Revistas
Autores:
Navarro-Ocón, A.; Blaya-Cánovas, J. L.; López-Tejada, A.; et al.
Revista:
PHARMACEUTICS
ISSN:
1999-4923
Año:
2022
Vol.:
14
N°:
3
Págs.:
505
Breast cancer is the most common type of malignancy and leading cause of cancer death among women worldwide. Despite the current revolutionary advances in the field of cancer immunotherapy, clinical response in breast cancer is frequently below expectations, in part due to various mechanisms of cancer immune escape that produce tumor variants that are resistant to treatment. Thus, a further understanding of the molecular events underlying immune evasion in breast cancer may guarantee a significant improvement in the clinical success of immunotherapy. Furthermore, nanomedicine provides a promising opportunity to enhance the efficacy of cancer immunotherapy by improving the delivery, retention and release of immunostimulatory agents in targeted cells and tumor tissues. Hence, it can be used to overcome tumor immune escape and increase tumor rejection in numerous malignancies, including breast cancer. In this review, we summarize the current status and emerging trends in nanomedicine-based strategies targeting cancer immune evasion and modulating the immunosuppressive tumor microenvironment, including the inhibition of immunosuppressive cells in the tumor area, the activation of dendritic cells and the stimulation of the specific antitumor T-cell response.
Revista:
SCIENCE TRANSLATIONAL MEDICINE
ISSN:
1946-6234
Año:
2022
Vol.:
14
N°:
627
Págs.:
eabc0700
Correction of enzymatic deficits in hepatocytes by systemic administration of a recombinant protein is a desired therapeutic goal for hepatic enzymopenic disorders such as acute intermittent porphyria ( AIP), an inherited porphobilinogen deaminase (PBGD) deficiency. Apolipoprotein A-I (ApoAI) is internalized into hepatocytes during the centripetal transport of cholesterol. Here, we generated a recombinant protein formed by linking ApoAI to the amino terminus of human PBGD (rhApoAI-PBGD) in an attempt to transfer PBGD into liver cells. In vivo experiments showed that, after intravenous injection, rhApoAI-PBGD circulates in blood incorporated into high-density lipoprotein (HDL), penetrates into hepatocytes, and crosses the blood-brain barrier, increasing PBGD activity in both the liver and brain. Consistently, the intravenous administration of rhApoAI-PBGD or the hyperfunctional rApoAI-PBGD-I129M/N340S (rApoAI-PBGDms) variant efficiently prevented and abrogated phenobarbital-induced acute attacks in a mouse model of AIP. One month after a single intravenous dose of rApoAI-PBGDms, the protein was still detectable in the liver, and hepatic PBGD activity remained increased above control values. A long-lasting therapeutic effect of rApoAI-PBGDms was observed after either intravenous or subcutaneous administration. These data describe a method to deliver PBGD to hepatocytes with resulting enhanced hepatic enzymatic activity and protection against AIP attacks in rodent models, suggesting that the approach might be an effective therapy for AIP.
Revista:
JOURNAL OF NANOBIOTECHNOLOGY
ISSN:
1477-3155
Año:
2021
Vol.:
19
N°:
1
Págs.:
102
Background: The immunomodulation of the antitumor response driven by immunocheckpoint inhibitors (ICIs) such as PD-L1 (Programmed Death Ligand-1) monoclonal antibody (alpha-PD-L1) have shown relevant clinical outcomes in a subset of patients. This fact has led to the search for rational combinations with other therapeutic agents such as Doxorubicin (Dox), which cytotoxicity involves an immune activation that may enhance ICI response. Therefore, this study aims to evaluate the combination of chemotherapy and ICI by developing Dox Immunoliposomes functionalized with monovalent-variable fragments (Fab') of alpha-PD-L1.
Results: Immunoliposomes were assayed in vitro and in vivo in a B16 OVA melanoma murine cell line over-expressing PD-L1. Here, immune system activation in tumor, spleen and lymph nodes, together with the antitumor efficacy were evaluated. Results showed that immunoliposomes bound specifically to PD-L1(+) cells, yielding higher cell interaction and Dox internalization, and decreasing up to 30-fold the IC50, compared to conventional liposomes. This mechanism supported a higher in vivo response. Indeed, immunoliposomes promoted full tumor regression in 20% of mice and increased in 1 month the survival rate. This formulation was the only treatment able to induce significant (p < 0.01) increase of activated tumor specific cytotoxic T lymphocytes at the tumor site.
