Peptide Drug Delivery Systems Research Articles

Discovery of a peptide proteolysis-targeting chimera (PROTAC) drug of p300 for prostate cancer therapy

The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Notably, p300 has been identified as an important co-activator of the androgen receptor (AR), highlighting its significance in prostate cancer progression. Moreover, recent studies have revealed the involvement of p300 in AR-independent oncogenes associated with NEPC. Therefore, the blockade of p300 may emerge as an effective therapeutic strategy to address the challenges posed by both CRPC and NEPC. We employed AI-assisted design to develop a peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading p300 invitro and invivo utilizing nano-selenium as a peptide drug delivery system. Our p300-targeting peptide PROTAC drug demonstrated effective p300 degradation and cancer cell-killing capabilities in both CRPC, AR-negative, and NEPC cells. This study demonstrated the efficacy of a p300-targeting drug in NEPC cells. In both AR-positive and AR-negative mouse models, the p300 PROTAC drug showed potent p300 degradation and tumor suppression. The design of peptide PROTAC drug targeting p300 is feasible and represents an efficient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC. The funding details can be found in the Acknowledgements section.

Biocompatible ionic liquid self-assembled transdermal delivery system (P-M IL/AKE) for significantly improved skin photoaging and reduced wrinkles

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.

Recent Advances in Delivery of Peptide and Protein Therapeutics to the Brain.

The classes of neuropharmaceuticals known as proteins and peptides serve as diagnostic tools and are involved in specific communication in the peripheral and central nervous systems. However, due to tight junctions resembling epithelial cells found in the blood-brain barrier (BBB) in vivo, they are typically excluded from transport from the blood to the brain. The drugs having molecular weight of less than 400 Dalton are able to cross the BBB via lipid-mediated free diffusion. However, large molecule therapeutics are devoid of these characteristics. As an alternative, these substances may be carried via chimeric peptide drug delivery systems, and assist in transcytosis through BBB with the aid of linker strategies. With their recent developments, several forms of nanoparticles, including poly (ethylene glycol)-poly(ε-caprolactone) copolymers, nanogels, liposomes, nanostructured lipid carriers, poly (D, L-lactide-co-glycolide) nanoparticles, chitosan, and solid lipid nanoparticles, have also been considered for their therapeutic applications. Moreover, the necessity for physiologic optimization of current drug delivery methods and their carriers to deliver therapeutic doses of medication into the brain for the treatment of various neurologic illnesses has also been emphasized. Therapeutic use of proteins and peptides has no neuroprotective impact in the absence of all these methods. Each tactic, however, has unique drawbacks and considerations. In this review, we discuss different drug delivery methods for therapeutic distribution of pharmaceuticals, primarily neuroproteins and neuropeptides, through endothelial capillaries via blood-brain barrier. Finally, we have also discussed the challenges and future perspective of protein and peptide therapeutics delivery to the brain. SIGNIFICANCE STATEMENT: Very few reports on the delivery of therapeutic protein and peptide nanoformulations are available in the literature. Herein, we attempted to discuss these nanoformulations of protein and peptide therapeutics used to treat brain diseases.

DNA Hydrogel-Based Nanocomplexes with Cancer-Targeted Delivery and Light-Triggered Peptide Drug Release for Cancer-Specific Therapeutics.

Cancer therapies based on chemotherapeutic drug delive ries have been the most facilitated studies. Recently, peptide drugs have emerged as anticancer drugs due to their less immunogenicity and lower production costs compared with other synthetics. However, still, the side effects of these chemotherapeutics on healthy tissues have been a great concern to deal with, and these side effects are usually caused by off-targeted delivery and unwanted leakage. In addition, peptides are easily degraded by enzyme attacks during delivery. To address these concerns, here, we developed a robust, cancer-specific peptide drug delivery system with negligible cytotoxicity in in vitro. A peptide drug delivery vehicle (Dgel-PD-AuNP-YNGRT) was constructed by stepwise functionalization on a nanoscale DNA hydrogel (Dgel). A cell-penetrating anticancer peptide drug, Buforin IIb, was loaded within the Dgel network via electrostatic attraction followed by AuNP assembly. The AuNPs were employed as photothermal reagents for light-triggered peptide drug release. An additional peptide, including a cancer-targeting YNGRT sequence, was also bound on the Dgel for cancer-cell-targeted delivery. According to the results obtained from the studies employing cancer cells as well as normal cells, Dgel-PD-AuNP-YNGRT nanocomplexes could be delivered specifically to cancer cells, activated by light illumination, and release anticancer peptide drugs to kill cancer cells with no cytotoxicity and negligible hazardous effect on normal cell lines. The obtained cell viability assay suggests that at a high intensity (15 W/cm2), photothermally triggered released peptide drug has shown up to 44% higher kill than only peptide drug treatments in cancer cells. Similarly, the Bradford assay demonstrated that up to 90% of peptide drugs were released with our engineered Dgel-PD-AuNP-YNGRT nanocomplex. The Dgel-PD-AuNP-YNGRT nanocomplex may serve as an ideal anticancer peptide drug delivery platform for safe, cancer-specific targeting and efficient peptide drug delivery in cancer therapy.

