclusion, the present study showed that SNAC altered the physical and barrier properties of PIM, but not of PGM. The effects of SNAC in PIM were not observed in the BM in vitro model. Altogether, the study highlights the need for further understanding how permeation enhancers influence the mucus barrier and illustrates that the selected mucus model for such studies should be chosen with care. [Display omitted] • SNAC increases viscosity of ex vivo PIM resulting in decreased particle diffusion. • Effects of SNAC are different in ex vivo PGM and PIM. • The BM model shows similar macromolecular permeability as ex vivo PIM. • Utilization of several techniques improves understanding of SNAC-mucus interactions. [ABSTRACT FROM AUTHOR]

The recombinant spider silk proteins (spidroins) are promising biomaterials for the use as drug delivery system (DDS) because of their non-cytotoxicity, low immunogenicity and customizable properties. However, most reported spidroin-based materials as DDS derive from the repetitive domain of dragline silk protein, limiting us to take advantage of their desirable properties for medical and industrial innovation. Here, we produced the recombinant aciniform silk protein (rAcSp2) that contains only the N-terminal domain and formulated it into nanoparticles for use as a DDS. We demonstrated that antitumor peptide drugs such as ChMAP-28 can be loaded onto rAcSp2 particles via electrostatic interaction, with a high loading capacity of up to 45 % (w/w) and nearly 100 % loading efficiency. In addition, the release of ChMAP-28 depends on the pH and ionic strength of the release buffer. In the meantime, rAcSp2 particles not only effectively reduce the toxicity of ChMAP-28 to normal cells, but also significantly enhance its anti-tumor activity. Therefore, our rAcSp2 particles are a promising novel particulate drug carrier system for the delivery of peptide drugs with anti-tumor activity. • We designed and prepared a novel spider silk nanoparticle (rAcSp2) based from the N-terminal domain of aciniform silk protein. • We demonstrated that the rAcSp2 can loaded with antitumor peptide drugs via electrostatic interaction. • The rAcSp2 particles exhibited approximately 45 % loading capacity, nearly 100 % loading efficiency, and demonstrated pH- and ionic-responsive release properties. [ABSTRACT FROM AUTHOR]

• A novel supramolecular ionic liquid (P-M IL) was synthesized and fully characterized. • An efficient self-assembled peptide drug delivery system (P-M IL /AKE) was constructed, and enhanced AKE's permeability, and bioactivity. • For the first time, quantum chemical calculations, homology modeling, molecular docking and binding free energy calculations were used to analyze the structural stability of the system, construct the 3D model, explore the interaction mode and reveal the theoretical basis of anti-wrinkle effect. • In vitro penetration experiments showed that P-M IL increased the cumulative absorption of AKE in the skin by more than five times, and demonstrated the biocompatibility and transdermal mechanism. • In vitro, in vivo and clinical anti-wrinkle experiments showed that P-M IL/AKE can significantly increase collagen protein secretion by human fibroblasts, improved skin photoaging and reduce the areas and volume of wrinkle in the eyes and tail. Most peptide drugs have good biological activity and safety, but their stability and permeability are poor, limiting their applications in the field of local drug delivery. Snake venom peptide (AKE) is a tripeptide with good anti-wrinkle effects, but its weak esterophilicity, poor penetration, and low bioavailability limit its full anti-wrinkle potential. To address this issue, a bioactive ionic liquid (P-M IL) was prepared and an efficient self-assembled peptide drug delivery system was constructed through AKE loading, which increased the cumulative absorption of AKE in the skin by more than five-fold, resulting in good biocompatibility. Further, P-M IL/AKE can significantly increase collagen protein secretion by human fibroblasts, improved skin photoaging and reduce the areas and volume of wrinkle in the eye tail lines. In addition, for the first time, quantum chemical calculations, homology modeling, molecular docking and binding free energy calculations were used to analyze the structural stability of the system, construct the 3D model, explore the interaction mode and reveal the theoretical basis of anti-wrinkle effect. Therefore, this supramolecular self-assembled transdermal drug delivery system has potential advantages, providing a novel approach for the highly efficient and non-invasive delivery of peptide drugs. [ABSTRACT FROM AUTHOR]

