TY  - THES
AB  - The cure of cancer represents an ultimate challenge for scientists from different fields.
Cancer complexity and diversity hamper the discovery of a broadly applicable treatment,
and consequently, cancer represents the second cause of premature death worldwide.
Despite the continuous approval of new drugs, the cancer burden keeps increasing due to
different factors and leaves a vast number of patients helpless. Conventional
chemotherapy still represents the backbone of cancer medical care. However, these agents
are not able to selectively accumulate at the disease site which limits their efficacy and
cause severe side effects. In the last years, targeted therapy has appeared as an innovative
approach to overcome the drawbacks shown by traditional chemotherapeutics. In this
approach, a cytotoxic agent is directed to the tumor site through the covalent conjugation
to homing devices (e.g. antibodies, small molecules).
Cryptophycins are cyclic depsipeptides with natural origin that present high cytotoxicity
against several cell lines. Although cryptophycins cannot be used as stand-alone agent
due to their side effects, they hold great potential as cytotoxic agent for tumor targeted
therapy. Therefore, the discovery of new cryptophycins that can be conjugated to homing
devices and their vectorization could be translated in a significant therapeutic activity.
In the first part (chapter 3), the discovery of new cryptophycin analogues that retain the
high cytotoxicity of the parent compound and present a functional group that can be used
for conjugation to a delivery vehicle was described. Moreover, the usage of molecular
dynamics to predict the biological activity of new analogues was explored.
The second part (chapters 4 and 5), describes the usage of cryptophycin-55 glycinate as
payload in small molecule-drug conjugates (SMDCs). In chapter 4, the payload was
conjugated to a ligand capable to target the carbonic anhydrase IX, a transmembrane
enzyme that is widely overexpressed in tumors. The cytotoxic activity of the resulting
conjugate was studied in vitro, and the therapeutic activity was investigated in mice. In
chapter 5, the payload was further explored by coupling it to a cyclic peptide targeting
the somatostatin receptor 2, a marker which is commonly overexpressed in
neuroendocrine tumors. The cytotoxicity of the conjugates was evaluated in a cell-based
assay. In this case, further investigations in their targeting properties and stability were
performed. Finally, the antitumor activity of the lead compound was investigated in vivo.
DA  - 2019
DO  - 10.4119/unibi/2934464
LA  - eng
PY  - 2019
TI  - Novel cryptophycin analogues and conjugates for tumor targeted therapy
UR  - https://nbn-resolving.org/urn:nbn:de:0070-pub-29344648
Y2  - 2024-11-22T07:05:42
ER  -