Polymeric micelles represent a promising drug carrier system that has gained considerable attention due to its simplicity, small sizes, and ability to solubilize water-insoluble drugs and accumulate specifically in the tumors. However, most of them do not possess any biological activity by themselves. One interesting approach in the design of a carrier is to incorporate components in the carrier system itself that exhibit favorable biological activity, either counteracting the side effects caused by the loaded anticancer drugs, or promoting synergistic effect with the incorporated drug.
We first developed a dual function carrier that is based on PEG-derivatized S-trans, transfarnesylthiosalicylic acid (FTS) (PEG5k-FTS2). FTS is a synthetic farnesylcysteine mimetic that acts as a potent and especially nontoxic Ras antagonist. In addition to retention of anti-Ras activity, PEG5k-FTS2 forms small-sized micelles that are capable of synergistic delivery of various hydrophobic agents. A further structure activity relationship (SAR) study was conducted in four PEG-FTS conjugates that vary in the molecular weight of PEG (PEG2K vs PEG5K) and the molar ratio of PEG/FTS (1/2 vs 1/4). We demonstrated that PEG5k-FTS4 formed the most stable mixed micelles with PTX among the four PEG-FTS conjugates.
Next, we examined whether the performance of PEG5k-FTS2 can be further improved via incorporation of Fmoc, based on our recent discovery of Fmoc as a novel and potent druginteractive motif. Our data showed that introduction of an Fmoc at the interfacial region of PEG5k-FTS2 led to a significant improvement in the drug loading capacity for a number of anticancer agents including paclitaxel (PTX), doxorubicin (DOX), curcumin, and etoposide. Finally, we established a reduction-sensitive delivery system by incorporation of an additional cleavable linkage (disulfide bond) into PEG5k-FTS2. We demonstrated that the incorporation of a disulfide linkage led to an enhanced release of FTS inside tumor cells, which was associated with an improved cytotoxicity against tumor cells.
In summary, our data demonstrated that PEG-derivatized FTS can serve as dual functional carrier for the targeted delivery of therapeutic agents and contribute additional effects with the loaded anticancer drug. Our improved dual function carrier represents a simple and effective targeted drug delivery system for cancer.
|School:||University of Pittsburgh|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 78/05(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Pharmacy sciences, Materials science|
|Keywords:||Cancer therapy, Polyethylene glycol, Targeted delivery, Transfarnesylthiosalicylic acid|
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