Lipid‐Conjugation of Endogenous Neuropeptides: Improved Biotherapy against Human Pancreatic Cancer

Abstract

Neuropeptides are small neuronal signaling molecules that act as neuromodulators for a variety of neural functions including analgesia, reproduction, social behavior, learning, and memory. One of the endogenous neuropeptides—Met-Enkephalin (Met-Enk), has been shown to display an inhibitory effect on cell proliferation and differentiation. Here, a novel lipid-modification approach is shown to create a small library of neuropeptides that will allow increased bioavailability and plasma stability after systemic administration. It is demonstrated, on an experimental model of human pancreatic adenocarcinoma, that lipid conjugation of Met-Enk enhances its tumor suppression efficacy compared to its nonlipidated counterparts, both in vitro and in vivo. More strikingly, the in vivo studies show that a combination therapy with a reduced concentration of Gemcitabine has suppressed the tumor growth considerably even three weeks after the last treatment.

From poly(alkyl cyanoacrylate) to squalene as core material for the design of nanomedicines

“…Considering squalene both acted as a promoiety and drug carrier, this concept led to very high drug loading nanoparticles (much higher than any other traditional drug-loaded nanoparticulate systems) and increased therapeutic efficacy compared to the free drugs. Proposed for the first time in 2006 [139], this versatile concept has been successfully applied to a broad range of different anticancer drugs [140,141,142,143,144], neuroprotective molecules [145], antibiotics [146,147], antiretrovirals [148,149], contrast agents [150], ligands [151], small peptides [152,153,154], fluorescent dyes, [151] siRNA [155,156] and also PEG [157]. A complete list of all synthetized prodrugs or conjugates with contrast agents and ligands is reported in Table 1.…”

Copy number alteration of neuropeptides and receptors in multiple cancers

“…Although neuropeptides have been used to improve biotherapy against Human pancreatic cancer 8 , the role of neuropeptides and their interacting receptors in cancers is unexplored. In this study, we created a comprehensive inventory of neuropeptides by searching all the known and putative mammalian neuropeptides.…”

Opioid Tripeptides Hybridized with trans‐1‐Cinnamylpiperazine as Proliferation Inhibitors of Pancreatic Cancer Cells in Two‐ and Three‐Dimensional in vitro Models

“…Improved selectivity and activity of peptides toward cancer might be achieved by modification of compound structure using lipophilic moieties. Researchers have shown that the linkage or incorporation of lipophilic units to various neuropeptides, including Met‐enkephalin, may induce significant inhibition of pancreatic carcinoma cells and increase the enzymatic stability of the molecule . We have also found that one of the best opioid peptidomimetics, named biphalin [(Tyr‐ d ‐Ala‐Gly‐Phe‐NH) 2 ], in addition to analgesic activity, possesses cytotoxic activity against selected tumor cells .…”

“…Researchers have shown that the linkage or incorporation of lipophilic units to variousn europeptides,i ncluding Met-enkephalin, may induce significant inhibition of pancreatic carcinoma cells and increase the enzymatic stability of the molecule. [7,8] We have also found that one of the best opioid peptidomimetics, namedb iphalin According to the World Health Organization, the mortality rate among patientsw ith pancreatic cancerw ill increasei nt he upcomingy ears. Gemcitabine is the first choice for treatment of pancreatic malignancy,b ut increasing resistance to this drug is decreasing its overall efficacy.S tudies on new therapies that target metabolicp athways, growth factor inhibitors, and tumor stroma or tumors tem cells are currently underway in many research groups.…”