Lymphatic transport of orally administered drugs

Several therapeutic molecules such as lipophilic drugs and peptides suffer from the problems of low oral bioavailability. Improvement of their bioavailability and simultaneous prevention of the oral degradation of the prone molecules appears to be a challenge. Lymphatic system, which is responsible for the maintenance of fluid balance, immunity and metastatic spread of cancers, is also found to play a major role in the oral absorption of lipids and lipophilic drugs from intestine. The specialized structure of gut associated lymphoid tissue can be utilized as a gateway for the delivery of particulate systems containing drugs. Even though a large gap has existed in the field of lymphatic drug delivery, the introduction of a large number of lipophilic drugs and peptides has brought a renewed interest of research in this area. In this review, the mechanisms of intestinal lymphatic drug transport, approaches taken for the delivery of macromolecules, lipophilic and peptide drugs, biochemical barriers involved in intestinal drug absorption, and animal models used in the studies of intestinal lymphatic drug transport has been discussed.     

Cell-permeable chameleonic peptides: Exploiting conformational dynamics in de novo cyclic peptide design

Membrane-traversing peptides offer opportunities for targeting intracellular proteins and oral delivery. Despite progress in understanding the mechanisms underlying membrane traversal in natural cell-permeable peptides, there are still several challenges to designing membrane-traversing peptides with diverse shapes and sizes. Conformational flexibility appears to be a key determinant of membrane permeability of large macrocycles. We review recent developments in the design and validation of chameleonic cyclic peptides, which can switch between alternative conformations to enable improved permeability through cell membranes, while still maintaining reasonable solubility and exposed polar functional groups for target protein binding. Finally, we discuss the principles, strategies, and practical considerations for rational design, discovery, and validation of permeable chameleonic peptides.     

综述——纳米材料与药物输递：脂质纳米粒在口服给药系统中的应用

脂质纳米粒是由固体脂肪酸或其酯类制成的一类纳米制剂,其生物相容性好、安全性好,所以在药物递送领域受到广泛关注．难溶性药物、多肽及蛋白质药物由于溶解度、跨膜能力以及稳定性等问题,导致口服生物利用度低,而利用脂质纳米粒作为其载体,口服给药后能显著改善药物的生物利用度,这使得脂质纳米粒在口服给药系统中得到了广泛的应用与研究．本文从口服脂质纳米粒的处方、制备工艺、吸收机制以及应用四个方面对其进行了详细的综述．     

Strategies for oral delivery of macromolecule drugs

Advances in biotechnology, gene manipulation, and protein engineering for macromolecule drugs, such as insulin, parathyroid hormone (PTH), calcitonin, human growth hormone, erythropoietin (EPO), and peptide YY (PYY) allow commercial production in large scale for diverse therapeutic uses. Other macromolecules, such as mucopolysaccharide heparin, have expanded markets through improvements in their pharmacokinetic and pharmacological effects. However, most products are available only as injectable forms and are limited to patients with no alternative therapeutic choices. Orally available macromolecule formulations are still unmet needs for improving patient compliance and expanding administration paradigms and indications. Oral delivery technologies including carrier systems, absorption enhancers, protease inhibitors, and modification by conjugating transporter or receptor recognition molecules have been developed and some are undergoing clinical studies. In this review, we discuss major obstacles for oral absorption of macromolecule drugs and summarize recent strategies to overcome the huddles related to enhancing intestinal permeation.     

Peptide delivery systems

Efficient delivery of peptide drugs to the desired site is very important. There are anumber of barriers that may limit using peptides as potential drugs, some of theseobstacles include poor biomembrane permeability, enzymatic degradation and lowpH. To improve peptide drug efficiency a selective drug delivery system is required.Here we review some of the delivery systems available for peptides and we will alsobriefly discuss peptides that have been used as delivery systems.     

Peptide delivery systems

Summary Efficient delivery of peptide drugs to the desired site is very important. There are a number of barriers that may limit using peptides as potential drugs, some of these obstacles include poor biomembrane permeability, enzymatic degradation and low pH. To improve peptide drug efficiency a selective drug delivery system is required. Here we review some of the delivery systems available for peptides and we will also briefly discuss peptides that have been used as delivery systems.     

