Institut Galien Paris Sud

The development of oral pediatric forms by pharmaceutical companies is still insufficient. In fact, many drugs used in paediatric oncology, such as temozolomide, are not labeled and adapted for paediatric use. Temozolomide (TMZ) is an alkylating agent used as the standard of care for many adult and pediatric brain tumours, such as neuroblastoma, glioblastoma and medulloblastoma. The present study was carried out to propose a suitable and palatable formulation of the oral liquid preparation of TMZ. The suspension is composed of TMZ suspended in SyrSpend SF pH 4, as well as TMZ crystallization stabilizing agents and sweetening agents. To reach this formulation, several taste-masking agents were evaluated. Here, we describe the method of preparation of the formation as well as the monocentric population treated with the formulation over a 5–year period. A 20 mg/mL TMZ suspension was developed. TMZ suspension is stable for 6 weeks, stored between 2 and 8 degrees, protected from light, and compatible with nasogastric tubes. Thirty-eight patients participated in the palatability study and choose cola flavour, and 104 patients were treated in Gustave Roussy with the developed suspension; no unexpected event was reported. To conclude, we propose here a new TMZ liquid formulation which is stable for at least 6 weeks and well-tolerated with extensive feedback.

Chemotherapy is almost exclusively administered via the intravenous (IV) route, which has serious limitations (e.g., patient discomfort, long hospital stays, need for trained staff, high cost, catheter failures, infections). Therefore, the development of effective and less costly chemotherapy that is more comfortable for the patient would revolutionize cancer therapy. While subcutaneous (SC) administration has the potential to meet these criteria, it is extremely restrictive as it cannot be applied to most anticancer drugs, such as irritant or vesicant ones, for local toxicity reasons. Herein, we report a facile, general and scalable approach for the SC administration of anticancer drugs through the design of well-defined hydrophilic polymer prodrugs. This was applied to the anticancer drug paclitaxel (Ptx) as a worst-case scenario due to its high hydrophobicity and vesicant properties (two factors promoting necrosis at the injection site), whereas polyacrylamide (PAAm) was chosen as a hydrophilic polymer for its biocompatibility and stealth properties. A small library of Ptx-based polymer prodrugs was designed by adjusting the nature of the linker (ester, diglycolate and carbonate), and then evaluated in terms of rheological/viscosity properties in aqueous solutions, drug release kinetics in PBS and in murine plasma, cytotoxicity on two different cancer cell lines, acute local and systemic toxicity, pharmacokinetics and biodistribution, and finally their anticancer efficacy. We demonstrated that Ptx-PAAm polymer prodrugs could be safely injected subcutaneously without inducing local toxicity while outperforming Taxol, the commercial formulation of Ptx, thus opening the door to the safe transposition from IV to SC chemotherapy.

Degradable polymer nanoparticles are almost exclusively obtained by formulation of preformed degradable polymers, such as aliphatic polyesters, thus resulting is very low nanoparticle concentrations and limited structural diversity. On the other hand, many different vinyl polymers can be obtained by polymerization in aqueous dispersed media, but their non-degradability limits their use especially in the biomedical field. Herein, we combined the best of both worlds by developing a two-step radical ring-opening copolymerization-induced self-assembly (rROPISA) process, allowing to generate aqueous suspensions of narrowly dispersed, degradable vinyl copolymer nanoparticles at 15 wt.% solid contents, containing cyclic ketene acetal (CKA) units in the nanoparticle core. This strategy relied on rROPISA in DMF, followed by a simple transfer step to water. It was successfully applied to the three main CKAs used in rROP and yielded nanoparticles of ~80–215 nm in diameter with tunable amount of CKA up to 21 mol.%. Successful incorporation of ester groups in the copolymers was demonstrated by hydrolytic degradation of both the copolymers and the nanoparticles. The nanoparticles’ cytocompatibility was then established by cell viability assays and cell morphology observation with three representative healthy cell lines. Not only this synthetic strategy could be of great potential for drug delivery applications, but it can also be beneficial to other research fields to yield more environmentally friendly materials involving the use of latexes, such as paints or coatings.

