136
5 Results
Over the last 40 years, impressive advancements toward the discovery of novel drugs as well as responsive multifunctional drug delivery systems (DDS) have been reported. As a consequence, out of
more than 200 different cancers, some highly lethal cancers are
now chronic diseases. Unfortunately, only limited progress has
been made for some specific forms of cancer such as PC. For this
complex disease, very sophisticated carriers should be designed to
bypass biological barriers with minimum cargo loss, and effective
and selective delivery to the desired pathological site, as demonstrated by the material described in this work.
An amphiphilic pentablock terpolypeptide was developed by
optimizing the macromolecular architecture and composition as
well as the 3D structure of the hydrophobic blocks. The final pentablock terpolypeptide exhibits a unique combination of properties
in the same molecule, which has not been achieved so far.
Simply mixing the polypeptide and gemcitabine dissolved in water
results in the facile formation of an injectable and quickly self-healing
hydrogel which forms in situ and can be injected in the least invasive way
close to cancer tissue. These properties rely on the secondary structure of
the hydrophobic part of the amphiphilic terpolypeptide. After implantation, the hydrogel becomes liquid only close to the cancer tissue, mainly
due to the lower pH of the pathological site, thus releasing the drug only
in the vicinity of cancer tissue.
The ability of these polypeptides to form hydrogels by adding
Milli-Q water depended on two parameters: their molecular and
compositional homogeneity and the PHIS/PBLG ratio. It was
found that the pentablocks should be well defined with a high
degree of molecular and compositional homogeneity in order to
form strong hydrogels. If the polydispersity was high by intentionally mixing two different polypeptides, or by intentionally omitting
one block, they either formed very weak hydrogels at higher polypeptide concentrations or did not gel at all.
This obliges the directional release of the drug toward the cancer rather than healthy tissue, as shown by in vivo experiments. It
was found that the delivery of only 40% of gemcitabine in one dose
directed by the hydrogel could slow down the development of the
cancer tissue to the same extent with the delivery of 100% of pure
gemcitabine in two doses, the typical chemotherapy used so far in
clinics. Therefore, we achieved the same or slightly better deceleration of tumor growth with fewer drugs and less number of doses
due to the guided delivery through the Hydrogem. The hydrogel
also responds to enzymes, rendering it biodegradable, thus not
requiring removal through resection following drug delivery.
Regarding the PHis/PBLG ratio, PHis 100 and PHis 70
formed a weak hydrogel at 20 °C, while its strength was highly
temperature dependent, and at 37 °C it was transformed into liquid. PHis 50 and PHis 30 formed strong hydrogels depending on
Hermis Iatrou et al.
5 Results
Over the last 40 years, impressive advancements toward the discovery of novel drugs as well as responsive multifunctional drug delivery systems (DDS) have been reported. As a consequence, out of
more than 200 different cancers, some highly lethal cancers are
now chronic diseases. Unfortunately, only limited progress has
been made for some specific forms of cancer such as PC. For this
complex disease, very sophisticated carriers should be designed to
bypass biological barriers with minimum cargo loss, and effective
and selective delivery to the desired pathological site, as demonstrated by the material described in this work.
An amphiphilic pentablock terpolypeptide was developed by
optimizing the macromolecular architecture and composition as
well as the 3D structure of the hydrophobic blocks. The final pentablock terpolypeptide exhibits a unique combination of properties
in the same molecule, which has not been achieved so far.
Simply mixing the polypeptide and gemcitabine dissolved in water
results in the facile formation of an injectable and quickly self-healing
hydrogel which forms in situ and can be injected in the least invasive way
close to cancer tissue. These properties rely on the secondary structure of
the hydrophobic part of the amphiphilic terpolypeptide. After implantation, the hydrogel becomes liquid only close to the cancer tissue, mainly
due to the lower pH of the pathological site, thus releasing the drug only
in the vicinity of cancer tissue.
The ability of these polypeptides to form hydrogels by adding
Milli-Q water depended on two parameters: their molecular and
compositional homogeneity and the PHIS/PBLG ratio. It was
found that the pentablocks should be well defined with a high
degree of molecular and compositional homogeneity in order to
form strong hydrogels. If the polydispersity was high by intentionally mixing two different polypeptides, or by intentionally omitting
one block, they either formed very weak hydrogels at higher polypeptide concentrations or did not gel at all.
This obliges the directional release of the drug toward the cancer rather than healthy tissue, as shown by in vivo experiments. It
was found that the delivery of only 40% of gemcitabine in one dose
directed by the hydrogel could slow down the development of the
cancer tissue to the same extent with the delivery of 100% of pure
gemcitabine in two doses, the typical chemotherapy used so far in
clinics. Therefore, we achieved the same or slightly better deceleration of tumor growth with fewer drugs and less number of doses
due to the guided delivery through the Hydrogem. The hydrogel
also responds to enzymes, rendering it biodegradable, thus not
requiring removal through resection following drug delivery.
Regarding the PHis/PBLG ratio, PHis 100 and PHis 70
formed a weak hydrogel at 20 °C, while its strength was highly
temperature dependent, and at 37 °C it was transformed into liquid. PHis 50 and PHis 30 formed strong hydrogels depending on
Hermis Iatrou et al.