Current Concepts in Intestinal Peptide Absorption

Today there is considerable interest in oral peptide delivery. However, oral administration of peptides is limited by a low bioavailability and a high variability in plasma levels. A review is given of the literature describing the major barriers in peptide absorption, the basic mechanisms of intestinal peptide transport, the experimental models and the pharmaceutical approaches currently used in the investigation of peptide and protein absorption processes.     

Engineering clinically relevant volumes of vascularized bone

Vascularization remains one of the most important challenges that must be overcome for tissue engineering to be consistently implemented for reconstruction of large volume bone defects. An extensive vascular network is needed for transport of nutrients, waste and progenitor cells required for remodelling and repair. A variety of tissue engineering strategies have been investigated in an attempt to vascularize tissues, including those applying cells, soluble factor delivery strategies, novel design and optimization of bio‐active materials, vascular assembly pre‐implantation and surgical techniques. However, many of these strategies face substantial barriers that must be overcome prior to their ultimate translation into clinical application. In this review recent progress in engineering vascularized bone will be presented with an emphasis on clinical feasibility.     

Enhancing oral vaccine potency by targeting intestinal M cells

The immune system in the gastrointestinal tract plays a crucial role in the control of infection, as it constitutes the first line of defense against mucosal pathogens. The attractive features of oral immunization have led to the exploration of a variety of oral delivery systems. However, none of these oral delivery systems have been applied to existing commercial vaccines. To overcome this, a new generation of oral vaccine delivery systems that target antigens to gut-associated lymphoid tissue is required. One promising approach is to exploit the potential of microfold (M) cells by mimicking the entry of pathogens into these cells. Targeting specific receptors on the apical surface of M cells might enhance the entry of antigens, initiating the immune response and consequently leading to protection against mucosal pathogens. In this article, we briefly review the challenges associated with current oral vaccine delivery systems and discuss strategies that might potentially target mouse and human intestinal M cells.     

生物大分子核酸药物制剂的研究现状与展望

目前生物大分子核酸药物研发亟待突破的瓶颈是,如何使核酸药物能克服生物学屏障,实现体内有效输送。无生物安全隐患并具低 免疫原性、高基因包封能力和易于制备的非病毒载体仍存在输送效率低和化学毒性大等缺陷,其临床应用受到限制。介绍核酸药物的研发 现状,主要对非病毒核酸载体的研究现状及发展动态进行总结性回顾分析,并指出,虽然非病毒载体尚存在不足之处,但其自身优势仍使 其具有成为未来核酸药物输送体系主体的广阔应用前景。     

Cationic lipid-mediated nucleic acid delivery: beyond being cationic

Realization of the potential of nucleic acids as drugs is intricately linked to their in vivo delivery. Cationic lipids demonstrated tremendous potential as safe, efficient and scalable in vitro carriers of nucleic acids. For in vivo delivery of nucleic acids, the extant two component liposomal preparations consisting of cationic lipids and nucleic acids have been largely found to be insufficient. Being a soft matter, liposomes readily respond to many physiological variables leading to complex component and morphological changes, thus confounding the efforts in a priori identification of a “competent” formulation. In the recent past many chemical moieties that provide advantage in facing the challenges of barriers in vivo, were incorporated into cationic lipids to improve the transfection efficiency. The cationic lipids, essential for DNA condensation and protection, definitely require additional components to be efficient in vivo. In addition, formulations of cationic lipid carriers with non-lipidic components, mainly peptides, have demonstrated success in in vivo transfection. The present review describes some recent successes of in vivo nucleic acid delivery by cationic lipids.     

Cell-penetrating peptides: from molecular mechanisms to therapeutics

The recent discovery of new potent therapeutic molecules which do not reach the clinic due to poor delivery and low bioavailability have made the delivery of molecules a keystone in therapeutic development. Several technologies have been designed to improve cellular uptake of therapeutic molecules, including CPPs (cell-penetrating peptides), which represent a new and innovative concept to bypass the problem of bioavailability of drugs. CPPs constitute very promising tools and have been successfully applied for in vivo. Two CPP strategies have been described to date; the first one requires chemical linkage between the drug and the carrier for cellular drug internalization, and the second is based on the formation of stable complexes with drugs, depending on their chemical nature. The Pep and MPG families are short amphipathic peptides, which form stable nanoparticles with proteins and nucleic acids respectively. MPG- and Pep-based nanoparticles enter cells independently of the endosomal pathway and efficiently deliver cargoes, in a fully biologically active form, into a large variety of cell lines, as well as in animal models. This review focuses on the structure-function relationship of non-covalent MPG and Pep-1 strategies, and their requirement for cellular uptake of biomolecules and applications in cultured cells and animal models.     