Conclusion: PD-L1 targeted liposomes encapsulating Dox have proved to be a rational combination able to enhance the modulation of the immune system by blocking PD-L1 and selectively internalizing Dox, thus successfully providing a dual activity offered by both, chemo and immune therapeutic strategies.
Revista:
FRONTIERS IN PHARMACOLOGY
ISSN:
1663-9812
Año:
2021
Vol.:
12
Págs.:
705443
V937 is an investigational novel oncolytic non-genetically modified Kuykendall strain of Coxsackievirus A21 which is in clinical development for the treatment of advanced solid tumor malignancies. V937 infects and lyses tumor cells expressing the intercellular adhesion molecule I (ICAM-I) receptor. We integrated in vitro and in vivo data from six different preclinical studies to build a mechanistic model that allowed a quantitative analysis of the biological processes of V937 viral kinetics and dynamics, viral distribution to tumor, and anti-tumor response elicited by V937 in human xenograft models in immunodeficient mice following intratumoral and intravenous administration. Estimates of viral infection and replication which were calculated from in vitro experiments were successfully used to describe the tumor response in vivo under various experimental conditions. Despite the predicted high clearance rate of V937 in systemic circulation (t(1/2) = 4.3 min), high viral replication was observed in immunodeficient mice which resulted in tumor shrinkage with both intratumoral and intravenous administration. The described framework represents a step towards the quantitative characterization of viral distribution, replication, and oncolytic effect of a novel oncolytic virus following intratumoral and intravenous administrations in the absence of an immune response. This model may further be expanded to integrate the role of the immune system on viral and tumor dynamics to support the clinical development of oncolytic viruses.
Revista:
BRITISH JOURNAL OF CANCER
ISSN:
0007-0920
Año:
2021
Vol.:
124
N°:
7
Págs.:
1275 - 1285
Background Anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibodies (mAbs) show remarkable clinical anti-tumour efficacy. However, rational combinations are needed to extend the clinical benefit to primary resistant tumours. The design of such combinations requires the identification of the kinetics of critical immune cell populations in the tumour microenvironment. Methods In this study, we compared the kinetics of immune cells in the tumour microenvironment upon treatment with immunotherapy combinations with different anti-tumour efficacies in the non-inflamed tumour model TC-1/A9. Tumour-bearing C57BL/6J mice were treated with all possible combinations of a human papillomavirus (HPV) E7 long peptide, polyinosinic-polycytidylic acid (PIC) and anti-PD-1 mAb. Tumour growth and kinetics of the relevant immune cell populations were assessed over time. The involvement of key immune cells was confirmed by depletion with mAbs and immunophenotyping with multiparametric flow cytometry. Results The maximum anti-tumour efficacy was achieved after intratumoural administration of HPV E7 long peptide and PIC combined with the systemic administration of anti-PD-1 mAb. The intratumoural immune cell kinetics of this combination was characterised by a biphasic immune response. An initial upsurge of proinflammatory myeloid cells led to a further rise in effector CD8(+) T lymphocytes at day 8. Depletion of either myeloid cells or CD8(+) T lymphocytes diminished the anti-tumour efficacy of the combination. Conclusions The anti-tumour efficacy of a successful immunotherapy combination in a non-inflamed tumour model relies on an early inflammatory process that remodels the myeloid cell compartment.
Revista:
CANCERS
ISSN:
2072-6694
Año:
2021
Vol.:
13
N°:
20
Págs.:
5049
Simple Summary: The clinical efficacy of immunotherapies when treating cold tumors is still low, and different treatment combinations are needed when dealing with this challenging scenario. In this work, a middle-out strategy was followed to develop a model describing the antitumor efficacy of different immune-modulator combinations, including an antigen, a toll-like receptor-3 agonist, and an immune checkpoint inhibitor in mice treated with non-inflamed tumor cells. Our results support that clinical response requires antigen-presenting cell activation and also relies on the amount of CD8 T cells and tumor resistance mechanisms present. This mathematical model is a very useful platform to evaluate different immuno-oncology combinations in both preclinical and clinical settings.
Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors. Tumor size of mice treated with TC-1/A9 non-inflamed tumors and the drug effects of an antigen, a toll-like receptor-3 agonist (PIC), and an immune checkpoint inhibitor (anti-programmed cell death 1 antibody) were modeled using Monolix and following a middle-out strategy. Tumor growth was best characterized by an exponential model with an estimated initial tumor size of 19.5 mm(3) and a doubling time of 3.6 days. In the treatment groups, contrary to the lack of response observed in monotherapy, combinations including the antigen were able to induce an antitumor response. The final model successfully captured the 23% increase in the probability of cure from bi-therapy to triple-therapy. Moreover, our work supports that CD8(+) T lymphocytes and resistance mechanisms are strongly related to the clinical outcome. The activation of antigen-presenting cells might be needed to achieve an antitumor response in reduced immunogenic tumors when combined with other immunotherapies. These models can be used as a platform to evaluate different immuno-oncology combinations in preclinical and clinical scenarios.
Revista:
PHARMACEUTICS
ISSN:
1999-4923
Año:
2020
Vol.:
12
N°:
6
Págs.:
595
Immunotherapy has changed the paradigm of cancer treatments. In this way, several combinatorial strategies based on monoclonal antibodies (mAb) such as anti (a)-PD-1 or anti (a)-PD-L1 are often reported to yield promising clinical benefits. However, the pharmacokinetic (PK) behavior of these mAbs is a critical issue that requires selective analytical techniques. Indeed, few publications report data on a-PD1/a-PD-L1 exposure and its relationship with therapeutic or toxic effects. In this regard, preclinical assays allow the time profiles of antibody plasma concentrations to be characterized rapidly and easily, which may help to increase PK knowledge. In this study, we have developed and validated two in-house ELISAs to quantify a-PD-1 and a-PD-L1 in plasma collected from tumor-bearing mice. The linear range for the a-PD-1 assay was 2.5-125 ng/mL and 0.11-3.125 ng/mL for the a-PD-L1 assay, whereas the intra-and inter-day precision was lower than 20% for both analytes. The PK characterization revealed a significant decrease in drug exposure after administration of multiple doses. Plasma half-life for a-PD-1 was slightly shorter (22.3 h) than for a-PD-L1 (46.7 h). To our knowledge, this is the first reported preclinical ELISA for these immune checkpoint inhibitors, which is sufficiently robust to be used in different preclinical models. These methods can help to understand the PK behavior of these antibodies under different scenarios and the relationship with response, thus guiding the choice of optimal doses in clinical settings.
Revista:
NANOMEDICINE
ISSN:
1743-5889
Año:
2019
Vol.:
17
Págs.:
13 - 25
Autores:
Yoncheva, K. (Autor de correspondencia); Merinos, M. ; Shenol, A.; et al.
Revista:
INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN:
0378-5173
Año:
2019
Vol.:
556
Págs.:
1 - 8
The present study evaluates the potential of encapsulated doxorubicin to reduce both the viability of melanoma cells and the tumor growth in a mouse melanoma model. The prepared doxorubicin loaded chitosan/alginate nanoparticles possessed mean diameter around 300 nm and negative zeta-potential. Classical molecular dynamic simulations revealed that the high encapsulation efficiency (above 90%) was mainly due to electrostatic interaction between doxorubicin and sodium alginate, although dipole-dipole and hydrophobic interactions might also contribute. The in vitro dissolution tests showed slower doxorubicin release in slightly alkaline medium (pH = 7.4) and faster release in acid one (pH = 5.5), indicating that higher concentration of doxorubicin might reach the acidic tumor tissue. The free and the encapsulated doxorubicin decreased the viability of melanoma cell lines (B16-F10 and B16-OVA) in a similar degree. However, the cytotoxic effect of the encapsulated doxorubicin still occurred in the more resistant B16-F10 cells even after removing the extracellular drug. The experiments on a syngeneic melanoma mouse model revealed that free and encapsulated doxorubicin elicited the control of the tumor growth (dose of 3 mg/kg). Thus, the encapsulation of doxorubicin into chitosan/alginate nanoparticles could be considered advantageous because of the better intracellular accumulation and longer cytotoxic effect on the investigated melanoma cells.
