RESUMEN
The situation of the COVID-19 pandemic reminds us that we permanently need high-value flexible solutions to urgent clinical needs including simplified diagnostic technologies suitable for use in the field and for delivering targeted therapeutics. From our perspective nanotechnology is revealed as a vital resource for this, as a generic platform of technical solutions to tackle complex medical challenges. It is towards this perspective and focusing on nanomedicine that we take issue with Prof Park's recent editorial published in the Journal of Controlled Release. Prof. Park argued that in the last 15 years nanomedicine failed to deliver the promised innovative clinical solutions to the patients (Park, K. The beginning of the end of the nanomedicine hype. Journal of Controlled Release, 2019; 305, 221-222 [1]. We, the ETPN (European Technology Platform on Nanomedicine) [2], respectfully disagree. In fact, the more than 50 formulations currently in the market, and the recent approval of 3 key nanomedicine products (e. g. Onpattro, Hensify and Vyxeos), have demonstrated that the nanomedicine field is concretely able to design products that overcome critical barriers in conventional medicine in a unique manner, but also to deliver within the cells new drug-free therapeutic effects by using pure physical modes of action, and therefore make a difference in patients lives. Furthermore, the >400 nanomedicine formulations currently in clinical trials are expecting to bring novel clinical solutions (e.g. platforms for nucleic acid delivery), alone or in combination with other key enabling technologies to the market, including biotechnologies, microfluidics, advanced materials, biomaterials, smart systems, photonics, robotics, textiles, Big Data and ICT (information & communication technologies) more generally. However, we agree with Prof. Park that " it is time to examine the sources of difficulty in clinical translation of nanomedicine and move forward ". But for reaching this goal, the investments to support clinical translation of promising nanomedicine formulations should increase, not decrease. As recently encouraged by EMA in its roadmap to 2025, we should create more unity through a common knowledge hub linking academia, industry, healthcare providers and hopefully policy makers to reduce the current fragmentation of the standardization and regulatory body landscape. We should also promote a strategy of cross-technology innovation, support nanomedicine development as a high value and low-cost solution to answer unmet medical needs and help the most promising innovative projects of the field to get better and faster to the clinic. This global vision is the one that the ETPN chose to encourage for the last fifteen years. All actions should be taken with a clear clinical view in mind, " without any fanfare", to focus "on what matters in real life", which is the patient and his/her quality of life. This ETPN overview of achievements in nanomedicine serves to reinforce our drive towards further expanding and growing the maturity of nanomedicine for global healthcare, accelerating the pace of transformation of its great potential into tangible medical breakthroughs.
Asunto(s)
Sistemas de Liberación de Medicamentos , Nanomedicina , Animales , COVID-19 , Ensayos Clínicos como Asunto , Infecciones por Coronavirus/terapia , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Humanos , Nanomedicina/métodos , Nanotecnología/métodos , Neoplasias/terapia , Pandemias , Neumonía Viral/terapiaRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Docetaxel/farmacología , Liposomas/administración & dosificación , Nanomedicina/métodos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Neoplasias de la Mama/patología , Proliferación Celular , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Docetaxel/farmacocinética , Femenino , Células HT29 , Humanos , Liposomas/química , Ratones , Distribución Tisular , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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).
