Abstract:Among noncovalent forces, electrostatic ones are the strongest and possess a rather long-range action. For these reasons, charges and counterions play a prominent role in self-assembly processes in water and therefore in many biological systems. However, the complexity of the biological media often hinders a detailed understanding of all the electrostatic-related events. In this context, we have studied the role of charges and counterions in the self-assembly of lanreotide, a cationic octapeptide. This peptide… Show more
“…The lines are guides to the eye, and the grey area indicates the region where we experimentally observe crystals. This diagram colligates data from this study and from references [31,37]. NB: The datapoint tagged 0 corresponds to a lanreotide derivative whose lysine side chain has been acetylated.…”
Section: Discussionmentioning
confidence: 92%
“… (diamonds) and Gobeaux et al . (circles). The ordinate reads the ‘normalized’ hindrance of the modifications, whether it is a chemical modification of the aromatic residue in position 4 (open diamonds), on the aliphatic residue on position 5 (triangles) or a change of counter‐ions (circles).…”
In the absence of efficient crystallization methods, the molecular structures of fibrous assemblies have so far remained rather elusive. In this paper, we present a rational method to crystallize the lanreotide octapeptide by modification of a residue involved in a close contact. Indeed, we show that it is possible to modify the curvature of the lanreotide nanotubes and hence their diameter. This fine tuning leads to crystallization because the radius of curvature of the initially bidimensional peptide wall can be increased up to a point where the wall is essentially flat and a crystal is allowed to grow along a third dimension. By comparing X-ray diffraction data and Fourier transform Raman spectra, we show that the nanotubes and the crystals share similar cell parameters and molecular conformations, proving that there is indeed a structural continuum between these two morphologies. These results illustrate a novel approach to crystallization and represent the first step towards the acquisition of an Å-resolution structure of the lanreotide nanotubes β-sheet assembly.
“…The lines are guides to the eye, and the grey area indicates the region where we experimentally observe crystals. This diagram colligates data from this study and from references [31,37]. NB: The datapoint tagged 0 corresponds to a lanreotide derivative whose lysine side chain has been acetylated.…”
Section: Discussionmentioning
confidence: 92%
“… (diamonds) and Gobeaux et al . (circles). The ordinate reads the ‘normalized’ hindrance of the modifications, whether it is a chemical modification of the aromatic residue in position 4 (open diamonds), on the aliphatic residue on position 5 (triangles) or a change of counter‐ions (circles).…”
In the absence of efficient crystallization methods, the molecular structures of fibrous assemblies have so far remained rather elusive. In this paper, we present a rational method to crystallize the lanreotide octapeptide by modification of a residue involved in a close contact. Indeed, we show that it is possible to modify the curvature of the lanreotide nanotubes and hence their diameter. This fine tuning leads to crystallization because the radius of curvature of the initially bidimensional peptide wall can be increased up to a point where the wall is essentially flat and a crystal is allowed to grow along a third dimension. By comparing X-ray diffraction data and Fourier transform Raman spectra, we show that the nanotubes and the crystals share similar cell parameters and molecular conformations, proving that there is indeed a structural continuum between these two morphologies. These results illustrate a novel approach to crystallization and represent the first step towards the acquisition of an Å-resolution structure of the lanreotide nanotubes β-sheet assembly.
“…In addition, the molecular bases of tumor response to SSAs are still unclear, although the application of proteomics to this field has led to promising results 60. Finally, the ongoing drug research has shown that LAN – above a critical assembly concentration of 20 mM – spontaneously forms hollow nanotubes when solubilized in pure water 61,62. Moreover, a recent study evaluated the utility of a self nano-emulsifying delivery system for model peptide LAN which provided a protective effect toward thiol–disulfide exchange reactions and can be useful to overcome sulfhydryl barrier of the gastrointestinal tract 63.…”
Somatostatin analogs (SSAs), which were initially used to control hormonal syndromes associated with neuroendocrine neoplasms (NENs), have been successfully proposed as antiproliferative agents, able to control tumor growth in patients affected by gastroenteropancreatic (GEP)-NENs. The development of long-acting formulations of SSAs which require only weekly or monthly injections can improve patient compliance. In particular, lanreotide (LAN) Autogel®, which is a viscous aqueous formulation supplied in ready-to-use prefilled syringes, can be administered every 28–56 days. Since its introduction in the clinical practice, several studies evaluated the clinical utility of LAN Autogel in the medical treatment of GEP-NENs. Although there is no evidence of an overall survival benefit, these studies confirm the efficacy of LAN Autogel in terms of benefit in progression-free survival, and in more than half of cases, a reduction of tumor markers can be observed during treatment with this drug. Moreover, LAN Autogel is widely recognized to be effective in controlling tumor-related symptoms in the majority of patients affected by GEP tumors, especially in patients affected by carcinoid syndrome, improving considerably patients’ quality of life.
“…After extensive work led by Cherif-Cheikh and Valery et al [19–28], the self-assembly process and liquid crystal structure of lanreotide depot formulation are now well characterized. The process starts with noncovalent peptide dimerization, formation, and growth of an open ribbon and ends with ribbon closure in the shape of a nanotube (Fig.…”
Section: Lanreotide Depot Formulationmentioning
confidence: 99%
“…Most importantly, in vitro experiments have shown that the nanotube assembly is completely reversible. At low lanreotide concentration, the nanotubes slowly disassemble, releasing the active drug [19, 23]. The slow and controlled drug release that starts immediately upon transfer into a dilute solution renders the nanotube formulation an ideal candidate for fast-acting and sustained delivery of lanreotide.Fig.…”
PurposePeptide drugs for antineoplastic therapies usually have low oral bioavailability and short in vivo half-lives, requiring less preferred delivery methods. Lanreotide depot is a sustained-release somatostatin analog (SSA) formulation produced via an innovative peptide self-assembly method. Lanreotide is approved in the USA and Europe to improve progression-free survival (PFS) in patients with unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and also approved in Europe for symptom control in carcinoid syndrome associated with GEP-NETs. This review discusses how the distinct molecule and formulation of lanreotide depot provide advantages to patients and health care providers, as well as the most recent clinical evidence demonstrating the safety and efficacy of lanreotide depot in inhibiting tumor growth and controlling hormonal symptoms in GEP-NETs.Methodology and ResultsThe lanreotide depot formulation confers a remarkable pharmacokinetic profile with no excipients, comprised only of lanreotide acetate and water. Of note, lanreotide depot constitutes an example for peptide self-assembly based formulations, providing insights that could help future development of sustained-release formulations of other antineoplastic peptides. Most patients with GEP-NETs will present with inoperable or incurable disease; thus, medical management for symptoms and tumor control plays a crucial role. Recent long-term clinical studies have demonstrated that lanreotide depot is well tolerated, prolongs PFS in GEP-NET patients, and significantly reduces symptoms related to carcinoid syndrome.ConclusionsThe unique depot formulation and delivery method of lanreotide confer advantages in the treatment of metastatic GEP-NETs, contributing to improvements in NET-related symptoms and PFS without reducing quality of life in this patient population.
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