Over the years, researchers have attempted to improve the potency of medicament utilization for the treatment of a variety of diseases. Drug targeting is a phenomenon in which a drug is distributed in the body in such a way that it interacts with the target tissue at a cellular or sub-cellular level to achieve a desired therapeutic response at the desired site while avoiding unwanted interactions at other sites. This can be accomplished using modern drug delivery system targeting methods such as niosomes. Niosomes are a novel drug delivery system that encapsulates the medication in a vesicle. The vesicle is made up of a nonionic surfactant bilayer. The particle size of the niosome must be in the range of 10 nm -100 nm. Niosomes are preferred over liposomes because they are more stable and less expensive. Niosomes enhance the pharmacological action of drug molecules by delaying the drug's clearance from circulation, protecting the drug from the biological environment, and limiting the effects to the target cells. It has applications in cancer treatment, as a carrier in hemoglobin, delivery of peptide drugs via the oral route, treatment of leishmaniasis, ophthalmic delivery, and as a carrier in dermal drug delivery. This review article focuses on the vesicular system's composition, benefits, types of niosomes, methods of preparation, characterization, and application. [ABSTRACT FROM AUTHOR]

Modern drug delivery technology began in 1952 with the advent of the Spansule® sustained-release capsule technology, which can deliver a drug for 12 h after oral administration through an initial immediate dose followed by the remaining released gradually. Until the 1980s, oral and transdermal formulations providing therapeutic durations up to 24 h for small molecules dominated the drug delivery field and the market. The introduction of Lupron Depot® in 1989 opened the door for long-acting injectables and implantables, extending the drug delivery duration from days to months and occasionally years. Notably, the new technologies allowed long-term delivery of peptide and protein drugs, although limited to parenteral administration. The introduction of the first PEGylated protein, Adagen®, in 1990 marked the new era of PEGylation, resulting in Doxil® (doxorubicin in PEGylated liposome) in 1995, Movantik® (PEGylated naloxone - naloxegol) in 2014, and Onpattro® (Patisiran - siRNA in PEGylated lipid nanoparticle) in 2018. Drug-polymer complexes were introduced, e.g., InFed® (iron-dextran complex injection) in 1974 and Abraxane® (paclitaxel-albumin complex) in 2005. In 2000, both Mylotarg™ (antibody-drug conjugate – gemtuzumab ozogamicin) and Rapamune® (sirolimus nanocrystal formulation) were introduced. The year 2000 also marked the launching of the National Nanotechnology Initiative by the U.S. government, which was soon followed by the rest of the world. Extensive work on nanomedicine, particularly formulations designed to escape from endosomes after being taken by tumor cells, along with PEGylation technology, ultimately resulted in the timely development of lipid nanoparticle formulations for COVID-19 vaccine delivery in 2020. While the advances in drug delivery technologies for the last seven decades are breathtaking, they are only the tip of an iceberg of technologies that have yet to be utilized in an approved formulation or even to be discovered. As life expectancy continues to increase, more people require long-term care for various diseases. Filling the current and future unmet needs requires innovative drug delivery technologies to overcome age-old familiar hurdles, e.g., improving water-solubility of poorly soluble drugs, overcoming biological barriers, and developing more efficient long-acting depot formulations. The lessons learned from the past are essential assets for developing future drug delivery technologies implemented into products. As the development of COVID-19 vaccines demonstrated, meeting the unforeseen crisis of the uncertain future requires continuous cumulation of failures (as learning experiences), knowledge, and technologies. Conscious efforts of supporting diversified research topics in the drug delivery field are urgently needed more than ever. [Display omitted] [ABSTRACT FROM AUTHOR]

The development of effective drug delivery systems is very challenging due to poor solubility, low membrane permeability, instability, and short biological half-life of active substances. Conventional drug delivery systems lack the features of extended drug release and targeted drug delivery. These issues can be solved by cyclodextrins and derivatives. Benefits include higher bioavailability, targeted drug delivery, non-toxicity, inclusion complex ability, and higher aqueous solubility. Cyclodextrin-conjugated nanoparticles combine the advantages of cyclodextrins and nanoparticles: enhanced water solubility and drug loading, targeted drug delivery with minimum toxicity to normal cells, greater surface area, improved drug loading and higher stability than other nanocarriers such as microparticles and liposomes. Here, I review cyclodextrin-containing nanoparticles and their applications in advanced drug delivery such as anticancer drugs, gene delivery, protein, and peptide drug delivery. Furthermore, this review also describes cyclodextrins applications using polymeric, gold, silver, magnetic, and lipid-based nanoparticles. Additionally, I present potential pharmaceutical applications of amphiphilic cyclodextrin-based nanoparticles in anticancer, antimicrobial, gene delivery, and miscellaneous administration routes of cyclodextrin-based nanoparticles such as nasal and transdermal. [ABSTRACT FROM AUTHOR]