Revista:
CPT: PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
ISSN:
2163-8306
Año:
2017
Vol.:
6
N°:
1
Págs.:
8 - 10
This commentary provides an overview of recent examples of pharmacometrics applied during the clinical development of two antagonists of the programmed death-1 (PD-1) cell surface receptor, pembrolizumab and nivolumab. Despite the remarkable achievements obtained in predicting the correct dosing schedule from different quantitative approaches, data indicated a great degree of heterogeneity in tumor response. To achieve therapeutic goals the search for predictive biomarkers associated with a lack of response and mechanism-based combination studies are warranted.
Revista:
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
ISSN:
0928-0987
Año:
2017
Vol.:
106
Págs.:
294 - 301
This study was aimed to evaluate the in vitro transdermal direct/pulsed current iontophoretic delivery of an amphiphilic model compound from various lipid vesicle-encapsulated formulations compared to free-drug formulation. Conventional, pegylated, ultradeformable liposomes (transfersomes) and ethosomes loaded with a negatively charged drug diclofenac sodium (DS) were prepared and characterized. All the liposomes possessed an average size of approximate to 100-150 nm and negative zeta potential. No changes in colloidal stability were detected after 8 h incubation of any vesicle formulation under constant or pulsed iontophoretic current. DS was released from all the liposome formulations with a similar, limited rate (approximate to 50% in 24 h), leading therefore to significantly lower transdermal fluxes across full-thickness porcine skin compared to the respective free drug formulation. From the tested lipid vesicle formulations, the transfersomes resulted in the highest passive flux and the ethosomes in the highest iontophoretic flux under direct constant current treatment. Higher negative surface charge of the vesicle led to better transport efficiency due to the higher mobility of the drug carrier under electric field. Pulsed current iontophoresis had no advantage over constant current treatment in combination with any type of lipid vesicular nanocarriers, in contrast to what has been described earlier with drug-loaded polymeric nano carriers.
Revista:
ONCOTARGET
ISSN:
1949-2553
Año:
2017
Vol.:
7
N°:
47
Págs.:
76891 - 76901
Revista:
INTERNATIONAL JOURNAL OF PHARMACOLOGY
ISSN:
1811-7775
Año:
2017
Vol.:
13
N°:
1
Págs.:
54 - 63
Objective: To describe quantitatively the variability associated to the pharmacokinetic (PK) processes of clarithromycin (CLA) in Mexican hospitalized patients with respiratory infection and to determine whether the 6-beta-hydroxycortisol (6 beta-OHC)/cortisol ratio, among other factors would partially explain such variability. Materials and Methods: Fifty three patients aged >18 years with respiratory disease treated with CLA were included in the study. An average of 3 blood samples per patient were obtained at approximately the following Times After Dosing (TAD): 0.5, 1.25, 2, 3, 4, 6, 9 and 12 h. Clarithromycin was given orally or i.v., twice daily at the dose of 500 mg. Around the same times at which blood samples were collected, one urine sample was obtained for determining the 6 beta-OHC/cortisol ratio. The serum concentration vs time data of CLA were modeled using the population approach with NONMEM 7.2. Results: A one-compartment disposition model with first-order rate of absorption and concentration independent distribution and elimination provided a reasonable description of the data. Absolute bioavailability of CLA was not different from 1 (p>0.05). The population estimate of total clearance was 14.6 L h(-1), lower than that reported previously for healthy volunteers. Final population model included body weight as the unique covariate affecting the apparent volume of distribution. Conclusion: The study population showed a total clearance lower than that reported for healthy volunteers from other countries, probably due to the low activity of CYP3A determined in this population. However, the CYP3A activity level did not result as a significative covariable of the CLA total clearance.
