Transport of peptide and protein drugs across biological membranes

Verhoef, J.; Boddé, Harry E.; Boer, Albertus G. de; Bouwstra, J.A.; Junginger, Hans E.; Merkus, F. W. H. M.; Breimer, D. D.

doi:10.1007/bf03190191

Cited by 52 publications

(14 citation statements)

References 89 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The release studies carried out in-vitro demonstrated that PBCA nanocapsules could suppress the release of insulin under acidic conditions (pH 1.2) and hence may protect the entrapped protein during its passage through the stomach where it has been reported that up to 30% of protein digestion can occur (Verhoef et al 1990). When exposed to media having a pH similar to that expected in the intestine (pH 6.8), a signi® cant proportion of the insulin is immediately released (approx 40% burst release).…”

Section: Intragastric Administrationmentioning

confidence: 99%

In-vitro release and oral bioactivity of insulin in diabetic rats using nanocapsules dispersed in biocompatible microemulsion

Watnasirichaikul

Rades

Tucker

et al. 2002

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

This study evaluated the potential of poly(iso-butyl cyanoacrylate) (PBCA) nanocapsules dispersed in a biocompatible microemulsion to facilitate the absorption of insulin following intragastric administration to diabetic rats. Insulin-loaded PBCA nanocapsules were prepared in-situ in a biocompatible water-in-oil microemulsion by interfacial polymerisation. The microemulsion consisted of a mixture of medium-chain mono-, di-and tri-glycerides as the oil component, polysorbate 80 and sorbitan mono-oleate as surfactants and an aqueous solution of insulin. Resulting nanocapsules were approximately 200 nm in diameter and demonstrated a high ef ciency of insulin entrapment ( " 80 %). In-vitro release studies showed that PBCA nanocapsules could suppress insulin release in acidic media and that release at near neutral conditions could be manipulated by varying the amount of monomer used for polymerisation.Subcutaneous administration of insulin-loaded nanocapsules to diabetic rats demonstrated that the bioactivity of insulin was largely retained following this method of preparing peptideloaded nanocapsules and that the pharmacodynamic response was dependent on the amount of monomer used for polymerisation. The intragastric administration of insulin-loaded nanocapsules dispersed in the biocompatible microemulsion resulted in a signi cantly greater reduction in blood glucose levels of diabetic rats than an aqueous insulin solution or insulin formulated in the same microemulsion. This study demonstrates that the formulation of peptides within PBCA nanocapsules that are administered dispersed in a microemulsion can facilitate the oral absorption of encapsulated peptide. Such a system can be prepared in-situ by the interfacial polymerisation of a water-in-oil biocompatible microemulsion.

show abstract

Section: Intragastric Administrationmentioning

confidence: 99%

In-vitro release and oral bioactivity of insulin in diabetic rats using nanocapsules dispersed in biocompatible microemulsion

Watnasirichaikul

Rades

Tucker

et al. 2002

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

show abstract

“…In light of the major constraints on the bioavailability of SH2 inhibitors (cell permeability, stability, and antigenicity), together with simplicity of synthesis, it is clear that smaller, less charged compounds with minimal peptidic character are ideal [240,241]. In terms of size and peptidic character, Src SH2 inhibitors roughly the size of dipeptides have been developed with lipophilic scaffolds [178] (Fig.…”

Section: Unavailability Of Sh2 Inhibitors and Other Challengesmentioning

confidence: 99%

Probing the Tyrosine Phosphorylation State in Breast Cancer by Src Homology 2 Domain Binding