Peptide-based drug delivery systems have many advantages when compared to synthetic systems in that they have better biocompatibility, biochemical and biophysical properties, lack of toxicity, controlled molecular weight via solid phase synthesis and purification. Lysosomes, solid lipid nanoparticles, dendrimers, polymeric micelles can be applied by intravenous administration, however they are of artificial nature and thus may induce side effects and possess lack of ability to penetrate the blood-brain barrier. An analysis of nontoxic drug delivery systems and an establishment of prospective trends in the development of drug delivery systems was needed. This review paper summarizes data, mainly from the past 5 years, devoted to the use of peptide-based carriers for delivery of various toxic drugs, mostly anticancer or drugs with limiting bioavailability. Peptide-based drug delivery platforms are utilized as peptide–drug conjugates, injectable biodegradable particles and depots for delivering small molecule pharmaceutical substances (500 Da) and therapeutic proteins. Controlled drug delivery systems that can effectively deliver anticancer and peptide-based drugs leading to accelerated recovery without significant side effects are discussed. Moreover, cell penetrating peptides and their molecular mechanisms as targeting peptides, as well as stimuli responsive (enzyme-responsive and pH-responsive) peptides and peptide-based self-assembly scaffolds are also reviewed. [ABSTRACT FROM AUTHOR]

[Display omitted] • Azide group enhances the drug release from PEGylated-rGO surface for more brush number containing shorter chains (PEG 500) and less brush number containing longer chain (PEG 2000). • PEG chain length does not affect the doxorubicin loading on graphene surface but effects the release of it. • PEG chain length used for rGO coating affects the drug release behavior. • Peptide base targeting agent (EPPT1) conjugation after drug loading on PEGylated-rGO surface slows down the release. • Loading drug as last step is better to obtain faster drug release from PEGylated-rGO surface. Reduced graphene oxide (rGO) is a restored, defect-free version of graphene oxide (GO) with regained graphene-like properties but encounters challenges in biomedical applications due to its low solubility. Especially for drug release applications, rGO's stronger π-π interaction of rGO compared to GO leads to low release, often demanding novel approaches for enhancement. The recently developed PEGylation method utilizes a copolymer with tunable PEG chain length and density for the PEGylation of GO simultaneously reduced to rGO, resulting in water-dispersible and biocompatible rGO-based nanoplatforms. This copolymer integrates functional monomers and enhances treatment options. Herein, we investigated how these PEGylation components and their incorporation order impact rGO's drug release behavior. A series of copolymers, (P(PEGMA- co -AzPMA- co -MMA- co -PMA), with different PEG brushes and azide groups, were synthesized via atom transfer radical polymerization. We explored the impact of ionic azide groups on drug release by comparing the azide-containing and azide-capped copolymers. Moreover, copolymers containing 500 or 2000 Da PEG brushes were compared to assess their role as a coating layer or diffusion barrier on drug release. Doxorubicin, a hydrophobic anticancer agent, was loaded onto the rGO surface before or after peptide-based targeting agent (EPPT1) conjugation. The results showed that the drug release behavior of 500 or 2000 Da PEG brushes containing rGO surfaces are different due to the density of PEG coating which makes the effect of azide groups not always visible. Incorporating the targeting peptide before drug loading was found to be optimal. The pH-dependent release profiles revealed 49 % and 44 % release from the rGO surface for the shorter and longer PEG brushes, respectively. Tuning the PEGylation components may further influence the release behavior. [ABSTRACT FROM AUTHOR]

Colon specific delivery of therapeutics have gained much attention of pharmaceutical researchers in the recent past. Colonic specific targeting of drugs is used not only for facilitating absorption of protein or peptide drugs, but also localization of therapeutic agents in colon to treat several colonic disorders. Among various biopolymers, guar gum (GG) exhibits pH dependent swelling, which allows colon specific release of drug. GG also shows microbial degradation in the colonic environment which makes it a suitable excipient for developing colon specific drug delivery systems. The uncontrolled swelling and hydration of GG can be controlled by structural modification or by grafting with another polymeric moiety. Several graft copolymerized guar gum derivatives are investigated for colon targeting of drugs. The efficacy of various guar gum derivatives are evaluated for colon specific delivery of drugs. The reviewed literature evidenced the potentiality of guar gum in localizing drugs in the colonic environment. This review focuses on the synthesis of several guar gum derivatives and their application in developing various colon specific drug delivery systems including matrix tablets, coated formulations, nano or microparticulate delivery systems and hydrogels. [Display omitted] [ABSTRACT FROM AUTHOR]