Revista:
NANOMEDICINE
ISSN:
1743-5889
Año:
2016
Vol.:
11
N°:
5
Págs.:
465 - 477
Aim: Development of EGF-liposomes (LP-EGF) for selective molecules delivery in tumors expressing EGFR. Material & methods: In vitro cellular interaction of EGF-LP and nontargeted liposomes (LP-N) was assayed at 37 and 4°C in cells expressing different EGFR levels. Receptor-mediated uptake was investigated by competition with a monoclonal antibody anti-EGFR. Selective intracellular drug delivery and efficacy was tested by oxaliplatin encapsulation. In vivo biodistribution of LP-N and LP-EGF was done in xenograft model. Results: LP-EGF was internalized by an active and selective mechanism through EGFR without receptor activation. Oxaliplatin LP-EGF decreased IC50 between 48 and 13% in cell EGFR+. LP-EGF was accumulated in tumor over 72 h postdosing, while LP-N in spleen. Conclusion: LP-EGF represents an attractive nanosystem for cancer therapy or diagnosis.
Revista:
CLINICAL PHARMACOKINETICS
ISSN:
0312-5963
Año:
2016
Vol.:
55
N°:
4
Págs.:
461 - 473
BACKGROUND AND OBJECTIVES:
Lanreotide Autogel (lanreotide Depot in the USA) has demonstrated anti-tumor activity and control of the symptoms associated with hormone hypersecretion in patients with neuroendocrine tumors. The objectives of this study were to describe the pharmacokinetics of lanreotide Autogel administered 4-weekly by deep subcutaneous injections of 60, 90, or 120 mg in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), to quantify the magnitude of inter-patient variability (IPV), and to identify those patient characteristics that impact on pharmacokinetics.
METHODS:
Analyses were based on pooled data from clinical trials. A total of 1541 serum concentrations from 290 patients were analyzed simultaneously by the population approach using NONMEM version 7.2. Covariates evaluated included demographics, renal and hepatic function markers, and disease-related parameters.
RESULTS:
Serum profiles were described by a one-compartment disposition model in which the absorption process was characterized by two parallel pathways following first- and zero-order kinetics. The estimated apparent volume of distribution was 18.3 L. The estimated apparent total serum clearance for a typical 74 kg patient was 513 L/day, representing a substantial difference in clearance in this population of patients with respect to healthy volunteers that could not be explained by any of the covariates tested. Body weight was the only covariate to show a statistically significant effect on the pharmacokinetic profile, but due to the overlap between the pharmacokinetic profiles of patients with lower or higher body weights the effect of body weight on clearance was not considered clinically relevant. The IPV was low for clearance (27%) and moderate to high for volume of distribution (150%) and the absorption constant (61%).
CONCLUSIONS:
Using two mechanisms of absorption, the pharmacokinetics of lanreotide Autogel were well-described in patients with GEP-NET. None of the patient characteristics tested were of clinical relevance to potential dose adjustment in clinical practice.
Revista:
JOURNAL OF CONTROLLED RELEASE
ISSN:
0168-3659
Año:
2015
Vol.:
210
Págs.:
26 - 36
Oxaliplatin (L-OH), a platinum derivative with good tolerability is currently combined with Cetuximab (CTX), a monoclonal antibody (mAb), for the treatment of certain (wild-type KRAS) metastatic colorectal cancer (CRC) expressing epidermal growth factor receptor (EGFR).
Improvement of L-OH pharmacokinetics (PK) can be provided by its encapsulation into liposomes, allowing a more selective accumulation and delivery to the tumor. Here, we aim to associate both agents in a novel liposomal targeted therapy by linking CTX to the drug-loaded liposomes. These EGFR-targeted liposomes potentially combine the therapeutic activity and selectivity of CTX with tumor-cell delivery of L-OH in a single therapeutic approach.
L-OH liposomes carrying whole CTX or CTX-Fab¿ fragments on their surface were designed and characterized. Their functionality was tested in vitro using four human CRC cell lines, expressing different levels of EGFR to investigate the role of CTX-EGFR interactions in the cellular binding and uptake of the nanocarriers and encapsulated drug. Next, those formulations were evaluated in vivo in a colorectal cancer xenograft model with regard to tumor drug accumulation, toxicity and therapeutic activity.
In EGFR-overexpressing cell lines, intracellular drug delivery by targeted liposomes increased with receptor density reaching up to 3-fold higher levels than with non-targeted liposomes. Receptor specific uptake was demonstrated by competition with free CTX, which reduced...
