Universität zu Köln

Feni, Lucia, Parente, Sara, Robert, Clemence, Gazzola, Silvia, Arosio, Daniela ORCID: 0000-0001-5486-3504, Piarulli, Umberto ORCID: 0000-0002-6952-1811 and Neundorf, Ines ORCID: 0000-0001-6450-3991 (2019). Kiss and Run: Promoting Effective and Targeted Cellular Uptake of a Drug Delivery Vehicle Composed of an Integrin-Targeting Diketopiperazine Peptidomimetic and a Cell-Penetrating Peptide. Bioconjugate Chem., 30 (7). S. 2011 - 2023. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-4812

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Abstract

Cell-penetrating peptides (CPPs) have emerged as powerful tools in terms of drug delivery. Those short, often cationic peptides are characterized by their usually low toxicity and their ability to transport diverse cargos inside almost any kinds of cells. Still, one major drawback is their nonselective uptake making their application in targeted cancer therapies questionable. In this work, we aimed to combine the power of a CPP (sC18) with an integrin-targeting unit (c[DKP-f3-RGD]). The latter is composed of the Arg-Gly-Asp peptide sequence cyclized via a diketopiperazine scaffold and is characterized by its high selectivity toward integrin alpha(v)beta(3). The two parts were linked via copper-catalyzed alkyne-azide click reaction (CuAAC), while the CPP was additionally functionalized with either a fluorescent dye or the anticancer drug daunorubicin. Both functionalities allowed a careful biological evaluation of these novel peptide-conjugates regarding their cellular uptake mechanism, as well as cytotoxicity in alpha(v)beta(3) integrin receptor expressing cells versus cells that do not express alpha(v)beta(3). Our results show that the uptake follows a kiss-and-run-like model, in which the conjugates first target and recognize the receptor, but translocate mainly by CPP mediation. Thereby, we observed significantly more pronounced toxic effects in alpha(v)beta(3) expressing U87 cells compared to HT-29 and MCF-7 cells, when the cells were exposed to the substances with only very short contact times (15 min). All in all, we present new concepts for the design of cancer selective peptide-drug conjugates.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Feni, Lucia UNSPECIFIED UNSPECIFIED UNSPECIFIED Parente, Sara UNSPECIFIED UNSPECIFIED UNSPECIFIED Robert, Clemence UNSPECIFIED UNSPECIFIED UNSPECIFIED Gazzola, Silvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Arosio, Daniela UNSPECIFIED orcid.org/0000-0001-5486-3504 UNSPECIFIED Piarulli, Umberto UNSPECIFIED orcid.org/0000-0002-6952-1811 UNSPECIFIED Neundorf, Ines UNSPECIFIED orcid.org/0000-0001-6450-3991 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-136022
DOI:	10.1021/acs.bioconjchem.9b00292
Journal or Publication Title:	Bioconjugate Chem.
Volume:	30
Number:	7
Page Range:	S. 2011 - 2023
Date:	2019
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	1520-4812
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CYCLIC RGD-PEPTIDOMIMETICS; LUNG-CANCER; IN-VIVO; ANTIBODY; ALPHA(V)BETA(3); SCAFFOLDS; INTERNALIZATION; CHEMOTHERAPY; CYCLIZATION; CHALLENGES Multiple languages Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13602