The oral route of protein and peptide drugs has been a popular method of drug delivery in recent years, although it is often a challenge to achieve effective drug release and minimize the barrier functions of the gastrointestinal tract. Gastrointestinal mucosa can capture and remove harmful substances; similarly, it can limit the absorption of drugs. Many drugs are effectively captured by the mucus and rapidly removed, making it difficult to control the release of drugs in the gastrointestinal tract. The use of drug carrier systems can overcome the mucosal barrier and significantly improve bioavailability. Nanoparticle drug carriers can protect the drug from degradation, transporting it to a predetermined location in the gastrointestinal tract to achieve more efficient and sustained drug delivery. It is becoming clearer that the characteristics of nanoparticles, such as particle size, charge, and hydrophobicity, are related to permeability of the mucosal barrier. This review focuses on the latest research progress of nanoparticles to penetrate the mucosal barrier, including the delivery methods of nanoparticles on the surface of gastrointestinal mucosa, and aims to summarize how successful oral nanoparticle delivery systems can overcome this biological barrier in the human body. In addition, the in vitro model based on gastrointestinal mucus is an important tool for drug research and development. Here, we discuss different types of drug delivery systems and their advantages and disadvantages in design and potential applications. Similarly, we reviewed and summarized various methods for evaluating oral nanoparticles in in vitro and in vivo models. [ABSTRACT FROM AUTHOR]

The nasal route is a potential alternative route for systemic availability of drugs restricted to intravenous administration, such as peptide and protein drugs and vaccines. Drugs have been delivered via the nasal route for medicinal and recreational use since ancient times. Because of the high penetrability, high vasculature, low enzymatic climate of nasal depression and evasion of hepatic first pass digestion are well appropriate for fundamental conveyance of medication atom by means of nose. The Nasal medical aid is that the one in every of the acknowledged style of treatment within the Ayurvedic System. It's called "NASAYA KARMA" for the Indian pharyngeal system This review provides a depth knowledge on all the factors that is affecting anf supporting nasal drug delivery. The nasal route of drug administration and various strategies for overcoming these factors for a better nasal drug administration. [ABSTRACT FROM AUTHOR]

Niosomes are a novel drug delivery system, in which the medication is encapsulated in a vesicle. The vesicle is composed of a bilayer of non-ionic surfactants. Niosomes are mostly preferred than liposomes because they are stable and cost effective. Niosomes potentiate the pharmacological action of the drug molecules by delaying the clearance of the drug from the circulation, protecting the drug from biological environment and restricting the effects only to the target cells. In novel drug delivery it has applications on treatment of cancer, used as a carrier in haemoglobin, delivery of the peptide drugs through oral route, in treatment of leishmaniasis, in ophthalmic delivery and as carrier in dermal drug delivery. This review article focuses on the composition, advantages, types of niosomes, methods of preparation, characterization and application of the vesicular system. [ABSTRACT FROM AUTHOR]

The preparation of precise macromolecules with multiple functionalities remains a challenge in drug delivery. Here, a method to prepare stoichiometrically precise tetrafunctional streptavidin conjugates is presented with an exemplary structure combining exactly one fluorescent label, one cell targeting group, one nucleus penetrating peptide and one drug molecule. [ABSTRACT FROM AUTHOR]

In this study, cyclic peptide (CP) with cyclooctaglycine model and gold nanoparticles (AuNP) with Au6 cluster model were used to examin the function of penicillamine (PCA) drug on ten different configurations of cyclic peptide-gold nanoparticles (CPAuNP). Binding energies, quantum molecular descriptors such as electrophilicity power (?), global hardness (?), and solubility energies were studied in aqueous solution and gas phase at the M06-2X density functional level. The binding energy analysis was performed on (CPAuNP/PCA1-10) structures to determine the most stable structure. The obtained values for solvation energies indicate that CPAuNPs can have an effective performance when used along with PCA drug, which is a major factor in drug delivery. The quantum molecular descriptors reveal that the reactivity of cyclic peptide (CP) and PCA drug increases in (CPAuNP/PCA1- 10) structures. AIM calculations for all structures show that intermolecular hydrogen bonding and Au-L (L = H, O, S, C, N) interactions play an important role for this drug delivery system. When the PCA drug is parallel to the CPAuNP carrier, interacting simultaneously with CP and AuNP, the structure is more stable than the structures in which the drug has interactions only with the CP or AuNP. [ABSTRACT FROM AUTHOR]

