Bioorganic & Medicinal Chemistry Letters
Camptothecins in tumor homing via an RGD sequence mimetic
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Domenico Alloatti, Giuseppe Giannini , Loredana Vesci, Massimo Castorina, Claudio Pisano,
Elena Badaloni, Walter Cabri
Corporate R&D, sigma-tau Industrie Farmaceutiche Riunite S.p.A., via Pontina Km 30.400, I-00040 Pomezia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A RGD peptide mimetic was conjugated to four camptothecins, with the purpose to improve their ther-
apeutic index. The conjugate derivatives were evaluated against two tumor cell lines, one overexpressing
integrins (human ovarian carcinoma, A2780) and a second one with a low integrin expression (human
prostate cancer, PC3). The in vitro screening was completed with the adhesion behavior to vitronectin.
Compound 8 (ST7456CL1) was selected for the in vivo investigation after stability tests over 24 h, in
PBS solution and in rat plasma, and compared to irinotecan. The former showed a prolonged half-life.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 8 June 2012
Revised 12 July 2012
Accepted 16 July 2012
Available online 26 July 2012
Keywords:
Tumor homing
Tumor-specific targeting
RGD mimetic and Integrin
Camptothecin–RGD mimetic conjugate
Anticancer drug delivery system
Traditional cancer chemotherapy is based on the assumption
that rapidly proliferating cancer cells are more likely to be killed
than quiescent normal cells. However the main drawback of this
approach is that cytotoxic agents have very poor specificity, and
lead to systemic toxicity. An ever-increasing knowledge of typical
receptors over-expressed by cancer cells allows the exploitation
of selective ligands which, properly conjugated with cytotoxic
agents, are able to address them selectively to the tumors.
This so-called tumor homing approach could be applied suc-
cessfully to overcome drug resistance and/or metastasis control.1,2
Similarly, a delivery system using luteinizing hormone-releasing
hormone (LHRH) was described as a targeting moiety for LHRH
receptors.3
The conjugate should be systemically non-toxic; this means
that the linker must be stable in circulation. Upon internalization
into the cancer cell the conjugate should be easily cleaved to
regenerate the active cytotoxic drug. To achieve effective tumor-
specific drug delivery it is important to take advantage of the mor-
phological and physiological differences between malignant and
normal tissues. Two main examples are (a) the anaerobic metabo-
lism which lowers tumor cell’s pH4,5 allowing the use of acid-sen-
sitive linkers and (b) tumor cell’s huge request of various nutrients
for which the cell itself overexpresses tumor-specific receptors
that can be used to target cytotoxic warhead. The latter case has
been particularly studied using tumor-targeting moieties such as
monoclonal antibodies, polyunsaturated fatty acids, hyaluronic
acid, small peptides and peptidomimetics.6
The highly restricted expression of integrin avb3 and avb5, over-
expressed on tumor endothelial and some epithelial cells, during tu-
mor growth, angiogenesis, invasion, and metastasis present an
interesting molecular target for tumor homing approach. That is
why among selective receptor-targeting small peptides, integrin-
mediated RGD peptides appear to be attractive candidates. The argi-
nine–glycine–aspartic acid (RGD) is a cell adhesion motif present in
many proteins of the extracellular matrix (ECM);7 Through this mo-
tif ECM proteins recognize aVb3 and aVb5 integrin receptors.
In the present study we investigated the usefulness of an RGD
mimetic as a carrier for antitumor drugs of the camptothecin ser-
ies. Among the different RGD mimetics available in the literature,
we focused our attention on 1, disclosed by Iwama et al.8 with
the aim of linking it to the cytotoxic derivative. We modified 1
by introducing in the side chain a suitable functional group for
the attachment of cytotoxic drugs.
Various 10-hydroxy-camptothecin derivatives were evaluated,
including SN38 (10-hydroxy-7-ethylcamptothecin), a well-known
drug already in clinical use as its prodrug form irinotecan,9 (see
Fig. 1).
The choice of the linker for conjugates with small peptide-
mimetics was very challenging, its requisites being: stability into
the bloodstream, lability into the tumor cell and resistance to plas-
ma peptidases from which it is not shielded by bulky antibodies as
it happens for immunoconjugates. Given some previous unpleas-
ant results with linear amides (internal cyclization, followed by
release of the two fragments, were frequently observed), we chose
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Corresponding author.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.