Despite tremendous interest in gene therapies, the systemic delivery of nucleic acids still faces substantial challenges. To successfully administer nucleic acids, one approach is to encapsulate them in lipid nanoparticles (LNPs). However, LNPs administered intravenously substantially accumulate in the liver where they are taken up by the reticuloendothelial system (RES). Here, we administer prior to the LNPs a liposome designed to transiently occupy liver cells, the Nanoprimer. This study demonstrates that the pretreatment of mice with the Nanoprimer decreases the LNPs’ uptake by the RES. By accumulating rapidly in the liver cells, the Nanoprimer improves the bioavailability of the LNPs encapsulating human erythropoietin (hEPO) mRNA or factor VII (FVII) siRNA, leading respectively to more hEPO production (by 32%) or FVII silencing (by 49%). The use of the Nanoprimer offers a new strategy to improve the systemic delivery of RNA-based therapeutics.
The development of new material platforms can improve our ability to study biological processes. Here, we developed a water-compatible variant of a click-like polymerization between alkynoates and secondary amines to form β-aminoacrylate synthetic polyethylene glycol (PEG) based hydrogels. These materials are easy to access-PEG alkynoate was synthesized on a 100 gram scale and the amines were available commercially; these materials are also operationally simple to formulate-gel formation occurred upon simple mixing of precursor solutions without the need for initiators, catalysts, nor specialized equipment. Three-dimensional cell culture experiments also indicated cytocompatibility of these gels with >90 % viability retained in THP-1 and NIH/3T3 cells after 72 hours in culture. This hydrogel system therefore represents an alternative platform to other click and click-like hydrogels with improved accessibility and user-friendliness for biomaterials application.
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Many therapeutic agents offer a low useful dose (dose responsible for efficacy)/useless dose (dose eliminated or responsible for toxicity) ratio, mainly due to the fact that therapeutic agents must ensure in one single object all the functions required to deliver the treatment, which leads to compromises in their physico-chemical design. Here we introduce the concept of priming the body to receive the treatment by uncorrelating these functions into two distinct objects sequentially administered: a nanoprimer occupying transiently the main pathway responsible for therapeutic agent limited benefit/risk ratio followed by the therapeutic agent. The concept was evaluated for different nature of therapeutic agents: For nanomedicines we designed a liposomal nanoprimer presenting preferential hepatic accumulation without sign of acute toxicity. This nanoprimer was able to increase the blood bioavailability of nanomedicine correlated with a lower hepatic accumulation. Finally this nanoprimer markedly enhanced anti-tumor efficacy of irinotecan loaded liposomes in the HT-29 tumor model when compared to the nanomedicine alone. Then, for small molecules we demonstrated the ability of a cytochrome inhibitor loaded nanoprimer to increase efficacy of docetaxel treatment. These results shown that specific nanoprimers could be designed for each family of therapeutic agents to answer to their specific needs.
Most drugs are metabolized by hepatic cytochrome P450 3A4 (CYP3A4), resulting in their reduced bioavailability. In this study, we present the design and evaluation of bio-compatible nanocarriers trapping a natural CYP3A4-inhibiting compound. Our aim in using nanocarriers was to target the natural CYP3A4-inhibiting agent to hepatic CYP3A4 and leave drug-metabolizing enzymes in other organs undisturbed. In the design of such nanocarriers, we took advantage of the nonspecific accumulation of small nanoparticles in the liver. Specific targeting functionalization was added to direct nanocarriers toward hepatocytes. Nanocarriers were evaluated in vitro for their CYP3A4 inhibition capacity and in vivo for their biodistribution, and finally injected 24 hours prior to the drug docetaxel, for their ability to improve the efficiency of the drug docetaxel. Nanoparticles of poly(lactic- co -glycolic) acid (PLGA) with a hydrodynamic diameter of 63 nm, functionalized with galactosamine, showed efficient in vitro CYP3A4 inhibition and the highest accumulation in hepatocytes. When compared to docetaxel alone, in nude mice bearing the human breast cancer, MDA-MB-231 model, they significantly improved the delay in tumor growth (treated group versus docetaxel alone, percent treated versus control ratio [%T/C] of 32%) and demonstrated a major improvement in overall survival (survival rate of 67% versus 0% at day 55).
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Given its potential for high-resolution, customizable, and waste-free fabrication of medical devices and in vitro biological models, 3-dimensional (3D) bioprinting has broad utility within the biomaterials field. Indeed, 3D bioprinting has to date been successfully used for the development of drug delivery systems, the recapitulation of hard biological tissues, and the fabrication of cellularized organ and tissue-mimics, among other applications. In this study, we highlight convergent efforts within engineering, cell biology, soft matter, and chemistry in an overview of the 3D bioprinting field, and we then conclude our work with outlooks toward the application of 3D bioprinting for ocular research in vitro and in vivo.
Introduction: To efficiently deliver treatment, nanomedicines must exhibit sufficient blood bioavailability for further accumulation at the target site. So far, a large part of the administered dose remains useless due to the high rate of clearance by the mononuclear phagocytic system (mainly by Kupffer cells). Here we propose a new approach to redefine nanomedicines bioavailability by priming the body before receiving the treatment as a sequential administration of a nanoprimer before the nanomedicine. The nanoprimer is a nanoparticle designed to transiently occupy the main pathway responsible for the limited bioavailability of nanomedicines. As such, the nanoprimer allows to redefine the bioavailability of different nanomedicines and improve treatment’s outcomes for a large panel of therapeutic agents (e. g. small molecules or nucleic acids). Methods: Optimization of nanomedicines bioavailability was performed using a liposomal nanoprimer with specific physico-chemical properties. First we evaluated the nanoprimer’s biodistribution by in vivo imaging system, and its accumulation within the different hepatic cell populations by flow cytometry. Then we evaluated the impact of this nanoprimer on the bioavailability of different nanomedicines: for this, blood bioavailability and biodistribution of irinotecan loaded liposomes or mRNA loaded nanoparticles (lipidic and polymeric) were evaluated by HPLC and fluorescence respectively. We compared distribution of each nanomedicine administered intravenously alone or 10min after a single intravenous (IV) injection of nanoprimer on HT29 (colorectal adenocarcinoma) xenografted mice. Finally, the impact of nanoprimer on efficacy was evaluated by a tumor growth delay experiment for irinotecan loaded liposomes by IV administration of nanoprimer 10min before irinotecan loaded liposomes in HT29 xenografted mice. Treatment cycle was repeated one week later. For nucleic acid loaded nanoparticles, the impact of the nanoprimer was evaluated by measuring transfection efficiency on HT29 xenografted mice 24h after IV administration of the nanoprimer 10min before nanomedicine. Results: liposomal nanoprimers present a rapid accumulation in the liver with a preferential localization in Kupffer cells and liver sinusoidal endothelial cells. This accumulation leads to transient cells saturation and decreased hepatic trapping of the nanomedicines. Increased bioavailability resulted in a higher accumulation of irinotecan loaded liposomes within the HT29 tumor and in an increased efficacy. Such a bioavailability increase is also related with the transfection profile obtained for the nucleic acid loaded nanoparticles. Here we showed that a same nanoprimer could be used to prime the body to receive different types of nanomedicines and improve treatment’s outcomes. Such approach may decrease compromises between bioavailability, efficacy and toxicity. Citation Format: matthieu germain, Laurence Poul, Julie Devalliere, Marion Paolini, Audrey Darmon, Maxime Bergere, Oceane Jibault, Francis Mpambani. Mononuclear phagocytic system occupancy to increase nanomedicines based treatment efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3613.
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