Controlled delivery technology of protein/peptide drugs from biodegradable particles has emerged as one of the eminent areas to overcome problems related to macromolecules formulation. The goal of the present study was to develop protein-loaded micro-particles using biodegradable polymer, polycaprolactone (PCL) and hydrogel from beluga cartilage. Bovine serum albumin (BSA) was used as a model for protein/ peptide molecules such as GnRH. The double emulsion (W/O/W) technique was selected as one of the most appropriate methods for preparing a drug delivery system for soluble proteins in water. The first emulsion was prepared using ultrasonic and the mechanical agitator was used for achieving the second emulsion. The hydrogel prepared by enzymatic digestion was used in the first aquatic solution. At the present investigation, three groups were considered as the drug delivery system: G1; (PCL/hydrogel/BSA), G2; (PCL/BSA) and G3; (PCL/Alginate/BSA). Findings showed that the morphology of particles was spherical and non-conglomerated in all groups. The comparison of average particle size among groups was also indicated that the particles. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (GNPs) are extremely useful for drug delivery, due in part to their highly tunable nature. However, this variability has prevented a clear understanding of the pharmacokinetics and toxicity of GNPs for drug delivery. Here, we present the clearance, organ distribution and acute toxicity testing of our drug delivery system which uses GNPs and two penta-peptides, to deliver a rationally designed peptide drug. We found that with or without our therapeutic, the GNP/peptide hybrid cleared rapidly from the blood in rats and accumulated mostly in the liver and spleen, although it was also detectable in several other organs. There were subtle but detectable differences between the behavior of our GNP hybrids with or without the therapeutic peptide. The GNP/peptide hybrid showed no evidence of toxicity at single doses up to 16 times the therapeutic dose, as measured by a battery of tests including, blood cell makeup, levels of markers of liver, kidney and spleen function, organ mass indexes, and histology. These results underline the importance of testing the pharmacokinetics and toxicity of all GNP preparations, as even minor changes to the surface coatings of GNPs can influence their behavior. On the other hand, the results herein can help guide the design and use of similar GNP/peptide drug delivery systems. [ABSTRACT FROM AUTHOR]

This work focuses on the dynamic properties and energetics of the protein/peptide drug during its transport through carbon nanotubes (CNTs). A systematic study was performed on the interaction between the peptide and the CNTs. In the molecular dynamics (MD) simulations, the protein/peptide molecule Zadaxin® is observed to be encapsulated inside the nanotube after its spontaneous insertion and oscillates around the center of the tube, where the van der Waals interaction energy is observed to be a minimum. Furthermore, it is found by performing steered MD simulations that the pulling force applied to the peptide reaches a maximum value, which demonstrates the ability of the CNTs to trap protein/peptide drugs. Such effects, attributed to van der Waals interactions, can be influenced by varying the lengths and diameters of the CNTs. Longer nanotubes provide a broader area to trap the peptide, while smaller nanotubes are able to encapsulate the peptide with a deeper interaction energy well. This investigation provides insights into nanoscale pharmaceutical drug delivery devices. [ABSTRACT FROM AUTHOR]

[Display omitted] • NFL-peptides adopt diverse ultrastructural organization when functionalizing liposomes. • The BIOT-NFL-peptide is the most adsorbed on the liposome surface. • NFL-peptides are enhancing cellular uptake of liposomes in GBM cells. • Liposome functionalization with NFL-peptides is a promising GBM targeting nanosystem. The NFL-peptide was discovered almost 20 years ago, and its targeting properties were assessed alone or in combination with lipid nanocapsules (LNC), magnetic porous silicon nanorods, or gold nanoparticles. Results highlighted a better targeting of cancer cells, in particular glioblastoma and pancreas cancer. Considering the large use of liposomes (LPs) as an hydrophilic drug delivery system, this study explored the possibility to functionalize liposomes with three different sequences of NFL-peptides: native (NFL-peptide), biotinylated (BIOT-NFL) and coupled to fluorescein (FAM-NFL). Dynamic Light Scattering (DLS) complemented by cryo-electron microscopy (CEM) showed a peculiar ultrastructural arrangement between NFL-peptides and liposomes. Based on this architectural interaction, we investigated the biological contribution of these peptides in LPs-DiD glioblastoma cellular uptake. Flow cytometry complemented by confocal microscopy experiments demonstrated a consequent and systematic increased uptake of LPs-DiD into F98 cells when their surface was decorated with NFL-peptides. The intra-cellular distribution of these liposomes via an organelle tracker indicated the presence of LPs-DiD in lysosomes after 4 h. Based on the properties of this NFL-peptide, we showed in this work the crucial role of NFL peptide as an effective and promising actor to potentiate nanoparticles entry in glioblastoma cell lines. [ABSTRACT FROM AUTHOR]

