环糊精及其衍生物在多肽/蛋白质类药物非注射给药体系中的应用

目前,多肽/蛋白质类药物多数需要采用注射剂型给药以确保其生物利用度。开发易于给药、病人顺应性高以及治疗费用更低的非注射剂型是非常有意义的。然而,多肽/蛋白质类药物直接进行非注射给药的生物利用度通常非常低,需要制备具有设计功能的载药系统,例如加入不同比例的酶抑制剂、吸收促进剂等以提高生物利用度。环糊精及其衍生物由于其能与客体分子形成包合物的特性,以及对粘膜的促渗透作用等,在多肽/蛋白质药物的非注射给药系统中获得了日益广泛的应用。综述了近年来环糊精及其衍生物在多肽/蛋白质类药物非注射给药体系中的应用情况。     

Physical blends of starch graft copolymers as matrices for colon targeting drug delivery systems

Colon targeting drug delivery systems have attracted many researchers due to the distinct advantages they present such as near neutral pH, longer transit time and reduced enzymatic activity. Moreover, in recent studies, colon specific drug delivery systems are gaining importance for use in the treatment of local pathologies of the colon and also for the systemic delivery of protein and peptide drugs.In previous works, our group has developed different types of hydrophilic matrices with grafted copolymers of starch and acrylic monomers with a wide range of physicochemical properties which have demonstrated their ability in controlled drug release. Since the cost of synthesizing a new polymeric substance and testing for its safety is enormous, polymer physical blends are frequently used as excipients in controlled drug delivery systems due to their versatility. So, the aim of this work is to combine two polymers which offer different properties such as permeability for water and drugs, pH sensitivity and biodegradability in order to further enhance the release performance of various drugs. It was observed that these physical blend matrices offer good controlled release of drugs, as well as of proteins and present suitable properties for use as hydrophilic matrices for colon-specific drug delivery.     

蛋白质和多肽药物长效性研究进展

基于分子生物学和重组技术的发展,蛋白质和多肽已经成为一类重要的药物,但是其稳定性差,生物利用率低,半衰期短等问题也日益受到关注。本文重点介绍了一些新的给药途径和给药系统,例如鼻腔、颊等给药途径以及黏膜给药系统、透皮给药系统、缓控释技术等给药系统的进展。综述了对于蛋白质和多肽药物进行定点突变和化学修饰,以达到增加其长效性的一些新方法。     

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.     

An antigenic HIV-1 peptide sequence engineered into the surface structure of transferrin does not elicit an antibody response.

One novel approach for the biological delivery of peptide drugs is to incorporate the sequence of the peptide into the structure of a natural transport protein such as human serum transferrin (HST). However, a potential drawback is that the HST may increase the immunoreactivity of the peptide, in the same way that carrier proteins can be used to generate highly immunogenic peptide hapten conjugates. In this study we have generated a recombinant HST carrier protein that contains a peptide substrate of HIV-1 protease (VSQNYPIVL). The protein retained native HST function, and the peptide was surface exposed since it was immunoreactive in native dot blots, and was cleaved by HIV-1 protease. Immunisation of rabbits with the recombinant protein elicited only a very poor anti-peptide immune response. In contrast, strong anti-peptide immune responses were raised against both the peptide alone, and a chemical conjugate of the peptide with HST. These data demonstrate that it is possible to attenuate the immune response normally directed against an immunogenic peptide sequence by engineering into a surface exposed loop of HST. These findings may have an important impact on the future design of peptide delivery systems.     

蛋白多肽类药物制剂的研究进展

相对于其他的给药途径,蛋白质多肽类药物的口服、经鼻、肺部给药途径更具可行性和商业价值。利用制剂学方法可提高蛋白质多肽类药物生物利用度。通过蛋白多肽类给药系统的评价,对近年来国内外此类药物在剂型、体内外稳定性及生物利用度等方面的研究进展予以综述。     

细胞穿膜肽介导蛋白/多肽类药物输送的研究进展

在当前药物研发中,蛋白/多肽类药物占据着重要地位。然而,此类药物大多需进入细胞内才能发挥作用,故细胞摄取率低的问 题成为制约其发展的关键因素。细胞穿膜肽是一类富含精氨酸的短肽,自身具有较强的生物膜穿透能力,可携带多种大分子甚至是纳米 粒入胞。因此,穿膜肽被广泛应用于药物输送,且基于穿膜肽介导药物胞内输送,成为解决蛋白/多肽类药物入胞问题的优选策略。主 要综述穿膜肽介导蛋白/多肽类药物输送用于不同疾病治疗的研究进展。     