Gastrointestinal Permeation Enhancers for the Development of Oral Peptide Pharmaceuticals.

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.

Protein and Peptide Based Drug Delivery- A Review

Biologics include vaccines, recombinant proteins, genes, synthetic tissues and viruses, which have emerged from molecular and cellular biology, with respect to unmet clinical needs and expanding indications. Hence it is important at this stage to outline the essential events that have led to the current level of interest in protein and peptide drug delivery systems. Polymers consisting of amino acids that are covalently linked by peptide bonds are known as Proteins and inturn peptides are small proteins composed of few dozen amino acids. Due to large molecular sizes of the proteins ranging from thousands to several millions atomic masses sizes; absorption through the epithelial barriers in the gastrointestinal tract is low. Moreover, proteins are rapidly degraded by digestive enzymes. As the bioavailability by oral route is poor they can be administered by other routes mainly by parenteral (IV, SC, IM) injections. The biological activity of proteins is strongly dependent on their molecular structure i.e 10 structure; the amino acid sequence, which ultimately dictates the non-covalent interactions and the 20i.e alpha helices and beta helices; the periodic spatial arrangement of the polypeptide chain backbone and 30; the 3-dimensional conformation of the whole molecule, including the positions of all amino acid side chains. Some proteins may consist of multiple peptide chains grouped together by non-covalent intermolecular interactions. The arrangement of these subunits relative to each other constitutes the 40structure. An alteration at any level of molecular structure leads to a change or loss of biological activity. The present review focuses on the development of various routes of drug administration, formulation as well as stability aspects of protein and peptide drug delivery system.

Archaeosomes for both cell-based delivery applications and drug-based delivery applications

Archaeosomes, or liposomes produced with one or more Archaeobacteria-specific ether lipids, are a novel kind of liposome found in Archaea. The fundamental structures of Achaean-type lipids are archaeol (diether) and/or caldarchaeol (tetraether). To make archaeosomes at any temperature in the physiological range or lower which enable thermally stable compounds to be encapsulated, traditional procedures like hydrated film sonicated, extrusion, and detergent dialysis are used. A multitude of physiological and environmental factors impact its stability. Archaeosomes are widely used as drug delivery systems for cancer vaccines, Chagas disease, proteins and peptides, gene delivery, antigen delivery, and administration of natural antioxidant compounds. The major purpose of this study was to look at how this unique carrier technology may be used in the pharmaceutical industry.

Protein and peptide drug delivery system: A brief review

Protein and peptide drug delivery system: A brief review

Oral delivery of protein and peptide drugs: from non-specific formulation approaches to intestinal cell targeting strategies.

The past few years has witnessed a booming market of protein and peptide drugs, owing to their superior efficiency and biocompatibility. Parenteral route is the most commonly employed method for protein and peptide drugs administration. However, short plasma half-life protein and peptide drugs requires repetitive injections and results in poor patient compliance. Oral delivery is a promising alternative but hindered by harsh gastrointestinal environment and defensive intestinal epithelial barriers. Therefore, designing suitable oral delivery systems for peptide and protein drugs has been a persistent challenge. This review summarizes the main challenges for oral protein and peptide drugs delivery and highlights the advanced formulation strategies to improve their oral bioavailability. More importantly, major intestinal cell types and available targeting receptors are introduced along with the potential strategies to target these cell types. We also described the multifunctional biomaterials which can be used to prepare oral carrier systems as well as to modulate the mucosal immune response. Understanding the emerging delivery strategies and challenges for protein and peptide drugs will surely inspire the production of promising oral delivery systems that serves therapeutic needs in clinical settings.