Because of its hydrophilic character the peptide drug Polymyxin B (PMB) cannot be incorporated in lipophilic nanocarrier systems such as self-emulsifying drug delivery systems (SEDDS) for oral administration. Due to the formation of imine conjugates between the primary amino groups of PMB and the carbonyl group of cinnamaldehyde, however, drug lipophilicity might be sufficiently raised for incorporation in SEDDS. Imine bonds were formed between the primary amino groups of PMB and the carbonyl group of cinnamaldehyde. PMB-cinnamaldehyde conjugate was characterized regarding degree of substitution, log P and release of PMB due to interaction with bovine serum albumin (BSA), SEDDS loading and cell viability. 87.1% of primary amines formed imines with cinnamaldehyde. Log P was increased 69.183 – folds. BSA triggered release of PMB was 45.2%, 64.9% and 80.6% within 16 h. Log D SEDDS/Release medium of PMB-cinnamaldehyde conjugate was 3.4. According to these findings, the concept of imine bond formation with cinnamaldehyde can be considered as a novel concept for increasing lipophilicity of the hydrophilic antibiotic peptide PMB. [ABSTRACT FROM AUTHOR]

Currently available drug delivery systems for oral diseases suffer from short retention time and poor local concentrations at the target site. A biodegradable stimulus-responsive hydrogel was synthesized in the present study to evaluate its application as an environmentally sensitive carrier for on-demand intraoral drug delivery. The hydrogel was synthesized from diacrylate-containing polyethylene glycol-based scaffolds and a cysteine-terminated peptide crosslinker (CGPQG↓IWGQC) via a Michael-type addition reaction. Because CGPQG↓IWGQC can be cleaved by matrix metalloproteinase 8 (MMP-8), minocycline hydrochloride, bovine serum albumin, or an antibacterial peptide (KSL) was incorporated into the scaffolds to evaluate the MMP-8-responsive release behavior of the on-demand drug delivery system. Hydrogel characterization and gelation kinetics were examined with gel time, Fourier-transform infrared spectroscopy, scanning electron microscopy, and measurements of rheologic parameters. Degradation behavior and MMP-8-responsive drug release were performed by high-performance liquid chromatography and protein-specific assay. Biocompatibility evaluation indicated that the hydrogels were noncytotoxic. Antibacterial testing demonstrated that the released drugs were able to maintain bioactivity. Taken together, these results suggest that the MMP-8-sensitive hydrogel is a promising candidate for on-demand intraoral localized drug delivery. Because MMP-8 is one of the most important biomarkers for periodontitis, the MMP-8-responsive hydrogel has potential to be used for in situ adaptive degradation in response to chronic periodontitis and peri-implantitis. This notion has to be tested in animal models of periodontal disease. [ABSTRACT FROM AUTHOR]

[Display omitted] Contact lenses (CLs) have been suggested as drug delivery platforms capable of increasing the drug residence time on the cornea and therefore its bioavailability. However, when targeting the posterior segment of the eye, the drug released from CLs still encounters the barrier effect of the ocular tissues, which considerably reduces the efficacy of administration. This work aims at the development of CLs able to simultaneously deliver an anti-inflammatory drug (dexamethasone sodium phosphate) and a cell-penetrating peptide (penetratin), the latter acting as a drug carrier across the tissues. Hydroxyethyl methacrylate (HEMA)-based hydrogels were functionalized with acrylic acid (AAc) and/or aminopropyl methacrylamide (APMA) to serve as CL materials with increased affinity for the drug and peptide. APMA-functionalized hydrogels sustained the dual release for 8 h, which is compatible with the wearing time of daily CLs. Hydrogels demonstrated suitable light transmittance, swelling capacity and in vitro biocompatibility. The anti-inflammatory activity of the drug was not compromised by the presence of the peptide nor by sterilization. The ocular distribution of the drug after 6 h of CL wearing was evaluated in vivo in rabbits and revealed that the amount of drug in the cornea and aqueous humor significantly increased when the drug was co-delivered with penetratin. [ABSTRACT FROM AUTHOR]

