A nanomedicine approach for the treatment of long-lasting pain.

This study explores the potential of a nanomedicine approach, using Leu-enkephalin-squalene nanoparticles (LENK-SQ NPs) for managing long-lasting pain. It was observed that the nanomedicine significantly improved the pharmacological efficacy of the Leu-enkephalin, a fast metabolized neuropeptide, in a rat model of acute inflammatory pain, providing local analgesic effect, while minimizing potential systemic side effects by circumventing central nervous system. The LENK-SQ NPs were tested in a rat model of postoperative pain (Brennan's rodent plantar incision model) using continuous infusion via Alzet® pump, with an additional bolus injection.

Nanomedicine and voltage-gated sodium channel blockers in pain management: a game changer or a lost cause?

Pain, a complex and debilitating condition affecting millions globally, is a significant concern, especially in the context of post-operative recovery. This comprehensive review explores the complexity of pain and its global impact, emphasizing the modulation of voltage-gated sodium channels (VGSC or NaV channels) as a promising avenue for pain management with the aim of reducing reliance on opioids. The article delves into the role of specific NaV isoforms, particularly NaV 1.

Assessment of Squalene-Adenosine Nanoparticles in Two Rodent Models of Cardiac Ischemia-Reperfusion.

Reperfusion injuries after a period of cardiac ischemia are known to lead to pathological modifications or even death. Among the different therapeutic options proposed, adenosine, a small molecule with platelet anti-aggregate and anti-inflammatory properties, has shown encouraging results in clinical trials. However, its clinical use is severely limited because of its very short half-life in the bloodstream.

Micro- and nanocarriers for pain alleviation.

Acute or chronic pain is a major source of impairment in quality of life and affects a substantial part of the population. To date, pain is alleviated by a limited range of treatments with significant toxicity, increased risk of misuse and inconsistent efficacy, owing, in part, to lack of specificity and/or unfavorable pharmacokinetic properties. Thanks to the unique properties of nanoscaled drug carriers, nanomedicine may enhance drug biodistribution and targeting, thus contributing to improved bioavailability and lower off-target toxicity.

Albumin-driven disassembly of lipidic nanoparticles: the specific case of the squalene-adenosine nanodrug.

In the field of nanomedicine, nanostructured nanoparticles (NPs) made of self-assembling prodrugs emerged in the recent years with promising properties. In particular, squalene-based drug nanoparticles have already shown their efficiency through in vivo experiments. However, a complete pattern of their stability and interactions in the blood stream is still lacking.

Translation of nanomedicines from lab to industrial scale synthesis: The case of squalene-adenosine nanoparticles.

A large variety of nanoparticle-based delivery systems have become increasingly important for diagnostic and/or therapeutic applications. Yet, the numerous physical and chemical parameters that influence both the biological and colloidal properties of nanoparticles remain poorly understood. This complicates the ability to reliably produce and deliver well-defined nanocarriers which often leads to inconsistencies, conflicts in the published literature and, ultimately, poor translation to the clinics.

Adenosine and lipids: A forced marriage or a love match?

Adenosine is a fascinating compound, crucial in many biochemical processes: this ubiquitous nucleoside serves as an essential building block of RNA, is also a component of ATP and regulates numerous pathophysiological mechanisms via binding to four extracellular receptors. Due to its hydrophilic nature, it belongs to a different world than lipids, and has no affinity for them. Since the 1970's, however, new discoveries have emerged and prompted the scientific community to associate adenosine with the lipid family, especially via liposomal preparations and bioconjugation.

Towards a clinical application of freeze-dried squalene-based nanomedicines.

Squalene-adenosine (SQAd) nanoparticles (NPs) were found to display promising pharmacological activity similar to many other nanomedicines, but their long-term stability was still limited, and their preparation required specific know-how and material. These drawbacks represented important restrictions for their potential use in the clinic. Freeze-drying nanoparticles is commonly presented as a solution to allow colloidal stability, but this process needs to be adapted to each nanoformulation.