Revista:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN:
0022-3565
Año:
2015
Vol.:
354
N°:
1
Págs.:
55 - 64
The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system-and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n = 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to drug effects and capable of following the maturation chain. Cell cycle dynamics were characterized by two new parameters, F-Prol (the fraction of proliferative [ Prol] cells that enters into the maturation chain) and k(cycle) (first-order rate constant governing cell cycle dynamics within the stem cell compartment). Both model parameters were identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by date from the literature. The estimates of F-Prol and k(cycle) were 0.58 and 1.94 day(-1), respectively. The new model could properly describe the neutropenic effects of diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction.
Revista:
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
ISSN:
0939-6411
Año:
2013
Vol.:
83
N°:
3
Págs.:
358 - 363
In this work, we have developed and evaluated a new targeted lipopolyplex (LPP), by combining polyethylenimine (PEI), 1,2-dioleoy1-3-(trimethylammonium) propane (DOTAP)/Chol liposomes, the plasmids pCMVLuc/pCMVIL-12, and the ligand folic acid (FA), able to transfect HeLa and B16-F10 cells in the presence of very high concentration of serum (60% FBS). These complexes (Fol-LPP) have a net positive surface charge. The combination of folic acid with lipopolyplexes also enhanced significantly the transfection activity of the therapeutic gene interleukin-12 (IL-12), without any significant cytotoxicity. The specificity of the folate receptor (FR)-mediated gene transfer was corroborated by employing a folate receptor deficient cell line (HepG2). This formulation improved gene delivery showed by conventional lipoplexes or polyplexes resulting an efficient, simple, and nontoxic method for gene delivery of therapeutic genes in vitro and very probably in vivo.
Revista:
EXPERT OPINION ON DRUG DELIVERY
ISSN:
1742-5247
Año:
2013
Vol.:
10
N°:
6
Págs.:
829 - 844
INTRODUCTION:
Liposomes represent a versatile system for drug delivery in various pathologies. Platinum derivatives have been demonstrated to have therapeutic efficacy against several solid tumors. But their use is limited due to their side effects. Since liposomal formulations are known to reduce the toxicity of some conventional chemotherapeutic drugs, the encapsulation of platinum derivatives in these systems may be useful in reducing toxicity and maintaining an adequate therapeutic response.
AREAS COVERED:
This review describes the strategies applied to platinum derivatives in order to improve their therapeutic activity, while reducing the incidence of side effects. It also reviews the results found in the literature for the different platinum-drugs liposomal formulations and their current status.
EXPERT OPINION:
The design of liposomes to achieve effectiveness in antitumor treatment is a goal for platinum derivatives. Liposomes can change the pharmacokinetic parameters of these encapsulated drugs, reducing their side effects. However, few liposomal formulations have demonstrated a significant advantage in therapeutic terms. Lipoplatin, a cisplatin formulation in Phase III, combines a reduction in the toxicity associated with an antitumor activity similar to the free drug. Thermosensitive or targeted liposomes for tumor therapy are also included in this review. Few articles about this strategy applied to platinum drugs can be found in the literature.
Revista:
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
ISSN:
0939-6411
Año:
2012
Vol.:
81
N°:
2
Págs.:
273 - 280
In this work, the Film Method (FM), Reverse-Phase Evaporation (REV), and the Heating Method (HM) were applied to prepare PEG-coated liposomes of oxaliplatin with natural neutral and cationic lipids, respectively. The formulations developed with the three methods, showed similar physicochemical characteristics, except in the loading of oxaliplatin, which was statistically lower (P < 0.05) using the HM. The incorporation of a semi-synthetic lipid in the formulation developed by FM, provided liposomes with a particle size of 115 nm associated with the lowest polydispersity index and the highest drug loading, 35%, compared with the other two lipids, suggesting aft increase in the membrane stability. That stability was also evaluated according to the presence of cholesterol, the impact of the temperature, and the application of different cryoprotectants during the lyophilization. The results indicated long-term stability of the developed formulation, because after its intravenous in vivo administration to HT-29 tumor bearing mice was able to induce an inhibition of tumor growth statistically higher (P < 0.05) than the inhibition caused by the free drug. In conclusion, the FM was the simplest method in comparison with REV and HM to develop in vivo stable and efficient PEG-coated liposomes of oxaliplatin with a loading higher than those reported for REV. (C) 2012 Elsevier B.V. All rights reserved.