Asunto(s)
Inhibidores del Citocromo P-450 CYP3A/farmacología , Portadores de Fármacos/química , Furocumarinas/farmacología , Hígado/efectos de los fármacos , Taxoides/farmacocinética , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A/química , Docetaxel , Portadores de Fármacos/farmacocinética , Femenino , Furocumarinas/química , Galactosamina/química , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Inactivación Metabólica , Ácido Láctico/química , Hígado/metabolismo , Ratones Desnudos , Nanopartículas/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Taxoides/administración & dosificación , Distribución TisularRESUMEN
Nanomedicines are mainly used as drug delivery systems; here we evaluate a new application - to inhibit a drug's metabolism thereby enhancing its effective dose. Micelles containing the natural furanocoumarin 6',7'-dihydroxybergamottin (DHB), a known CYP450 inhibitor, were developed to transiently block hepatic CYP450-mediated drug metabolism and increase the bioavailability of the oncology drug docetaxel. Administered in mice 24h prior to the drug, DHB-micelles enhanced antitumor efficacy in the tumor xenograft models HT-29 and MDA-MB-231, when compared to the drug alone. These DHB-micelles have similar composition to marketed docetaxel-micelles for human use. Despite not being optimized in terms of targeting hepatocytes, they do represent the first injectable example of nanosized metabolism-blocking agents and open the way for further work on such nanomedicines in man.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450/administración & dosificación , Micelas , Nanomedicina/métodos , Animales , Antineoplásicos , Línea Celular Tumoral , Sistema Enzimático del Citocromo P-450 , Humanos , Masculino , RatonesRESUMEN
Radio-enhancers, metal-based nanosized agents, could play a key role in oncology. They may unlock the potential of radiotherapy by enhancing the radiation dose deposit within tumors when the ionizing radiation source is 'on', while exhibiting chemically inert behavior in cellular and subcellular systems when the radiation beam is 'off'. Important decision points support the development of these new type of therapeutic agents originated from nanotechnology. Here, we discuss from an industry perspective, the interest of developing radio-enhancer agents to improve tumor control, the relevance of nanotechnology to achieve adequate therapeutic attributes, and present some considerations for their development in oncology.
Asunto(s)
Nanopartículas del Metal/administración & dosificación , Nanopartículas del Metal/química , Nanocápsulas/química , Neoplasias/tratamiento farmacológico , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Radioterapia/métodos , Animales , Humanos , Nanocápsulas/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/químicaRESUMEN
Radiotherapy has a universal and predictable mode of action, that is, a physical mode of action consisting of the deposit of a dose of energy in tissues. Tumour cell damage is proportional to the energy dose. However, the main limitation of radiotherapy is the lack of spatial control of the deposition of energy, that is, it penetrates the healthy tissues, damages them and renders unfeasible delivery of an efficient energy dose when tumours are close to important anatomical structures. True nanosized radiation enhancers may represent a disruptive approach to broaden the therapeutic window of radiation therapy. They offer the possibility of entering tumour cells and depositing high amounts of energy in the tumour only when exposed to ionizing radiations (on/off activity). They may unlock the potential of radiation therapy by rendering the introduction of a greater energy dose, exactly within the tumour structure without passing through surrounding tissues feasible. Several nanosized radiation enhancers have been studied in in vitro and in vivo models with positive results. One agent has received the authorization to conduct clinical trials for human use. Opportunities to improve outcomes for patients receiving radiotherapy, to create new standards of care and to offer solutions to new patient populations are looked over here.
Asunto(s)
Nanopartículas/uso terapéutico , Neoplasias/radioterapia , Planificación de la Radioterapia Asistida por Computador/métodos , Humanos , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/tendenciasRESUMEN
BACKGROUND: Hafnium oxide, NBTXR3 nanoparticles were designed for high dose energy deposition within cancer cells when exposed to ionizing radiation. The purpose of this study was to assess the possibility of predicting in vitro the biological effect of NBTXR3 nanoparticles when exposed to ionizing radiation. METHODS: Cellular uptake of NBTXR3 nanoparticles was assessed in a panel of human cancer cell lines (radioresistant and radiosensitive) by transmission electron microscopy. The radioenhancement of NBTXR3 nanoparticles was measured by the clonogenic survival assay. RESULTS: NBTXR3 nanoparticles were taken up by cells in a concentration dependent manner, forming clusters in the cytoplasm. Differential nanoparticle uptake was observed between epithelial and mesenchymal or glioblastoma cell lines. The dose enhancement factor increased with increase NBTXR3 nanoparticle concentration and radiation dose. Beyond a minimum number of clusters per cell, the radioenhancement of NBTXR3 nanoparticles could be estimated from the radiation dose delivered and the radiosensitivity of the cancer cell lines. CONCLUSIONS: Our preliminary results suggest a predictable in vitro biological effect of NBTXR3 nanoparticles exposed to ionizing radiation.
