Kanser Tedavisinde Kullanılacak Aktif Hedeflendirilmiş Farmasötik Nano Taşıyıcılar
Özet
The use of various targeted nanocarriers has turned out to be one of the most important areas of
nanomedicine. These carriers are nanosized materials that can carry various drugs and/or imaging agents. It is also possible to increase local drug concentration and to control drug release via targeted nanocarriers. Among the many possible targets for such nanocarriers, tumors have been most often investigated. Current cancer
treatments include surgical intervention, radiation and chemotherapeutic drugs,
which often also kill healthy cells and cause toxicity to the patient. Therefore, it is
important to actively target of such drugs in the form of nanocarriers to cancerous
cells. Paclitaxel, a diterpenoid extracted from Taxus brevifolia, is a strong mitotic
inhibitor of cell replication used in various cancer treatments including breast,
ovarian, liver, head and neck cancers. It has very low water solubility. Because of
this, it is currently used in a formulation made with Cremophor EL and ethanol 1:1
(v/v) and subsequently diluted in saline solutions prior to i.v. administration.
However, this Cremophor EL/ethanol mixture provokes serious undesirable side
effects, such as hypersensitivity, nephrotoxicity, and neurotoxicity. In attempts to
minimize these problems, a variety of paclitaxel drug delivery systems have been
investigated. In this thesis, micelle formulations were prepared to increase the water
solubility and bioefficiency of Paclitaxel. Furthermore, uptake and pharmacological
effect of Paclitaxel was investigated by conjugating with specific ligands.
Polyethylene glycol-phosphatidylethanolamine was used for the preparation of
Paclitaxel-loaded micelles. To facilitate the intracellular and targeted delivery of
these micelles, a cell penetrating peptide (TAT) and 2C5 monoclonal antibody were
added into the formulations. As it is well known, most antitumor agents are not very
effective in chemotherapy because of multidrug resistance in various tumor cells.
After identification of P-gp as a major cause of MDR in in vitro cell studies,
tremendous efforts have been made for the identification of more effective treatment
methods for the P-gp inhibition. For this purpose, P-gp inhibitors were added in the
formulations. In vitro characterization studies such as micellar size, zeta potential,
micellar solubilization, encapsulation efficiency and in vitro release studies were
performed. Cytotoxicity and anticancer activity studies were also investigated on
resistant/unresistant cells by using cell culture techniques. Paclitaxel together with
different P-gp inhibitors were loaded at high amounts in the micelles. By this means,
aqueous solubility of paclitaxel were increased from 0,3 μg/mL to 1095 μg/mL.
Cytotoxicity against cancer cells was found to be higher in the formulations
containing both active substances, due to the inhibition of P-gp. TAT peptidemodified
micelles have shown high cellular uptake. However, cytotoxicity was found
to be higher in the 2C5 modified micelles. The obtained results indicate that,
Paclitaxel resistance could be reversed by an anticancer drug and P-gp inhibitor coloaded
active targeted micelle formulations.