Review physical and chemical aspects of stabilization of compounds in silk

The challenge of stabilization of small molecules and proteins has received considerable interest. The biological activity of small molecules can be lost as a consequence of chemical modifications, while protein activity may be lost due to chemical or structural degradation, such as a change in macromolecular conformation or aggregation. In these cases, stabilization is required to preserve therapeutic and bioactivity efficacy and safety. In addition to use in therapeutic applications, strategies to stabilize small molecules and proteins also have applications in industrial processes, diagnostics, and consumer products like food and cosmetics. Traditionally, therapeutic drug formulation efforts have focused on maintaining stability during product preparation and storage. However, with growing interest in the fields of encapsulation, tissue engineering, and controlled release drug delivery systems, new stabilization challenges are being addressed; the compounds or protein of interest must be stabilized during: (1) fabrication of the protein or small molecule-loaded carrier, (2) device storage, and (3) for the duration of intended release needs in vitro or in vivo. We review common mechanisms of compound degradation for small molecules and proteins during biomaterial preparation (including tissue engineering scaffolds and drug delivery systems), storage, and in vivo implantation. We also review the physical and chemical aspects of polymer-based stabilization approaches, with a particular focus on the stabilizing properties of silk fibroin biomaterials.     

Mucosal adjuvants and delivery systems for protein-, DNA- and RNA-based vaccines

Almost all vaccinations today are delivered through parenteral routes. Mucosal vaccination offers several benefits over parenteral routes of vaccination, including ease of administration, the possibility of self-administration, elimination of the chance of injection with infected needles, and induction of mucosal as well as systemic immunity. However, mucosal vaccines have to overcome several formidable barriers in the form of significant dilution and dispersion; competition with a myriad of various live replicating bacteria, viruses, inert food and dust particles; enzymatic degradation; and low pH before reaching the target immune cells. It has long been known that vaccination through mucosal membranes requires potent adjuvants to enhance immunogenicity, as well as delivery systems to decrease the rate of dilution and degradation and to target the vaccine to the site of immune function. This review is a summary of current approaches to mucosal vaccination, and it primarily focuses on adjuvants as immunopotentiators and vaccine delivery systems for mucosal vaccines based on protein, DNA or RNA. In this context, we define adjuvants as protein or oligonucleotides with immunopotentiating properties co-administered with pathogen-derived antigens, and vaccine delivery systems as chemical formulations that are more inert and have less immunomodulatory effects than adjuvants, and that protect and deliver the vaccine through the site of administration. Although vaccines can be quite diverse in their composition, including inactivated virus, virus-like particles and inactivated bacteria (which are inert), protein-like vaccines, and non-replicating viral vectors such as poxvirus and adenovirus (which can serve as DNA delivery systems), this review will focus primarily on recombinant protein antigens, plasmid DNA, and alphavirus-based replicon RNA vaccines and delivery systems. This review is not an exhaustive list of all available protein, DNA and RNA vaccines, with related adjuvants and delivery systems, but rather is an attempt to highlight many of the currently available approaches in immunopotentiation of mucosal vaccines.     

<Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">Ex Vivo</Emphasis> Evaluations of Lipid Anti-Cancer Nanoformulations: Insights and Assessment of Bioavailability Enhancement

Lipid-based nanoformulations have been extensively investigated for improving oral efficacy of plethora of drugs. Chemotherapeutic agents remain a preferred option for effective management of cancer; however, most chemotherapeutic agents suffer from limitation of poor oral bioavailability that is associated with their physicochemical properties. Drug delivery via lipid-based nanosystems possesses strong rational and potential for improving oral bioavailability of such anti-cancer molecules through various mechanisms, viz. improving their gut solubilisation owing to micellization, improving mucosal permeation, improving lymphatic uptake, inhibiting intestinal metabolism and/or inhibiting P-glycoprotein efflux of molecules in the gastrointestinal tract. Various in vitro characterization techniques have been reported in literature that aid in getting insights into mechanisms of lipid-based nanodevices in improving oral efficacy of anti-cancer drugs. The review focuses on different characterization techniques that can be employed for evaluation of lipid-based nanosystems and their role in effective anti-cancer drug delivery.     

