From Bench to Bedside—An Example of an In Situ Hydrogel in In Vivo Applications - In-Situ Gelling Polymers: For Biomedical Applications - page 215

treatment by investigating new polymer carriers and pharmacological agents is well
accentuated. Cellular proliferation inhibitors like paclitaxel are known to be effec-
tive against gliomas; however their systemic administration has been limited due to
their poor penetration into the CNS. So, incorporating paclitaxel in a thermo-sen-
sitive polymer depot delivery system can enhance its efficacy in cancer treatment.
The safety and potential synergistic effects of Oncogel™ on rats challenged with
intracranial 9L glioma was demonstrated in a study which combined Oncogel™
with radiotherapy [ 15 ]. Oncogel™ was intracranially implanted into 60 animals and
divided into placebo (ReGel™), XRT, Oncogel™ 6.0 mg/m or Oncogel™ with sin-
gle dose 20 Gy XRT. Animals treated with just Regel™ showed no increase in sur-
vival when compared to the controls but animals administered with Oncogel™ and
XRT had a statistically significant increase in survival when compared to XRT alone
( P = 0.0182). These results were further supported by another study which claimed
the safety of 6.3 mg/ml of paclitaxel for intracranial injection in rats [ 16 ]. It was also
established that combining Oncogel™ acts as a radiation sensitizer, thus, combin-
ing Oncogel™ treatment with radiation therapy is more effective than just the stand
alone treatment.
Advancement in oncology research identified multiple signaling pathways to
play a significant role in tumor progression. So, application of combination therapies
which synergistically target different pathways could improve the efficacy of can-
cer therapies. Temozolomide (TMZ) is an alkylating agent shown to have improved
survival in patients with glioblastoma [ 17 ]. Paclitaxel is a mitotic inhibitor which is
effective against glioma in vitro and also makes the glioma cells sensitive to radi-
ation therapy. As TMZ and paclitaxel have different mechanisms of action, it was
hypothesized that the combination of TMZ (oral and local) and OncoGel™ might
have a better synergistic effect in a rodent model of gliosarcoma. Oncogel™ + TMZ
in general prolonged survival and no signs of systemic or neurological toxicity were
observed. The combination of OncoGel™ with oral or local TMZ resulted in 57 and
100 % long term survivors, respectively, proving the local delivery of TMZ to be
a better option of treatment. Since most of patients suffering from glioma undergo
radiation therapy, the efficacy of Oncogel™ + TMZ + RT was also explored. The
strong therapeutic effect of the treatment regimen involving this triple combina-
tion was indicated by the statistically longer survival ( P < 0.0001) as compared to
the combination of oral TMZ and XRT [ 18 ]. However, the ineffective correlation
between animal model and human response was recognized and an attempt was
made to increase the effectiveness of a drug delivery device by using computational
models combining fluid transport and mass transport submodels [ 14 ]. The study
attempted to bridge the gap between the rat model and the human tissue by using
a simplified model to compare the paclitaxel distribution in the two systems. The
therapeutic penetration distance from the injection site was found to be 1-2 mm
(Fig. 2 a). Though the rat and human brains have a similar penetration distances,
the fraction of brain tissue exposed to therapeutic concentration of paclitaxel was
reported to be higher in rats than humans.