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Conventional chemotherapy with chemotherapeutic agents is the treatment of choice for many cancers, but its effectiveness has been limited. Most anticancer drugs have nonspecific action and distribution in normal tissues that result in toxic side effects (1,2). The use of nanocarriers can improve the pharmacological properties of traditional chemotherapeutics because of enhanced permeability and retention (EPR) effect, called passive targeting (3,4). Although there are numerous nanocarriers available for such delivery, liposomes are the most investigated and well-characterized drug delivery systems (5). Doxil, a stealth liposomal formulation of doxorubicin, is the first approved nanomedicine with prolonged circulation time and significant reduced cardiac toxicity compared with free doxorubicin and higher drug delivery to tumors (6). To improve the homing of drug carriers within tumor tissue and enhance the selective delivery of the anticancer drugs to tumor cells, liposomal formulations have been decorated with cancer-targeting ligands on their surface (7,8). Targeting ligands have special affinity for a receptor expressed selectively by the tumor or tumor vasculature cells (and not expressed by normal cells) and accumulate preferentially in these cells (9,10). HDM2 is an important negative regulator of the p53 tumor suppressor and it is interesting that significant levels of HDM2 were found in the membranes of a variety of cancer cells but not in the membranes of several untransformed cell lines (11). In several human malignancies, the association between HDM2 and clinical outcome has been studied. These findings expressed the utility of HDM2 as a clinical prognostic marker in a wide variety of tumors including breast, prostate, colon, glioblastoma, head/neck, ovarian and pancreatic cancers (12,13). Therefore, design of molecules with tendency to bind HDM2 receptor could become an important target for cancer therapy (14). One of these molecules is a synthetic peptide PNC27 which shows intriguing potential as a cancer therapy (15-17). This peptide is composed of a portion of HDM2-binding domain from p53 attached to a membrane-penetrating peptide on its carboxyl terminal end which enables its intracellular uptake (11). Numerous studies showed that binding of PNC27 peptide to HDM2 in cancer cell membrane induced membranolysis and the cancer cells died by necrosis, not apoptosis (15,18). Binding of PNC27 peptide to HDM2 causes helical conformation changes in HDM2 protein which lead to form pore in the cell...