Mayer¹

2004

View full text Add to dashboard Cite

Pubhc reporting burden for Ms collection of information is estimated to average 1 hour per response, Including the lime for reviewing instructions, searching existing data sources gathering and maintaininn the data neededI andcompletingland renewing this collection of information. Send comments regarding this burden estimate or any other asped of this collection of InfoirnaBorf iffsSÄto" educing this burden to Washington Headquarters AUTHOR(S)Bruce J. Mayer PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)University Abstract (Maximum 200 Words) (abstract should contain no proprietary or confidential information)Improved molecular diagnostic methods that can classify tumors and predict their response to therapy have enormous potential to improve the effectiveness breast cancer treatments. The overall goal of this project is to develop a novel molecular diagnostic method, i: termed SH2 profiling, that can classify cell samples based on their global protein tyrosine phosphorylation state. The first aim is to use an existing SH2 profiling method, based on far-Western blotting, to analyze fresh surgical breast cancer samples. The second aim is to o develop a more high-throughput quantitative reversed-phase SH2 profiling format, and test its usefulness in classifying breast cancer samples. The third aim is to develop histochemical SH2 profiling methods that can be used to analyze archived, formalin-fixed tissue sections, and perform pilot retrospective studies to determine whether SH2 binding patterns have potential prognostic value. In the past year we have made great progress in developing the reversed-phase array and histochemical SH2 profiling formats, and results suggest that these quantitative methods will be useful in classifying breast cancer samples. In the coming year, once HSRRB approval for use of human samples is secured, we will begin to apply these new methods to the analysis of actual breast cancer specimens. SUBJECT TERMS Conclusions 9References 10 Appendices 10-93Mayer, B.J. INTRODUCTIONThe focus is this study is to test whether a novel molecular diagnostic approach, SH2 profiling, can serve as a useful prognostic tool to classify breast cancer. SH2 domains are small protein modules that bind specifically to tyrosine phosphorylated peptides. These domains play an important role in normal signal transduction, mediating the formation of multiprotein complexes in response to changes in tyrosine phosphorylation [1,2]. There are ~116 SH2 domains in the human genome, and different SH2 domains recognize different tyrosine phosphorylated proteins. SH2 profiling is a method in which a battery SH2 domain probes is used to provide a snapshot of the global state of tyrosine phosphorylation in a cell sample [3,4]. Different breast cancers are likely to have different patterns of tyrosine phosphorylation, reflecting differences in the signal transduction pathways active in the tumor, and thus SH2 profiling has the potential to provide a biologically relevant means to classify these tumors. In this project we prop...

show abstract

“…The desired outcomes of such modifications may include improved bioavailability of drugs that are poorly absorbed by the gastrointestinal tract (e.g. by increasing uptake into the lymphatic system, thereby avoiding first‐pass metabolism), 1–3 enhanced transport across epithelial barriers, such as intestinal mucosa, 4 nasal and pulmonary mucosae 5 and skin, 6,7 or delivery across the blood–brain barrier. 8 Alternatively, increasing the lipophilicity may result in specific localization of drugs 9 or their slow release, 2 decreasing the required therapeutic dosage, frequency of administration and/or the severity of side effects.…”

Section: Introductionmentioning

confidence: 99%

Tris Lipidation: A Chemically Flexible Technology For Modifying The Delivery Of Drugs and Genes

Lockett¹,

Reilly

Manthey

et al. 2000

Clin Exp Pharma Physio

View full text Add to dashboard Cite

1. One of the major challenges in the development of pharmaceuticals is their formulation with other materials to give them the desired bioavailability profile when administered into the body. 2. We have developed a flexible platform technology (Tris lipidation) to simply and effectively alter the lipophilicity of drugs. As implied by the name, the technology uses the common buffer Tris as a linker between the drugs of interest and a domain of variable hydrophobicity. 3. We demonstrate, using a mouse melanoma model, that Tris-lipidated conjugates of the widely used cytotoxic and anti-inflammatory drug methotrexate (MTX) display enhanced potency in the local treatment of tumours and reduced systemic toxicity when compared with the unconjugated drug. 4. With genes now being predicted to be the pharmaceuticals of the future, we show that Tris-lipidated cationic peptides can efficiently deliver DNA into (transfect) cells in culture. Furthermore, by comparing the abilities of variants of these Tris-based cationic lipids to transfect cultured cells, we demonstrate that modifications made to variable regions of Tris-lipidated compounds can dramatically alter their delivery profiles.

show abstract

Transport of peptide and protein drugs across biological membranes

Cited by 52 publications

References 89 publications

In-vitro release and oral bioactivity of insulin in diabetic rats using nanocapsules dispersed in biocompatible microemulsion

In-vitro release and oral bioactivity of insulin in diabetic rats using nanocapsules dispersed in biocompatible microemulsion

Probing the Tyrosine Phosphorylation State in Breast Cancer by Src Homology 2 Domain Binding

Tris Lipidation: A Chemically Flexible Technology For Modifying The Delivery Of Drugs and Genes

Contact Info

Product

Resources

About