多肽和蛋白质药物的吸入给药

概述了多肽和蛋白质药物的肺吸收机制和用于吸入给药的研究进展,并简要讨论了多肽和蛋白质药物在用于吸入给药时存在的问题及今后的发展方向,为多肽和蛋白质药物的吸入给药研究提供一定的参考。     

Investigation of archaeosomes as carriers for oral delivery of peptides

Oral administration of peptide and protein drugs faces a big challenge partly due to the hostile gastrointestinal (GI) environment. Lipid-based delivery systems are attractive because they offer some protection for peptides and proteins. In this context, we prepared a special lipid-based oral delivery system: archaeosomes, made of the polar lipid fraction E (PLFE) extracted from Sulfolobus acidocaldarius, and explored its potential as an oral drug delivery vehicle. Our study demonstrates that archaeosomes have superior stability in simulated GI fluids, and enable fluorescent labeled peptides to reside for longer periods in the GI tract after oral administration. Although archaeosomes have little effect on the transport of insulin across the Caco-2 cell monolayers, the in vivo experiments indicated that archaeosomes containing insulin induced lower levels of blood glucose than a conventional liposome formulation. These data indicate that archaeosomes could be a potential carrier for effective oral delivery of peptide drugs.     

Nose-to-brain peptide delivery – The potential of nanotechnology

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.     

The nasal delivery of peptides and proteins.

Many drugs of the future will be therapeutically active peptides and proteins developed through recombinant-DNA technology. A major factor limiting their exploitation is the current lack of appropriate non-parenteral delivery systems. Nasal systems incorporating absorption enhancers may provide a convenient, efficient means of administering protein and peptide therapeutics.     

肠道病原菌侵袭素在药物纳米载体中的应用

口服给药是药物递送系统中的优选途径。然而,在通过胃肠道时,肠细胞的低渗透性经常会阻碍药物的有效递送。包囊药物能够解决这一问题的关键,取决于其中的细胞侵袭性靶向基团包裹的纳米颗粒系统。这种药物递送系统的侵入特性是由细菌侵袭素的关键成分提供,这些成分具有快速调节药物穿越肠细胞的作用,从而促进宿主细胞对药物的有效吸收。此综述重点阐述细菌侵袭系统,对合适的侵袭素分别从功能和分子结构、作为靶向药物的相对价值以及在使用过程中可能存在的误区依次进行探讨。此外,对口服给药方法的改进和未来前景也进行了讨论。     

Recent Trends in Drug Delivery System Using Protein Nanoparticles

Engineered nanoparticles that can facilitate drug formulation and passively target tumours have been under extensive research in recent years. These successes have driven a new wave of significant innovation in the generation of advanced particles. The fate and transport of diagnostic nanoparticles would significantly depend on nonselective drug delivery, and hence the use of high drug dosage is implemented. In this perspective, nanocarrier-based drug targeting strategies can be used which improve the selective delivery of drugs to the site of action, i.e. drug targeting. Pharmaceutical industries majorly focus on reducing the toxicity and side effects of drugs but only recently it has been realised that carrier systems themselves may pose risks to the patient. Proteins are compatible with biological systems and they are biodegradable. They offer a multitude of moieties for modifications to tailor drug binding, imaging or targeting entities. Thus, protein nanoparticles provide outstanding contributions as a carrier for drug delivery systems. This review summarises recent progress in particle-based therapeutic delivery and discusses important concepts in particle design and biological barriers for developing the next generation of particles drug delivery systems.     

A peptide carrier for the delivery of biologically active proteins into mammalian cells.

The development of peptide drugs and therapeutic proteins is limited by the poor permeability and the selectivity of the cell membrane. There is a growing effort to circumvent these problems by designing strategies to deliver full-length proteins into a large number of cells. A series of small protein domains, termed protein transduction domains (PTDs), have been shown to cross biological membranes efficiently and independently of transporters or specific receptors, and to promote the delivery of peptides and proteins into cells. TAT protein from human immunodeficiency virus (HIV-1) is able to deliver biologically active proteins in vivo and has been shown to be of considerable interest for protein therapeutics. Similarly, the third alpha-helix of Antennapedia homeodomain, and VP22 protein from herpes simplex virus promote the delivery of covalently linked peptides or proteins into cells. However, these PTD vectors display a certain number of limitations in that they all require crosslinking to the target peptide or protein. Moreover, protein transduction using PTD-TAT fusion protein systems may require denaturation of the protein before delivery to increase the accessibility of the TAT-PTD domain. This requirement introduces an additional delay between the time of delivery and intracellular activation of the protein. In this report, we propose a new strategy for protein delivery based on a short amphipathic peptide carrier, Pep-1. This peptide carrier is able to efficiently deliver a variety of peptides and proteins into several cell lines in a fully biologically active form, without the need for prior chemical covalent coupling or denaturation steps. In addition, this peptide carrier presents several advantages for protein therapy, including stability in physiological buffer, lack of toxicity, and lack of sensitivity to serum. Pep-1 technology should be extremely useful for targeting specific protein-protein interactions in living cells and for screening novel therapeutic proteins.     

