The self‐assembling peptide EAK16‐II is capable of stabilizing hydrophobic compounds to form microcrystal suspensions in aqueous solution. Here, the ability of this peptide to stabilize the hydrophobic anticancer agent ellipticine is investigated. The formation of peptide‐ellipticine suspensions is monitored with time until equilibrium is reached. The equilibration time is found to be dependent on the peptide concentration. When the peptide concentration is close to its critical aggregation concentration, the equilibration time is minimal at 5 h. With different combinations of EAK16‐II and ellipticine concentrations, two molecular states (protonated or cyrstalline) of ellipticine could be stabilized. These different states of ellipticine significantly affect the release kinetics of ellipticine from the peptide‐ellipticine complex into the egg phosphatidylcholine vesicles, which are used to mimic cell membranes. The transfer rate of protonated ellipticine from the complex to the vesicles is much faster than that of crystalline ellipticine. This observation may also be related to the size of the resulting complexes as revealed from the scanning electron micrographs. In addition, the complexes with protonated ellipticine are found to have a better anticancer activity against two cancer cell lines, A549 and MCF‐7. This work forms the basis for studies of the peptide‐ellipticine suspensions in vitro and in vivo leading to future development of self‐assembling peptide‐based delivery of hydrophobic anticancer drugs.
Neurofibromatosis type 1 (NF1) patients are prone to the development of malignant tumors, the most common being Malignant Peripheral Nerve Sheath Tumor (MPNST). NF1-MPNST patients have an overall poor survival due to systemic metastasis. Currently, the management of MPNSTs includes surgery and radiation; however, conventional chemotherapy is not very effective, underscoring the need for effective biologically-targeted therapies. Recently, the NF1 gene product, neurofibromin, was shown to negatively regulate the phosphoinositide-3-kinase (PI3K)/Protein Kinase-B (Akt)/mammalian Target Of Rapamycin (mTOR) pathway, with loss of neurofibromin expression in established human MPNST cell lines associated with high levels of mTOR activity. We developed and characterized a human NF1-MPNST explant grown subcutaneously in NOD-SCID mice, to evaluate the effect of the mTOR inhibitor rapamycin. We demonstrate that rapamycin significantly inhibited human NF1-MPNST mTOR pathway activation and explant growth in vivo at doses as low as 1.0 mg/kg/ day, without systemic toxicities. While rapamycin was effective at reducing NF1-MPNST proliferation and angiogenesis, with decreased CyclinD1 and VEGF respectively, there was no increase in tumor apoptosis. Rapamycin effectively decreased activation of S6 downstream of mTOR, but there was accompanied increased Akt activation. This study demonstrates the therapeutic potential and limitations of rapamycin in NF1-associated, and likely sporadic, MPNSTs.Malignant Peripheral Nerve Sheath Tumors (MPNST) have an incidence of 0.001% in the general population, however, as many as 5-10% of individuals with the inherited cancer syndrome, neurofibromatosis type 1 (NF1) will develop an MPNST in their lifetime. In adults with NF1, MPNSTs are the most common malignancy and the major source of morbidity.1 The poor survival associated with NF1-associated MPNST (NF1-MPNST) reflects the earlier age of onset, multiple MPNSTs, and their overall resistance to conventional chemo-and radiation treatment. Unfortunately, pre-or postoperative adjuvant chemotherapy is not effective 2 and the five year survival after MPNST diagnosis is $20% for individuals with NF1.3 In addition, these tumors have a high propensity to metastasize to bone and lung, even after surgical excision and local radiation therapy. 4 As such, there is a recognized need for effective targeted biological therapies for NF1-MPNSTs.With the identification of the NF1 protein (neurofibromin), it became possible to consider treatments that reverse the biochemical abnormalities resulting from loss of neurofibromin function in NF1-MPNST. Neurofibromin functions in part as a Ras GTPase Activating Protein (Ras-GAP) by accelerating the conversion of active, GTP-bound p21-Ras to inactive, GDP-bound Ras and reducing p21-Ras stimulation of cell growth. We and others have previously shown that p21-ras-GTP levels are elevated in human NF1-MPNST tumors. 5,6 However, biological therapies targeting p21-Ras activation, such as farnesyltransferase inhibitors (FTIs), ...
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