Peptide drugs have been used in the treatment of multiple pathologies. During peptide discovery, it is crucially important to be able to map the potential sites of cleavages of the proteases. This knowledge is used to later chemically modify the peptide drug to adapt it for the therapeutic use, making peptide stable against individual proteases or in complex medias. In some other cases it needed to make it specifically unstable for some proteases, as peptides could be used as a system to target delivery drugs on specific tissues or cells. The information about proteases, their sites of cleavages and substrates are widely spread across publications and collected in databases such as MEROPS. Therefore, it is possible to develop models to improve the understanding of the potential peptide drug proteolysis. We propose a new workflow to derive protease specificity rules and predict the potential scissile bonds in peptides for individual proteases. WebMetabase stores the information from experimental or external sources in a chemically aware database where each peptide and site of cleavage is represented as a sequence of structural blocks connected by amide bonds and characterized by its physicochemical properties described by Volsurf descriptors. Thus, this methodology could be applied in the case of non-standard amino acid. A frequency analysis can be performed in WebMetabase to discover the most frequent cleavage sites. These results were used to train several models using logistic regression, support vector machine and ensemble tree classifiers to map cleavage sites for several human proteases from four different families (serine, cysteine, aspartic and matrix metalloproteases). Finally, we compared the predictive performance of the developed models with other available public tools PROSPERous and SitePrediction. [ABSTRACT FROM AUTHOR]

Abstract Transporter-targeted nanoparticulate drug delivery systems (nano-DDS) have emerged as promising nanoplatforms for efficient drug delivery. Recently, great progress in transporter-targeted strategies has been made, especially with the rapid developments in nanotherapeutics. In this review, we outline the recent advances in transporter-targeted nano-DDS. First, the emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery are reviewed. These include improvements in the oral absorption of protein and peptide drugs, facilitating the intravenous-to-oral switch in cancer chemotherapy. Secondly, the recent advances in transporter-assisted brain-targeting nano-DDS are discussed, focusing on the specific transporter-based targeting strategies. Recent developments in transporter-mediated tumor-targeting drug delivery are also discussed. Finally, the possible transport mechanisms involved in transporter-mediated endocytosis are highlighted, with special attention to the latest findings of the interactions between membrane transporters and nano-DDS. Graphical abstract The recent trends in transporter-targeted nano-DDS is reviewed: (i) the emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery; (ii) the recent advances in transporter-assisted brain-targeting nano-DDS; (iii) recent developments in transporter-mediated tumor-targeting drug delivery; and (iv) the possible transport mechanisms involved in the transporter-mediated endocytosis. fx1 [ABSTRACT FROM AUTHOR]