Routes and barriers associated with protein and peptide drug delivery system.

Proteins and peptide drugs have a great therapeutic potential and their usage in the treatment of various severe diseases has revolutionised the fields of pharmaceuticals and biotechnology. For successful therapeutic effects, various efforts have been made for effective delivery of proteins/peptide drugs through various routes of administrations. Parenteral and non-parenteral drug deliveries are regarded as significant routes of drug absorption. In addition to intravenous, subcutaneous and intramuscular routes, the oral route is more effective for protein and peptides therapeutics. However, there is a need to improve non-parenteral drug delivery systems (DDS) to increase drug absorption in a more effective way. The present narrative review was planned to describe routes and barriers for protein/peptide drugs and how to improve drug delivery systems in an effective way. For this purpose, numerous research articles were searched from year 2000-2021 using search engines like PubMed, Google Scholar, Medline and ISI Web of Knowledge, and Bioline International while applying different keywords such as 'protein and peptide drugs', 'drug delivery systems', 'parenteral and non-parenteral routes of drug delivery' and 'physicochemical barriers'. It was concluded that the success of the therapeutics is strongly influenced by the differential delivery of targeted antigen, the choice of targeting protein or peptide, and drug-release characteristics of the linker used. Furthermore, there should be an improvement in non-parenteral DDSs so that the drugs might be administered in an appropriate manner.

Enzyme-Induced Transformable Peptide Nanocarriers with Enhanced Drug Permeability and Retention to Improve Tumor Nanotherapy Efficacy.

Temporal persistence is as important for nanocarriers as spatial accuracy. However, because of the insufficient aggreagtion and short retention time of chemotherapy drugs in tumors, their clinical application is greatly limited. A drug delivery approach dependent on the sensitivity to an enzyme present in the microenvironment of the tumor is designed to exhibit different sizes in different sites, achieving enhanced drug permeability and retention to improve tumor nanotherapy efficacy. In this work, we report a small-molecule peptide drug delivery system containing both tumor-targeting groups and enzyme response sites. This system enables the targeted delivery of peptide nanocarriers to tumor cells and a unique response to alkaline phosphatase (ALP) in the tumor microenvironment to activate morphological transformation and drug release. The amphiphilic peptide AYR self-aggregated into a spherical nanoparticle structure after encapsulating the lipid-soluble model drug doxorubicin (DOX) and rapidly converted to nanofibers via the induction of ALP. This morphological transformation toward a high aspect ratio allowed rapid, as well as effective drug release to tumor location while enhancing specific toxicity to tumor cells. Interestingly, this "transformer"-like drug delivery strategy can enhance local drug accumulation and effectively inhibit drug efflux. In vitro along with in vivo experiments further proved that the permeability and retention of antitumor drugs in tumor cells and tissues were significantly enhanced to reduce toxic side effects, and the therapeutic effect was remarkably improved compared with that of nondeformable drug-loaded peptide nanocarriers. The developed AYR nanoparticles with the ability to undergo morphological transformation in situ can improve local drug aggregation and retention time at the tumor site. Our findings provide a new and simple method for nanocarrier morphology transformation in novel cancer treatments.

Nuclear Magnetic Resonance Spectroscopy: A Multifaceted Toolbox to Probe Structure, Dynamics, Interactions, and Real-Time In Situ Release Kinetics in Peptide-Liposome Formulations.

Liposomal formulations represent attractive biocompatible and tunable drug delivery systems for peptide drugs. Among the tools to analyze their physicochemical properties, nuclear magnetic resonance (NMR) spectroscopy, despite being an obligatory technique to characterize molecular structure and dynamics in chemistry as well as in structural biology, yet appears to be rather sparsely used to study drug-liposome formulations. In this work, we exploited several facets of liquid-state NMR spectroscopy to characterize liposomal delivery systems for the apelin-derived K14P peptide and K14P modified by Nα-fatty acylation. Various liposome compositions and preparation modes were analyzed. Using NMR, in combination with cryo-electron microscopy and dynamic light scattering, we determined structural, dynamic, and self-association properties of these peptides in solution and probed their interactions with liposomes. Using 31P and 1H NMR, we characterized membrane fluidity and thermotropic phase transitions in empty and loaded liposomes. Based on diffusion and 1H NMR experiments, we localized and quantified peptides with respect to the interior/exterior of liposomes and changes over time and upon thermal treatments. Finally, we assessed the release kinetics of several solutes and compared various formulations. Taken together, this work shows that NMR has the potential to assist the design of peptide/liposome systems and more generally drug delivery systems.