Degradable polymer nanoparticles are almost exclusively obtained by formulation of preformed degradable polymers, such as aliphatic polyesters, thus resulting is very low nanoparticle concentrations and limited structural diversity. On the other hand, many different vinyl polymers can be obtained by polymerization in aqueous dispersed media, but their non-degradability limits their use especially in the biomedical field. Herein, we combined the best of both worlds by developing a two-step radical ring-opening copolymerization-induced self-assembly (rROPISA) process, allowing to generate aqueous suspensions of narrowly dispersed, degradable vinyl copolymer nanoparticles at 15 wt.% solid contents, containing cyclic ketene acetal (CKA) units in the nanoparticle core. This strategy relied on rROPISA in DMF, followed by a simple transfer step to water. It was successfully applied to the three main CKAs used in rROP and yielded nanoparticles of ~80–215 nm in diameter with tunable amount of CKA up to 21 mol.%. Successful incorporation of ester groups in the copolymers was demonstrated by hydrolytic degradation of both the copolymers and the nanoparticles. The nanoparticles’ cytocompatibility was then established by cell viability assays and cell morphology observation with three representative healthy cell lines. Not only this synthetic strategy could be of great potential for drug delivery applications, but it can also be beneficial to other research fields to yield more environmentally friendly materials involving the use of latexes, such as paints or coatings.

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. In this work we assess the behavior of squalene-adenosine (SQAd) nanoparticles - whose neuroprotective effect has already been demonstrated in murine models - in the presence of fetal bovine serum (FBS) and of bovine serum albumin (BSA), the main protein of blood plasma. Extensive physicochemical characterizations were performed using Small Angle Neutron Scattering (SANS), cryogenic transmission electron microscopy (Cryo-TEM), circular dichroism (CD), steady-state fluorescence spectroscopy (SSFS) and isothermal titration calorimetry (ITC) as well as in silico by means of ensemble docking simulations with human serum albumin (HSA). Significant changes in the colloidal stability of the nanoparticles in the presence of serum albumin were observed. SANS, CD and SSFS analyses demonstrated an interaction between SQAd and BSA, with a partial disassembly of the nanoparticles in the presence of BSA and the formation of a complex between SQAd and BSA. The interaction free energy of SQAd nanoparticles with BSA derived from ITC experiments, is about -8 kcal mol-1 which is further supported in silico by ensemble docking simulations. Overall, our results show that serum albumin partially disassembles SQAd nanoparticles by extracting individual SQAd monomers from them. As a consequence, the SQAd nanoparticles would act as a circulating reservoir in the blood stream. The approach developed in this study could be extended to other soft organic nanoparticles.

Ethionamide (ETH) is one of the most widely used second-line chemotherapeutic drugs for the treatment of multi-drug-resistant tuberculosis. The bioactivation and activity of ETH is dramatically potentiated by a family of molecules called "boosters" among which BDM43266 is one of the most potent. However, the co-administration of these active molecules is hampered by their low solubility in biological media and by the strong tendency of ETH to crystallize. A novel strategy that involves synthesizing a codrug able to self-associate into nanoparticles prone to be taken up by infected macrophages is proposed here. This codrug is designed by tethering N-hydroxymethyl derivatives of both ETH and its booster through a glutaric linker. This codrug self-assembles into nanoparticles of around 200 nm, stable upon extreme dilution without disaggregating as well as upon concentration. The nanoparticles of the codrug can be intranasally administered overcoming the unfavorable physico-chemical profiles of the parent drugs. Intrapulmonary delivery of the codrug nanoparticles to Mtb infected mice via the intranasal route at days 7, 9, 11, 14, 16 and 18 post-infection reduces the bacterial load in the lungs by a factor of 6.

Background: Hereditary transthyretin amyloidosis (ATTR) is a multisystemic disease involving mainly the peripheral nervous system and the heart. Liver transplantation (LT) is the reference treatment for ATTR neuropathy and preoperative detection of high risk patients is crucial. We aimed to document the causes of death of ATTR patients after LT, their temporal trends, and to evaluate whether the available preoperative tools that predict the risk of death after LT for hereditary ATTR amyloidosis matched with these trends.Methods: A retrospective longitudinal cohort study was performed on 215 consecutive ATTR patients who underwent LT between January 1993 and January 2011. Each patient’s death cause and timing were classified.Results: Over a median follow up of 5.9 years, 84 patients died. The rate of death was higher in the first year following LT than thereafter (13.0 vs. 4.3 ± 1.8%/year; p = .004). Cardiac events ranked as the leading cause of death (C: 38%), followed by infections (I: 24%), graft complications (G: 17%), end stage amyloidosis, stroke and others (ASO: 7% each). Deaths due to graft complications and infections (GI) occurred earlier than those due to end stage amyloidosis and stroke. Death prediction was less accurate for GI-related mortality than for other causes, which blunted the accuracy of the early-term risk prediction scores.Conclusions In ATTR amyloidosis, cardiac events were the leading cause of death after liver transplantation. Close preoperative evaluation allowed for accurate mid-term prediction of mortality, but the high rate of graft complications and infections blunted the early-term risk prediction.