Abstract Dermal application of peptides as drugs is an interesting and growing field in therapeutics. Besides therapy, they are increasingly used as cosmetic agents. Peptide delivery into the skin is highly challenging since they provide disadvantageous properties like a high molecular weight, hydrophilicity, polarity and susceptibility to enzymatic degradation. The aim of the presented study was to improve the bioavailability of a dermal administered tetrapeptide GEKG (amino acid sequence in one-letter notation). A nano-sized carrier system (microemulsion, ME) of w/o type was therefore developed since ME provide excellent penetration enhancing properties. Furthermore, enhancers were used to increase the penetration capacity of GEKG. The penetration of GEKG from the ME and enhancer-containing emulsions was compared to the penetration from a standard formulation. For this purpose ex vivo penetration studies with human skin were performed, which provide insights into dermal penetration and also localization and distribution of the active substances in each skin layer as well as the influence of vehicle variations. Experiments with three incubation times (30, 100, 300 min) and 5000 ppm GEKG in the formulations clearly show that the nano-sized carrier system is significantly better suited to transport GEKG rapidly into upper and deeper vital skin layers as well as through the skin compared to the standard cream. Studies with o/w emulsions containing 5% glyceryl caprylate/caprate 2.0× or 1.5× as enhancer and 50 ppm peptide revealed only a tendency to increased penetration into the SC and for the formulation with glyceryl caprylate/caprate 1.5× into the vital epidermis compared to the standard cream without additional enhancer. Significant better penetration rates were observed for the ME with 50 ppm GEKG. It can be concluded that liquid nano-sized systems are significantly more effective as carriers for extremely hydrophilic peptides used in cosmetics and also in therapeutics than classic cosmetic emulsions or enhancer-containing emulsions. Chemical compounds Tetrapeptide-21 (CAS: 960608-17-7) glyceryl caprylate/caprate (CAS: 73398-61-5) sorbitan oleate (CAS: 1338-43-8) polyglyceryl-4 laurate (CAS: 75798-42-4) butylene glycol (CAS: 107-88-0) isopropyl palmitate (CAS: 142-91-6) Graphical abstract Improved dermal penetration of GEKG after application of a microemulsion containing 5000 ppm (A) or 50 ppm peptide (B). Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial tissue of the joints. Inadequately controlled disease may cause severe joint damage and deformity. Currently, the anti-arthritic drugs are given systemically, and therefore, they are widely distributed to other organs that are not the intended therapeutic targets. Accordingly, using a particular dose/regimen of a drug to achieve an effective local concentration of the drug in arthritic joints may lead to expected adverse effects involving other organs. Thus, improved methods of drug delivery are needed for arthritis therapy. One attractive approach is the targeting of a systemically administered drug to the inflamed joints. We describe here a prototypic drug delivery system using a novel peptide ligand denoted as ART-1. We previously reported ART-1 (=ADK) as a peptide that preferentially homes to the inflamed joints of arthritic rats and binds to synovial endothelial cells. We tested the ART-1-coated liposomes encapsulating a fluorescent compound for binding to activated endothelial cells in vitro and homing to arthritic joints in vivo, compared to control liposomes lacking the ART-1 coating. Similar liposomes but encapsulating an immunomodulatory cytokine interleukin-27 (ART-1-IL-27 liposomes) were tested for their anti-arthritic activity compared with control liposomes. ART-1-displaying liposomes showed better binding to endothelial cells as well as in vivo homing to arthritic joints compared to control liposomes. Furthermore, ART-1-IL-27 liposomes, when intravenously injected to arthritic rats after the onset of arthritis, were more effective in suppressing disease progression than control-IL-27 liposomes lacking ART-1 or free IL-27 at an equivalent dose of IL-27. In addition, ART-1-directed liposomal IL-27 had a better safety profile than undirected liposomal IL-27 or free IL-27, thereby offering an improved therapeutic index for IL-27 therapy. These results provide a proof-of concept for the use of a novel joint-homing peptide for targeted delivery of drugs including biologics or small molecule compounds to arthritic joints with enhanced efficacy and reduced systemic exposure. This targeted therapy platform may be suitable for use in RA patients. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Despite the increasing number of effective therapeutics for eye diseases, their treatment is still challenging due to the presence of effective barriers protecting eye tissues. Cell Penetrating Peptides (CPPs), synthetic and natural short amino acid sequences able to cross cellular membrane thanks to a transduction domain, have been proposed as possible enhancing strategies for ophthalmic delivery. In this review, a general description of CPPs classes, design approaches and proposed cellular uptake mechanisms will be provided to the reader as an introduction to ocular CPPs application, together with an overview of the main problems related to ocular administration. The results obtained with CPPs for the treatment of anterior and posterior segment eye diseases will be then introduced, with a focus on non-invasive or minimally invasive administration, shifting from CPPs capability to obtain intracellular delivery to their ability to cross biological barriers. The problems related to in vitro , ex vivo and in vivo models used to investigate CPPs mediated ocular delivery will be also addressed together with potential ocular toxicity issues. [ABSTRACT FROM AUTHOR]

Nose-to-brain (N-to-B) delivery offers to protein and peptide drugs the possibility to reach the brain in a non-invasive way. This article is a comprehensive review of the state-of-the-art of this emerging peptide delivery route, as well as of the challenges associated to it. Emphasis is given on the potential of nanosized drug delivery carriers to enhance the direct N-to-B transport of protein or peptide drugs. In particular, polymer- and lipid- based nanocarriers are comparatively analyzed in terms of the influence of their physicochemical characteristics and composition on their in vivo fate and efficacy. The use of biorecognitive ligands and permeation enhancers in order to enhance their brain targeting efficiency is also discussed. The article concludes highlighting the early stage of this research field and its still unveiled potential. The final message is that more explicatory PK/PD studies are required in order to achieve the translation from preclinical to the clinical development phase. [ABSTRACT FROM AUTHOR]

[Display omitted] The global pharmaceutical market has recently shifted its focus from small molecule drugs to peptide, protein, and nucleic acid drugs, which now comprise a majority of the top-selling pharmaceutical products on the market. Although these biologics often offer improved drug specificity, new mechanisms of action, and/or enhanced efficacy, they also present new challenges, including an increased potential for degradation and a need for frequent administration via more invasive administration routes, which can limit patient access, patient adherence, and ultimately the clinical impact of these drugs. Controlled-release systems have the potential to mitigate these challenges by offering superior control over in vivo drug levels, localizing these drugs to tissues of interest (e.g., tumors), and reducing administration frequency. Unfortunately, adapting controlled-release devices to release biologics has proven difficult due to the poor stability of biologics. In this review, we summarize the current state of controlled-release peptides and proteins, discuss existing techniques used to stabilize these drugs through encapsulation, storage, and in vivo release, and provide perspective on the most promising opportunities for the clinical translation of controlled-release peptides and proteins. [ABSTRACT FROM AUTHOR]