Asunto(s)
Hafnio/farmacología , Nanopartículas del Metal/administración & dosificación , Óxidos/farmacología , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Supervivencia Celular , Humanos , Técnicas In Vitro , Microscopía Electrónica de Transmisión , Dosis de Radiación , Células Tumorales Cultivadas , Rayos XRESUMEN
Since the discovery of cisplatin about 40 years ago, the design of innovative metal-based anticancer drugs is a growing area of research. Transition metal coordination complexes offer potential advantages over the more common organic-based drugs, including a wide range of coordination number and geometries, accessible redox states, tunability of the thermodynamics and kinetics of ligand substitution, as well as a wide structural diversity. Metal-based substances interact with cell molecular targets, affecting biochemical functions resulting in cancer cell destruction. Radionuclides are another way to use metals as anticancer therapy. The metal nucleus of the unstable radionuclide becomes stable by emitting energy. The biological effect in different tissues is obtained by the absorption of this energy from the radiation emitted by the radionuclide, the principal target generally agreed for ionizing radiations being DNA. A new area of clinical research is now emerging using the same experimental metal elements, but in a radically different manner: metals and metal oxides used as crystalline nanosized particles. In this field, man-made functionalized nanoparticles of high electron density and well-defined size and shape offer the possibility of entering cancer cells and depositing high amounts of energy in the tumor only when exposed to ionizing radiations (on/off activity). These nanoparticles, such as hafnium oxide engineered as 50 nm-sized spheres, functionalized with a negative surface (NBTXR3 nanoparticles), have been developed as selective radioenhancers, which represents a breakthrough approach for the local treatment of solid tumors. The properties of NBTXR3 nanoparticles, their chemistry, size, shape and surface charge, have been designed for efficient tumor cell uptake. NBTXR3 brings a physical mode of action, that of radiotherapy, within the cancer cells themselves. Physicochemical characteristics of NBTXR3 have demonstrated a very promising benefit-risk ratio for human healthcare across a broad non-clinical program. NBTXR3 has entered clinical development in therapy of advanced soft tissue sarcomas and head and neck cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Nanopartículas del Metal/uso terapéutico , Neoplasias/radioterapia , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , PronósticoRESUMEN
Improved drug delivery control during chemotherapy has the potential to increase the therapeutic index. MRI contrast agent such as iron oxide nanoparticles can be co-encapsulated with drugs in nanocarrier liposomes allowing their tracking and/or visualization by MRI. Furthermore, the combination of a thermosensitive liposomal formulation with an external source of heat such as high intensity focused ultrasound guided by MR temperature mapping allows the controlled local release of the content of the liposome. MRI-guided high-intensity focused ultrasound (HIFU), in combination represents a noninvasive technique to generate local hyperthermia for drug release. In this study we used ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) encapsulated in thermosensitive liposomes to obtain thermosensitive magnetoliposomes (TSM). The transverse and longitudinal relaxivities of this MRI contrast agent were measured upon TSM membrane phase transition in vitro using a water bath or HIFU. The results showed significant differences for MRI signal enhancement and relaxivities before and after heating, which were absent for nonthermosensitive liposomes and free nanoparticles used as controls. Thus, incorporation of USPIO as MRI contrast agents into thermosensitive liposomes should, besides TSM tumor accumulation monitoring, allow the visualization of TSM membrane phase transition upon temperature elevation. In conclusion, HIFU under MR image guidance in combination with USPIO-loaded thermosensitive liposomes as drug delivery system has the potential for a better control of drug delivery and to increase the drug therapeutic index.