Clostridial neurotoxins as a drug delivery vehicle targeting nervous system

Several neuronal disorders require drug treatment using drug delivery systems for specific delivery of the drugs for the targeted tissues, both at the peripheral and central nervous system levels. We describe a review of information currently available on the potential use of appropriate domains of clostridial neurotoxins, tetanus and botulinum, for effective drug delivery to neuronal systems. While both tetanus and botulinum neurotoxins are capable of delivering drugs the neuronal cells, tetanus neurotoxin is limited in clinical use because of general immunization of population against tetanus. Botulinum neurotoxin which is also being used as a therapeutic reagent has strong potential for drug delivery to nervous tissues.     

Cyclodextrins in drug delivery: An updated review

The purpose of this review is to discuss and summarize some of the interesting findings and applications of cyclodextrins (CDs) and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important CD applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. In addition to their well-known effects on drug solubility and dissolution, bioavailability, safety, and stability, their use as excipients in drug formulation are also discussed in this article. The article also focuses on various factors influencing inclusion complex formation because an understanding of the same is necessary for proper handling of these versatile materials. Some important considerations in selecting CDs in drug formulation such as their commercial availability, regulatory status, and patent status are also summarized. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes. Published: October 14, 2005     

3-D tissue culture systems for the evaluation and optimization of nanoparticle-based drug carriers

Nanoparticle carriers are attractive vehicles for a variety of drug delivery applications. In order to evaluate nanoparticle formulations for biological efficacy, monolayer cell cultures are typically used as in vitro testing platforms. However, these studies sometimes poorly predict the efficacy of the drug in vivo. The poor in vitro and in vivo correlation may be attributed in part to the inability of two-dimensional cultures to reproduce extracellular barriers, and may also be due to differences in cell phenotype between cells cultured as monolayers and cells in native tissue. In order to more accurately predict in vivo results, it is desirable to test nanoparticle therapeutics in cells cultured in three-dimensional (3-D) models that mimic in vivo conditions. In this review, we discuss some 3-D culture systems that have been used to assess nanoparticle delivery and highlight several implications for nanoparticle design garnered from studies using these systems. While our focus will be on nanoparticle drug formulations, many of the systems discussed here could, or have been, used for the assessment of small molecule or peptide/protein drugs. We also offer some examples of advancements in 3-D culture that could provide even more highly predictive data for designing nanoparticle therapeutics for in vivo applications.     

Liposomal Delivery of Peptides and Proteins

Abstract

Controlled delivery of peptide and protein drugs constitutes a major challenge. As these compounds are generally not therapeutically active after oral administration, the parenteral route is the preferred route for their administration. However, when administered parenterally, they often show a very short circulation and biological half-life necessitating repeated injections. Further medical application and commercialization of these agents requires development of viable delivery systems to improve their therapeutic behavior (1–3). In this contribution examples of liposomal delivery approaches for peptides and proteins will be briefly described. These examples include the parenteral delivery of vasopressin, interleukin-2, tissue plasminogen activator, diphtheria toxin, and prodrug activating enzymes, and the oral delivery of antigens.     

Transferrin trojan horses as a rational approach for the biological delivery of therapeutic peptide domains.

One novel approach for the biological delivery of peptide drugs is to incorporate the sequence of the peptide into the structure of a natural transport protein, such as human serum transferrin. To examine whether this is feasible, a peptide sequence cleavable by the human immunodeficiency virus type 1 protease (VSQNYPIVL) was inserted into various regions of human serum transferrin, and the resultant proteins were tested for function. Experimentally, molecular modeling was used to identify five candidate insertion sites in surface exposed loops of human serum transferrin that were distant from biologically active domains. These insertions were cloned using polymerase chain reaction mutagenesis, and the proteins were expressed using a baculovirus expression vector system. Analysis of the mutant proteins provided a number of important findings: (a) they retained native human serum transferrin function, (b) the inserted peptide sequence was surface exposed, and most importantly, (c) two of these mutants could be cleaved by human immunodeficiency virus-1 protease. In conclusion, this investigation has validated the use of human serum transferrin as a carrier protein for functional peptide domains introduced into its structure using protein engineering. These findings will be useful for developing a novel class of therapeutic agents for a broad spectrum of diseases.