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Design of a Tumor-Homing Cell-Penetrating Peptide
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0001-6107-0844
2008 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 19, no 1, 70-75 p.Article in journal (Refereed) Published
Abstract [en]

Chemotherapy is often limited by toxicity to normal cells. Therefore, an ideal anticancer drug should discriminate between normal tissue and tumors. This would require a target receptor molecule mostly present in tumors. The cyclic peptide cCPGPEGAGC (PEGA) is a homing peptide that has previously been shown to accumulate in breast tumor tissue in mice. PEGA peptide does not cross the plasma membrane per se; however, when attached to the cell-penetrating peptide pVEC, the conjugate is taken up by different breast cancer cells in vitro. Additionally, the homing capacity of the PEGA-pVEC is conserved in vivo, where the conjugate mainly accumulates in blood vessels in breast tumor tissue and, consequently is taken up. Furthermore, we show that the efficacy of the anticancer drug, chlorambucil, is increased more than 4 times when the drug is conjugated to the PEGA-pVEC chimeric peptide. These data demonstrate that combining a homing sequence with a cell-penetrating sequence yields a peptide that combines the desirable properties of the parent peptides. Such peptides may be useful in diagnostics and delivery of therapeutic agents to an intracellular location in a specific tumor target tissue.

Place, publisher, year, edition, pages
2008. Vol. 19, no 1, 70-75 p.
Keyword [en]
Cell-penetrating peptide, Homing peptide, Drug delivery, Tumor targeting
National Category
Biochemistry and Molecular Biology Neurosciences
Identifiers
URN: urn:nbn:se:su:diva-25661DOI: 10.1021/bc0701139ISI: 000252520300012OAI: oai:DiVA.org:su-25661DiVA: diva2:200171
Available from: 2009-01-08 Created: 2008-12-08 Last updated: 2015-04-21Bibliographically approved
In thesis
1. Rational modifications of cell-penetrating peptides for drug delivery: Applications in tumor targeting and oligonucleotide delivery
Open this publication in new window or tab >>Rational modifications of cell-penetrating peptides for drug delivery: Applications in tumor targeting and oligonucleotide delivery
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

High molecular weight biomolecules are becoming important in the development of new therapeutics. However, their size and nature creates a major limitation for their application – poor penetration through biological membranes. A new class of peptides, cell-penetrating peptides (CPPs), has shown the capability to transport various macromolecules inside the cells. However, there are at least two limiting factors for successful application of CPPs: the lack of cell-type specificity and restricted bioavailability resulting from endocytic uptake of CPPs and entrapment in endosomal compartments.

This thesis aims at designing delivery vehicles for therapeutic substances. In papers I-III, the CPPs have been rationally modified in order to achieve in vivo selectivity towards cancer cells. The first two papers employ tumor homing peptides as targeting moieties coupled to the N-termini of CPPs. In the third paper, a CPP is C-terminally prolonged with a matrix metalloproteinase 2 (MMP-2) specific cleavage site followed by an inactivating amino acid sequence. In tissues overexpressing MMP-2, i. e. in proximity to cancer, the CPP is activated after proteolytic removal of the inactivating sequence, thus the cargo can be transported inside the cells. In paper IV, several CPPs have been N-terminally modified with a stearyl moiety and applied for the delivery of splice-correcting oligonucleotides. We show that stearyl-TP10 is as effective in oligonucleotide delivery as Lipofectamine™ 2000. Moreover, stearyl-TP10 has preserved efficacy in serum and is not toxic to cells. In conclusion, the rational modifications of CPPs greatly potentiate their application in cargo delivery both in vitro and in vivo.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi, 2009. 47 p.
Keyword
Cell-penetrating peptide, oligonucleotide, drug delivery, tumor targeting
National Category
Neurosciences
Research subject
Neurochemistry and Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-8374 (URN)978-91-7155-792-6 (ISBN)
Public defence
2009-01-30, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2009-01-08 Created: 2008-12-08 Last updated: 2010-03-09Bibliographically approved
2. Cell-penetrating peptides in cargo delivery: In vitro studies on uptake and in vivo studies on tumor targeting
Open this publication in new window or tab >>Cell-penetrating peptides in cargo delivery: In vitro studies on uptake and in vivo studies on tumor targeting
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The capability of cell-penetrating peptides (CPPs) to transport cargos over different cellular membranes both in vitro and in vivo have drawn major attention in the past decade. Three main topics on the application of CPPs have been studied in this thesis.

First, several well-known CPPs, with fluorescein as a cargo, were shown to translocate into Nicotiana tabacum cultivar SR-1 protoplasts. By coupling different cargos to CPP it might be possible to effectively transport them inside the plant protoplasts. The translocation of CPPs into plant protoplasts might open up a new method for transformation of plant cells.

Next, the cell-penetrating ability of the novel peptide YTA2 was characterized and it was established that chemical coupling between YTA2 and the protein cargo is not needed for the transport of the cargo over the cellular membrane in vitro. The delivery of proteins into cells by mere coincubation with CPPs is an improvement, since the chemical coupling between the CPP and the cargo molecule, which adds time-consuming synthesis and purification steps, can be omitted.

Finally, by conjugating each of the two breast tumor homing peptides, the cyclic cCPGPEGAGC (PEGA) or the linear CREKA peptide, to the CPP pVEC, two cell-penetrating peptides with homing properties were obtained. Both, PEGA-pVEC and CREKA-pVEC were taken up by different breast cancer cells in vitro. Moreover, the homing capacity of the PEGA-pVEC and CREKA-pVEC was conserved in vivo, where the conjugates mainly accumulated in blood vessels in breast tumor tissue and were subsequently translocated into cells. Conjugating the anti-cancer drug chlorambucil to PEGA-pVEC or CREKA-pVEC markedly improved its efficiency. Furthermore, systemic treatment of tumor-bearing mice with chlorambucil-CREKA-pVEC significantly reduced tumor growth compared to control groups. These tumor-homing CPPs might improve both diagnosis and treatment of breast cancer tumors, by conjugation to therapeutic agents.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi, 2008. 67 p.
National Category
Neurosciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-7263 (URN)978-91-7155-554-0 (ISBN)
Public defence
2008-02-01, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Opponent
Supervisors
Available from: 2008-01-10 Created: 2008-01-10 Last updated: 2015-03-23Bibliographically approved

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