Development of drug-branched peptides complexes for
cancer cells tracing and killing
aDipartimento
b
Eleonora Tenori,a Stefano Menichetti,a Chiara Falciani,b Luisa Braccib
di Chimica ‘Ugo Schiff’, Università di Firenze, Via della Lastruccia 13, 50019, Sesto Fiorentino (FI), Italy
Dipartimento di Biologia Molecolare, Università di Siena, Via Fiorentina 1, 53100 Siena, Italy
[email protected]
Peptides are used as carriers for the targeted delivery of cytotoxic agents into tumor cells. When synthesized as dendrimers
they are suitable for in vivo use due to their stability in human plasma (up to 24 hours). Tetrabranched peptide of Neurotensin
(NT4) is among the better candidates for peptide based therapy due to the high incidence and density of its receptors on
tumor cells.
DMTr
O
= QLYENKPRRPYIL = NEUROTENSIN
Q = Glutamic acid, L = Leucine, …
F
NH
NH
N
N
O
N
DMTrO
DMTrO
O
O
O F
O
O
RESIN
NH2
O
i. Coupling
F
O
OH
O
OH
O
2-deoxy-5-fluorouridine
5 FdU
Gemcitabine
O
ii. Resin cleavage
O
O
OH
O
OH
O
O
H3CO
HO
HO
2-methoxyestradiol
Estradiol
= Neurotensin
receptor
O
COOH
O
OH
O
O
Healthy cell
=
Cancer cell
O
O
O
O
O
O
OH
O
O
O
Combretastatin
β−Lapachone
In vivo tests show an increased activity of the NT4-drug toward three different cell lines representing the diverse tumors that
over-express NT receptors [HT-29 (colon adenocarcinoma), PANC-1 (pancreas epitheloid carcinoma) and PC-3 (prostate
carcinoma)] with respect to the free drug and to the drug linked to a branched peptide containing an unrelated sequence.
=
NT4-drug
=
ScrambledNT4-drug
=
Free drug
= HT-29
= PC-3
= PANC-1
A ‘click chemistry’ strategy has been planned to perform the coupling of the drugs to the peptide after the cleavage from the
resin, avoiding the exposure of the complexes to acid conditions in which some of them has turned out to be unstable.
O
F
O
N
O
HO
O
N3
O
O
OCH3
OCH3
N
NH
N
N
O
HO
HO
O
OCH3
H3CO
NH2
O
F
NH
O
O
O
O
F
F
O
O
Nanoparticles are defined ‘little bombs promising a big bang for cancer patients’, owing unique dimensions, wide-ranging
functionalities on the surface and controllable drug release that make them promising carriers for therapeutics. In particular,
they act like multi-drug carriers, allowing to target a huge number of anti-cancer agents in cancer cells.
DRUG
O
F
=
N
N
N
O
HO
O
O
SH
O
S
NH
N
=S
DRUG