Squalene-Adenosine Nanoparticles: Ligands of Adenosine Receptors or Adenosine Prodrug?

Adenosine receptors (ARs) represent key drug targets in many human pathologies, including cardiovascular, neurologic, and inflammatory diseases. To overcome the very rapid metabolization of adenosine, metabolically stable AR agonists and antagonists were developed. However, few of these molecules have reached the market due to efficacy and safety issues.

Design, Preparation and Characterization of Modular Squalene-based Nanosystems for Controlled Drug Release.

This article reviews the innovative and original concept the "squalenoylation", a technology allowing the formulation of a wide range of drug molecules (both hydrophilic and lipophilic) as nanoparticles. The "squalenoylation" approach is based on the covalent linkage between the squalene, a natural and biocompatible lipid belonging to the terpenoid family, and a drug, in order to increase its pharmacological efficacy. Fundamentally, the dynamically folded conformation of squalene triggers the resulting squalene-drug bioconjugates to self-assemble as nanoparticles of 100-300 nm.

Conjugation of squalene to gemcitabine as unique approach exploiting endogenous lipoproteins for drug delivery.

Once introduced in the organism, the interaction of nanoparticles with various biomolecules strongly impacts their fate. Here we show that nanoparticles made of the squalene derivative of gemcitabine (SQGem) interact with lipoproteins (LPs), indirectly enabling the targeting of cancer cells with high LP receptors expression. In vitro and in vivo experiments reveal preeminent affinity of the squalene-gemcitabine bioconjugates towards LP particles with the highest cholesterol content and in silico simulations further display their incorporation into the hydrophobic core of LPs.

Influence of the nanoprecipitation conditions on the supramolecular structure of squalenoyled nanoparticles.

Hydrophobic organic compounds dissolved in a polar solvent can self-assemble into nanoparticles (NPs) upon nanoprecipitation into water. In the present study, we have investigated the structure of squalenacetyl-adenosine (SQAc-Ad) nanoparticles which were previously found to exhibit impressive neuroprotective activity. When obtained by nanoprecipitation of a SQAc-Ad ethanolic solution into water, two different supramolecular organizations of SQAc-Ad NPs were evidenced, depending on the water-to-ethanol volume ratio.

Pharmacokinetics, biodistribution and metabolism of squalenoyl adenosine nanoparticles in mice using dual radio-labeling and radio-HPLC analysis.

Adenosine is a pleiotropic endogenous nucleoside with potential neuroprotective pharmacological activity. However, clinical use of adenosine is hampered by its extremely fast metabolization. To overcome this limitation, we recently developed a new squalenoyl nanomedicine of adenosine [Squalenoyl-Adenosine (SQAd)] by covalent linkage of this nucleoside to the squalene, a natural lipid.

Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury.

There is an urgent need to develop new therapeutic approaches for the treatment of severe neurological trauma, such as stroke and spinal cord injuries. However, many drugs with potential neuropharmacological activity, such as adenosine, are inefficient upon systemic administration because of their fast metabolization and rapid clearance from the bloodstream. Here, we show that conjugation of adenosine to the lipid squalene and the subsequent formation of nanoassemblies allows prolonged circulation of this nucleoside, providing neuroprotection in mouse stroke and rat spinal cord injury models.

Self-assembly of squalene-based nucleolipids: relating the chemical structure of the bioconjugates to the architecture of the nanoparticles.

Squalene-based nucleolipids, including anticancer or antiviral prodrugs, gave rise to nanoparticles displaying a diversity of structures upon nanoprecipitation in water. Synchrotron small-angle X-ray scattering and cryo-TEM imaging revealed that both the nature of the nucleoside and the position of the squalene moiety relative to the nucleobase determined the self-assembly of the corresponding bioconjugates. It was found that small chemical differences resulted in major differences in the self-organization of nucleolipids when squalene was grafted onto the nucleobase whereas only lamellar phases were observed when squalene was linked to the sugar moiety.