Asunto(s)
Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/efectos de la radiación , Liposomas/química , Imagen por Resonancia Magnética/métodos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/efectos de la radiación , Sonicación/métodos , Medios de Contraste/química , Medios de Contraste/efectos de la radiación , Calor , Liposomas/efectos de la radiación , Campos Magnéticos , Ensayo de Materiales , SonidoRESUMEN
AIM: There is considerable interest in approaches that could improve the therapeutic window of radiotherapy. In this study, hafnium oxide nanoparticles were designed that concentrate in tumor cells to achieve intracellular high-energy dose deposit. MATERIALS & METHODS: Conventional methods were used, implemented in different ways, to explore interactions of these high-atomic-number nanoparticles and ionizing radiation with biological systems. RESULTS: Using the Monte Carlo simulation, these nanoparticles, when exposed to high-energy photons, were shown to demonstrate an approximately ninefold radiation dose enhancement compared with water. Importantly, the nanoparticles show satisfactory dispersion and persistence within the tumor and they form clusters in the cytoplasm of cancer cells. Marked antitumor activity is demonstrated in human cancer models. Safety is similar in treated and control animals as demonstrated by a broad program of toxicology evaluation. CONCLUSION: These findings, supported by good tolerance, provide the basis for developing this new type of nanoparticle as a promising anticancer approach in human patients.
Asunto(s)
Hafnio/administración & dosificación , Nanopartículas/administración & dosificación , Neoplasias/radioterapia , Óxidos/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Simulación por Computador , Endosomas/metabolismo , Endosomas/patología , Femenino , Hafnio/efectos adversos , Hafnio/farmacocinética , Humanos , Ratones , Ratones Desnudos , Modelos Biológicos , Método de Montecarlo , Nanopartículas/efectos adversos , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Óxidos/efectos adversos , Óxidos/farmacocinética , Fármacos Sensibilizantes a Radiaciones/efectos adversos , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Radiografía , Carga Tumoral/efectos de la radiación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A new versatile hybrid nanocarrier has been designed using a "soft chemistry" synthesis, to efficiently encapsulate a photosensitizer - the protoporphyrin IX (Pp IX) - while preserving its activity intact in biological environment for advantageous use in photodynamic therapy (PDT). The synthesized Pp IX silica-based nanocarriers show to be spherical in shape and highly monodisperse with size extending from 10 nm up to 200 nm according to the synthesis procedure. Upon laser irradiation, the entrapped Pp IX shows to efficiently deliver reactive oxygen species (ROS) which are responsible for damaging tumor tissues. The ability of Pp IX silica-based nanocarriers to induce tumor cell death has been tested successfully in vitro. The stability of the Pp IX silica-based nanocarriers has been followed by UV-vis absorption and fluorescence emission in aqueous media and in 100% mouse serum media. The flexibility of the nanocarrier silica core has been examined as the key parameter to tune the Pp IX stability in biological environment. Indeed, an additional biocompatible inorganic surface coating performed on the Pp IX silica-based nanocarriers to produce an optimized bilayer coating demonstrates to significantly enhance the Pp IX stabilization in biological environments. Such versatile hybrid nanocarriers open new perspectives for PDT.
Asunto(s)
Portadores de Fármacos/síntesis química , Nanopartículas/química , Fármacos Fotosensibilizantes/administración & dosificación , Protoporfirinas/administración & dosificación , Animales , Línea Celular Tumoral , Portadores de Fármacos/química , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Protoporfirinas/química , Especies Reactivas de Oxígeno/metabolismo , Dióxido de Silicio/química , Espectrofotometría UltravioletaRESUMEN
Protoporphyrin IX (Pp IX) silica nanoparticles, developed for effective use in photodynamic therapy (PDT), were explored in in vitro and in vivo models with the ambition to improve knowledge on the role of biological factors in the photodamage. Pp IX silica nanoparticles are found efficient at temperature with extreme metabolic downregulation, which suggest a high proportion of passive internalization. For the first time, clearance of silica nanoparticles on tumor cells is established. Cell viability assessment in six tumor cell lines is reported. In all tumor types, Pp IX silica nanoparticles are more efficient than free Pp IX. A strong fluorescence signal of reactive oxygen species generation colocalized with Pp IX silica nanoparticles, correlates with 100% of cell death. In vivo studies performed in HCT 116, A549 and glioblastoma multiforme tumors-bearing mice show tumor uptake of Pp IX silica nanoparticles with better tumor accumulation than the control alone, highlighting a high selectivity for tumor tissues. As observed in in vitro tests, tumor cell type is likely a major determinant but tumor microenvironment could more influence this differential time accumulation dynamic. The present results strongly suggest that Pp IX silica nanoparticles may be involved in new alternative local applications of PDT.