Carrier‐Based Systems as Strategies for Oral Delivery of Therapeutic Peptides and Proteins: A Mini‐Review

Peptides and proteins play an essential role in biological systems and the human body. Deficiency or dysfunction of peptides and proteins such as insulin can lead to various illnesses. The therapeutic use of peptides and proteins in some illnesses such as diabetes, cardiovascular disease, autoimmunity, and cancer, among others, is highly considered. Peptides and proteins have large molecular structures and are generally hydrophilic, and maintaining their spatial composition or tertiary configurations are necessary for their pharmacological activities. Maintaining the stability of the protein structure and composition is therefore very important and necessary to maintain functionality. There are different routes for peptides and proteins administration such as injection (subcutaneous, intravenous, and intramuscular), oral, nasal, pulmonary, rectal, and ocular routes. The oral administration route is better accepted by the patient due to safety and ease of use. However, oral administration often is unsuitable because of the physicochemical properties and macromolecular structure of proteins and the presence of gastrointestinal (GI) enzymes under an acidic environment within the stomach. Proteins and peptides undergo enzymatic degradation, tertiary structural alteration, and low absorption. This necessitates the need to use alternative oral drug delivery systems for peptides and proteins that maintain their overall structure and enhances their absorption and bioavailability. In this article, we review carrier-based oral drug delivery systems that were suitable for peptides and proteins.

Patient-centric design for peptide delivery: Trends in routes of administration and advancement in drug delivery technologies

Utilizing peptides as therapeutic agents is considered an attractive approach for the treatment of various diseases due to their high binding and selectivity to novel drug targets. However, the physicochemical properties of peptides make them challenging to administer exogenously, which places a high burden on drug delivery technology selection to successfully achieve the desired response. Various peptide drug delivery systems have been used in clinical and marketed products to overcome the problems associated with exogenous administration of peptide therapeutics. This review details the trends observed pertaining to the delivery of peptides such as changes in the routes of administration, advancements in formulation platforms, patient-centric product design, and various other aspects of peptide delivery.

Self-Assembled Peptide Drug Delivery Systems.

Over the past several decades, rapid advances have been made in the application of nanomaterials in the biomedical field including bioimaging and drug delivery. Owing to the natural biocompatibility, diverse design, and dynamic self-assembly, peptides can be used as modules to construct self-assembled peptide-based nanomaterials, which have a high potential in reducing drug toxicity, improving drug targeting, and enhancing drug delivery efficiency. In this review, three typical design strategies of self-assembled peptide nanomaterials for drug delivery have been summarized including ex situ construction, in situ morphological transformation, and in situ construction of peptide drug delivery systems (PDDs). Drugs can be loaded to peptide nanomaterials by physical encapsulation or chemical conjugation methods, showing enhanced retention effects at tumor sites to increase the uptake rate of drugs. Interestingly, drug-free peptide nanomaterials also can be nanomedicines for delivery. These advances implicate the bright prospect of the self-assembled peptide in intelligent nanomedicine and clinical translation.

Approaches and Recent Advances in Protein and Peptide Drug Delivery System

Approaches and Recent Advances in Protein and Peptide Drug Delivery System

The Cell Membrane of Sulfolobus spp.-Homeoviscous Adaption and Biotechnological Applications.