Oral Delivery of Lactoferrin: A Review

Lactoferrin (Lf), as a therapeutic protein drug, has attracted much interest due to its many important roles in human and animal health and development. Oral delivery offers the most convenient way for supplementing Lf. However, the bioavailability of orally administered Lf is limited by a number of barriers associated with protein absorption. During the past decade, several oral delivery systems have been developed to preserve Lf stability in order to enhance gastric residence time and improve its bioavailability. This review summarizes various pharmaceutical strategies currently under investigation including: PEGylation, absorption enhancers, enzymatic inhibitors and advanced drug carrier systems.     

Lipid-based colloidal carriers for peptide and protein delivery--liposomes versus lipid nanoparticles

This paper highlights the importance of lipid-based colloidal carriers and their pharmaceutical implications in the delivery of peptides and proteins for oral and parenteral administration. There are several examples of biomacromolecules used nowadays in the therapeutics, which are promising candidates to be delivered by means of liposomes and lipid nanoparticles, such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC). Several production procedures can be applied to achieve a high association efficiency between the bioactives and the carrier, depending on the physicochemical properties of both, as well as on the production procedure applied. Generally, this can lead to improved bioavailability, or in case of oral administration a more consistent temporal profile of absorption from the gastrointestinal tract. Advantages and drawbacks of such colloidal carriers are also pointed out. This article describes strategies used for formulation of peptides and proteins, methods used for assessment of association efficiency and practical considerations regarding the toxicological concerns.     

Methods and strategies of peptide ligation.

This review focuses on the concept, methods, and strategies of orthogonal peptide ligation. It updates our previous review in 1999 on the same subject matter in Biopolymers (Peptide Science, 1999, Vol. 51, p. 311). Orthogonal peptide ligation is an amino terminal specific method to couple chemically unprotected peptides or proteins derived from synthetic or biosynthetic sources. Unlike conventional chemical methods, peptide ligation methods do not require coupling reagents or protection schemes, but are achieved through a variable chemoselective capture step and then an invariable intramolecular acyl transfer reaction. It is also a convergent method with the fewest steps. More than a dozen orthogonal ligation methods have been developed based on captures by either imine or thioester chemistries to afford native and unusual amino acids at ligation sites of linear, branched, or cyclic peptides. The ligation strategies for multiple segments including sequential and tandem ligations are also discussed.     

Gene delivery system: a developing arena of study for the new era of medicine

Gene therapy concept has been being overcome massive challenges from 1972 in ethical, socio-economical and developmental issues. In this review, we have attempted to go through almost all the arenas and described in a methodical way that reflects not only the initial ethical and scientific thoughts but also adorned a solid depiction of gene therapy related physico-chemical barriers, approaches and strategies till to date.     

Stimuli-responsive nanoassemblies for targeted delivery against tumor and its microenvironment

Despite the emergence of various cancer treatments, such as surgery, chemotherapy, radiotherapy, and immunotherapy, their use remains restricted owing to their limited tumor elimination efficacy and side effects. The use of nanoassemblies as delivery systems in nanomedicine for tumor diagnosis and therapy is flourishing. These nanoassemblies can be designed to have various shapes, sizes, and surface charges to meet the requirements of different applications. It is crucial for nanoassemblies to have enhanced delivery of payloads while inducing minimal to no toxicity to healthy tissues. In this review, stimuli-responsive nanoassemblies capable of combating the tumor microenvironment (TME) are discussed. First, various TME characteristics, such as hypoxia, oxidoreduction, adenosine triphosphate (ATP) elevation, and acidic TME, are described. Subsequently, the unique characteristics of the vascular and stromal TME are differentiated, and multiple barriers that have to be overcome are discussed. Furthermore, strategies to overcome these barriers for successful drug delivery to the targeted site are reviewed and summarized. In conclusion, the possible challenges and prospects of using these nanoassemblies for tumor-targeted delivery are discussed. This review aims at inspiring researchers to develop stimuli-responsive nanoassemblies for tumor-targeted delivery for clinical applications.