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.
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).
Introduction: The benefit of a nanomedicine is due to its bioavailability, its intrinsic efficacy balanced with its toxicity profile. The nanomedicine should exhibit sufficient blood bioavailability for efficient 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 hepatic Kupffer cells). Enhanced bioavailability can be achieved by modifying physico-chemical properties of the nanomedicine but such modification affects also its efficacy and toxicity profiles. Ultimately, nanomedicines design results usually in a compromise between bioavailability, efficacy or toxicity. Here we propose a new approach to change the way nanomedicine are biodistributed, by priming the body to receive the treatment. This approach relies on the 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 the nanomedicine. As such, the nanoprimer allows to redefine the bioavailability of the nanomedicine. Methods: For proof of concept we designed a liposomal nanoprimer with specific physico-chemical properties. Its biodistribution was evaluated by labelling with gold nanoparticles. 24h after intravenous (IV) administration on mice, gold quantification was performed on sampled organs by ICPMS. Toxicity evaluation was performed by 3 IV injections of nanoprimer spaced of 24h on mice followed by a one week follow up of body weight and clinical signs. Histological liver and spleen observations and transaminases titration were performed 1 and 7 days after last injection. Evaluation of the impact of nanoprimer on nanomedicines bioavailability was performed by in vivo follow up of a fluorescent nanomedicine IV injected 10min after nanoprimer IV injection. Tumor growth delay experiment was performed by IV administration of nanoprimer 10min before irinotecan loaded liposomes on mice xenografted with HT29 (colorectal adenocarcinoma) tumor model once the tumor reached 150mm3. Treatment was repeated one week later. Results: The liposomal nanoprimer presents a preferential hepatic accumulation. No signs of systemic or hepatic toxicity were observed with maximized dose of this nanoprimer. Nanomedicine bioavailability studies showed a transient increase of nanomedicine blood bioavailability correlated with a lower hepatic accumulation when combined to nanoprimer. Finally efficacy study showed that nanoprimer markedly enhanced anti-tumor efficacy of irinotecan loaded liposomes in the HT-29 model when compared to the nanomedicine alone. Body priming may benefit to a wide variety of existing products modulating their bioavailability and may open perspective to design new nanomedicines by decreasing the notion of compromise between bioavailability, efficacy and toxicity. Citation Format: Matthieu Germain, Laurence Poul, Marie-Edith Meyre, Marion Paolini, Francis Mpambani, Maxime Bergere, Agnes Pottier, Laurent Levy. Redefine nanomedicine products bioavailability to improve anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-072.
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.
Orexin-A (OxA) and orexin-B (OxB) are hypothalamic peptides involved in the sleep/wake control which interact with two class A GPCR, OX1R and OX2R. We have demonstrated that OX1R was highly expressed in digestive cancers including cancer of colon1, pancreas2 and liver. In these cancers, orexin-A induces a mitochondrial apoptosis and a strong inhibition of tumor growth in nude mice xenografted with digestive cancer cell lines1,2. In the present work, we have compared and combined the effect of OxA and NAB-paclitaxel which represents the “gold standard” reference in the chemotherapeutic treatment of pancreas cancer, on their anti-tumoral properties. The incubation of AsPC-1 pancreatic cancer cell line which expressed OX1R, with 0.1μM OxA or 0.1 μM NAB-paclitaxel reveals a cell growth inhibition of 36% and 51%, respectively. The addition of 0.1 μM OxA and 0.1μM NAB-paclitaxel on AsPC-1 cells reveals a significantly cell growth inhibition of 70% suggesting that the double treatment was more efficient than individual treatment. Moreover, the addition of 0.1μM OxA and 0.1 μM NAB-paclitaxel induces 25% of cell apoptosis determined by annexin-V labeling, as compared to single treatment with 0.1μM OxA (18%) or 0.1 μM NAB-paclitaxel (12%). Additionally, we explore the sequential treatment by OxA and NAB-paclitaxel on cell growth of AsPC-1 cells. Our results evidenced than 48h treatment by OxA followed by 48h treatment of NAB-paclitaxel induced an inhibition of 35% of cell growth. In contrast, the reverse treatment (48H NAB-paclitaxel followed by 48h OxA) induces an inhibition of cell growth of 60%. OxA intraperitoneal injection (2 injections/week of 1.12 μmoles/kg OxA and/or NAB-paclitaxel) in nude mice xenografted with AsPC-1 cells, shows that OxA and NAB-paclitaxel induces an inhibition of tumoral volume of 60% and 62%, respectively. Moreover, injection of OxA plus NAB-paclitaxel induces an inhibition of tumoral volume of 70%. Sequential treatments of xenografted tumors in mice with OxA and NAB-paclitaxel was investigated and revealed 72% tumor growth inhibition when mice were treated 30 days with OxA followed by 30 days with NAB-paclitaxel and 83% tumor growth inhibition when they were treated 30 days with NAB-paclitaxel followed by 30 days with OxA. These results indicate that: 1) the addition of OxA and NAB-paclitaxel improves the effect of individual treatment; 2) the sequential treatment consisting of first OxA treatment followed by NAB-paclitaxel treatment was more efficient than reverse treatment. In conclusion, OxA was close to NAB-paclitaxel treatment in term of response and suggest that combined treatment OxA/ NAB-paclitaxel represents a new promising pancreas cancer therapy 1Voisin et al., Cancer research 2011, 71:3341-51 2Speisky et al., AACR annual meeting, 2014, San Diego, USA Citation Format: Thierry Voisin, Dina Plaut, Stephanie Dayot, Maxime Bergere, Valerie Gratio, Pascal Nicole, Anne Couvelard, Alain Couvineau. Combination treatment of orexin-A and NAB-paclitaxel in pancreas cancer: in vitro and in vivo studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4581.
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