The microbial cell membrane is affected by physicochemical parameters, such as temperature and pH, but also by the specific growth rate of the host organism. Homeoviscous adaption describes the process of maintaining membrane fluidity and permeability throughout these environmental changes. Archaea, and thereby, Sulfolobus spp. exhibit a unique lipid composition of ether lipids, which are altered in regard to the ratio of diether to tetraether lipids, number of cyclopentane rings and type of head groups, as a coping mechanism against environmental changes. The main biotechnological application of the membrane lipids of Sulfolobus spp. are so called archaeosomes. Archaeosomes are liposomes which are fully or partly generated from archaeal lipids and harbor the potential to be used as drug delivery systems for vaccines, proteins, peptides and nucleic acids. This review summarizes the influence of environmental parameters on the cell membrane of Sulfolobus spp. and the biotechnological applications of their membrane lipids.

Advanced trends in protein and peptide drug delivery: a special emphasis on aquasomes and microneedles techniques.

Proteins and peptides have a great potential as therapeutic agents; they have higher efficiency and lower toxicity, compared to chemical drugs. However, their oral bioavailability is very low; also, the transdermal peptide delivery faces absorption limitations. Accordingly, most of proteins and peptides are administered by parenteral route, but there are many problems associated with this route such as patient discomfort, especially for pediatric use. Thus, it is a great challenge to develop drug delivery systems for administration of proteins and peptides by routes other than parenteral one. This review provides an overview on recent advances adopted for protein and peptide drug delivery, focusing on oral and transdermal routes. This is followed by an emphasis on two recent approaches adopted as delivery systems for protein and peptide drugs, namely aquasomes and microneedles. Aquasomes are nanoparticles fabricated from ceramics developed to enhance proteins and peptides stability, providing an adequate residence time in circulation. It consists of ceramic core coated with poly hydroxyl oligomer, on which protein and peptide drug can be adsorbed. Aquasomes preparation, characterization, and application in protein and peptide drug delivery are discussed. Microneedles are promising transdermal approach; it involves creation of micron-sized pores in the skin for enhancing the drug delivery across the skin, as their length ranged between 150 and 1500μm. Types of microneedles with different drug delivery mechanisms, characterization, and application in protein and peptide drug delivery are discussed. Graphical abstract.

Artificial Molecular Chaperone Systems for Proteins, Nucleic Acids, and Synthetic Molecules.

Molecular chaperones play critical roles in biological functions. They are closely involved in the maintenance of cell homeostasis, proper folding of proteins and nucleic acids, and inhibition of irreversible aggregation in denatured proteins. In addition to protein production, molecular chaperone function is widely recognized as important for peptide and protein drug delivery systems. Therefore, much effort has been made in recent decades to develop chaperone-mimetic molecules that have similar structures and biological functions to natural chaperones. These artificial molecular chaperone systems have been demonstrated to facilitate proper protein and nucleic acid folding, in addition to the formation of higher-order structures of synthetic molecules. Furthermore, the functions of these artificial systems show promising clinical applications in drug delivery and biomolecule detection. This topical review focuses on recent advances in the design, construction, characterization, and potential applications of different artificial molecular systems with distinct functional roles, such as the folding of water-soluble and membrane proteins, nucleic acids, and the self-assembly of synthetic molecules. Strategies used in the construction of some artificial molecule chaperone systems for proteins (such as pairs of amphiphilic molecules or self-assembled nanogels) and their applications as biomaterials are described. Specific examples from each design strategy are also highlighted to demonstrate the mechanisms, challenges, and limitations of the different artificial molecular systems. By highlighting the many new developments that have expanded the applications of the artificial chaperones beyond protein folding, this review aims to stimulate further studies on their design and applications.

The effect of chitosan and PEG polymers on stabilization of GF-17 structure: A molecular dynamics study

We examine the interactions of chitosan and polyethylene glycol (PEG) with antimicrobial peptide GF-17 to identify a suitable carrier to improve the peptide drug delivery systems. To this end, the molecular dynamics simulations are used to determine the interactions of a typical antimicrobial peptide GF-17 with the chitosan and PEG polymers. The findings indicate the great potential of the peptide to maintain its secondary structure in the adjacent to chitosan polymers. During the interaction with chitosan polymers, the structure of the peptide has smaller fluctuations compared to the PEG polymers. Also, in the presence of both the polymers, the PEG polymers are situated closer to the peptide than chitosan polymers. Moreover, the analysis indicates that the acidic residues and phenylalanine play a crucial role in peptide-polymer interactions. This research provides a valuable insight into the design of polymer surfaces for drug delivery applications such as controlled-release peptide delivery systems.