Synthesis and physicochemical characterization of new squalenoyl amphiphilic gadolinium complexes as nanoparticle contrast agents.

A family of novel amphiphilic gadolinium chelates was successfully obtained by coupling the hydrophilic DOTA ligand [1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane] to squalenoyl moieties. Thanks to the self-assembling properties of their squalenoyl lipophilic moieties, all these derivatives were able to form, without any adjuvant, micellar or liposome-like supramolecular nanoassemblies, endowed with high relaxivities (r(1) = 15-22 mM(-1) s(-1) at 20 MHz and 37 °C). The remarkably high payloads of Gd(3+) ions reached 10 to 17 wt %.

Interaction of self-assembled squalenoyl gemcitabine nanoparticles with phospholipid-cholesterol monolayers mimicking a biomembrane.

Gemcitabine (dFdC or Gem) is a water-soluble cytotoxic drug, with poor cellular uptake in the absence of a nucleoside transporter. To improve its diffusion through membranes, it was modified by grafting of a squalenoyl moiety. In water, this derivative is able to form stable and monodispersed nanoparticles made of inverse hexagonal phases.

Liposomal squalenoyl-gemcitabine: formulation, characterization and anticancer activity evaluation.

A new prodrug of gemcitabine, based on the covalent coupling of squalene to gemcitabine (GemSQ), has been designed to enhance the anticancer activity of gemcitabine, a nucleoside analogue active against a wide variety of tumors. In the present study, the feasibility of encapsulating GemSQ into liposomes either PEGylated or non-PEGylated has been investigated. The in vivo anticancer activity of these formulations has been tested on subcutaneous grafted L1210wt leukemia model and compared to that of free gemcitabine.

Interaction of a new anticancer prodrug, gemcitabine-squalene, with a model membrane: coupled DSC and XRD study.

Gemcitabine is an anticancer nucleoside analogue active against a wide variety of solid tumors. However it is rapidly deaminated to an inactive metabolite, leading to short biological half-life and induction of resistance. A new prodrug of gemcitabine, coupling squalene to gemcitabine (GemSq), has been designed to overcome the above drawbacks.

Squalenoyl nucleoside monophosphate nanoassemblies: new prodrug strategy for the delivery of nucleotide analogues.

4-(N)-1,1',2-trisnor-squalenoyldideoxycytidine monophosphate (SQddC-MP) and 4-(N)-1,1',2-trisnor-squalenoylgemcitabine monophosphate (SQdFdC-MP) were synthesized using phosphoramidite chemistry. These amphiphilic molecules self-assembled to about hundred nanometers size nanoassemblies in aqueous medium. Nanoassemblies of SQddC-MP displayed significant anti-HIV activity whereas SQdFdC-MP nanoassemblies displayed promising anticancer activity on leukemia cells.

Squalenoyl nanomedicine of gemcitabine is more potent after oral administration in leukemia-bearing rats: study of mechanisms.

In an earlier report, we demonstrated the superior anticancer efficacy of orally administered squalenoyl gemcitabine (SQdFdC) nanomedicine over its parent drug gemcitabine on rats bearing RNK-16 large granular lymphocytic (LGL) leukemia. In the present communication, we investigated the mechanisms behind this observation both at the cell and tissue level. The mechanisms were investigated by performing cytotoxicity, cell uptake, and biodistribution experiments.

Squalenoylation favorably modifies the in vivo pharmacokinetics and biodistribution of gemcitabine in mice.

Gemcitabine (2',2'-difluorodeoxyribofuranosylcytosine; dFdC) is an anticancer nucleoside analog active against wide variety of solid tumors. However, this compound is rapidly inactivated by enzymatic deamination and can also induce drug resistance. To overcome the above drawbacks, we recently designed a new squalenoyl nanomedicine of dFdC [4-N-trisnorsqualenoyl-gemcitabine (SQdFdC)] by covalently coupling gemcitabine with the 1,1',2-trisnorsqualenic acid; the resultant nanomedicine displayed impressively greater anticancer activity compared with the parent drug in an experimental murine model.