Revista:
NANOMEDICINE
ISSN:
1743-5889
Año:
2011
Vol.:
6
N°:
1
Págs.:
89 - 98
Aims: In this work, we have evaluated the ability of targeted lipoplexes to enhance transgene expression in EGF receptor (EGFR) overexpressing tumor cells by using lipoplexes. Materials & methods: We prepared DOTAP/cholesterol liposomes modified with EGF at 0.5/1, 1/1, 2/1 and 5/1 lipid/DNA (+/-) charge ratio by sequentially mixing the liposomes with the ligand and addling the reporter or the therapeutic plasmid gene, pCMVLuc (pVR1216) or pCMVIL12, respectively. HepG2, DHDK12proB and SW620 cells were used for in vitro experiments, which were performed in the presence of 60% serum. Results: The characterization of EGF-lipoplexes indicated a size close to 300 nm and a variable net surface charge as a function of the amount of EGF associated to the cationic liposomes. EGF-lipoplexes, which showed an increased transfection activity, were positively charged, noncytotoxic and highly effective in protecting DNA from DNase I attack. Transfection activity in vitro resulted in an enhancement in the luciferase and IL-12 expression by EGF-lipoplexes compared with those without ligand (plain-lipoplexes) and to naked DNA. The results observed in SW620 cells, which are deficient in EGFR, confirmed that DNA uptake was predominantly via EGFR-mediated endocytosis. In vivo transfection activity was confirmed by luciferase imaging in living mice. Bioluminiscence could be detected mainly in the lung with a maximum signal 24 h after application. The resulting EGF-lipoplexes significantly ...
Revista:
J CLIN PHARMACOL
ISSN:
0091-2700
Año:
2011
Vol.:
52
N°:
4
Págs.:
487-498
Revista:
PHARMACEUTICAL RESEARCH
ISSN:
0724-8741
Año:
2010
Vol.:
27
N°:
3
Págs.:
431 - 441
Revista:
Microchemical Journal
ISSN:
0026-265X
Año:
2010
Vol.:
96
N°:
2
Págs.:
415 - 421
Revista:
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
ISSN:
0939-6411
Año:
2010
Vol.:
74
N°:
2
Págs.:
265 - 274
Biodegradable poly (lactic-co-glycolic) acid (PLGA) nanoparticles incorporating cisplatin have been developed to evaluate its in vivo efficacy in tumor-bearing mice.
In vitro Study proved two mechanisms of action for cisplatin depending on the dose and the rate at which this dose is delivered. In vivo study, 5 mg/kg of cisplatin nanoparticles administered to mice, exhibited a tumour inhibition similar to free cisplatin, although the area under cisplatin concentration-time Curve between 0 and 21 days (AUC(0-21)) had lower Value for the formulation than for drug solution (P < 0.05). This result was associated with a higher activation of apoptosis in tumor, mediated by caspase-3, after nanoparticles administration. Toxicity measured as the change in body weight, and blood urea nitrogen (BUN) plasma levels showed that cisplatin nanoparticles treatment did not induce significant changes in both parameters compared to control, while for free drug, a statistical (P < 0.01) increase was observed. In addition, a good correlation was found between time profiles of tumor volume and vascular endothelial growth factor (VEGF) plasma levels, suggesting that its expression could help to follow the efficacy of the treatment. Therefore, the PLGA nanoparticles seem to provide a promising carrier for cisplatin administration avoiding its side effects without a reduction of the efficacy, which was consistent with a higher activation of apoptosis than free drug.
Nacionales y Regionales
Título:
Desarrollo de nuevas terapias antitumorales de elevada eficacia y especificidad y baja toxicidad para administración oral
Código de expediente:
RTC-2014-2589-1
Investigador principal:
José Ignacio Fernández de Trocóniz Fernández
Financiador:
MINISTERIO DE CIENCIA E INNOVACIÓN
Convocatoria:
2014 MINECO Retos Colaboración
Fecha de inicio:
29/01/2014
Fecha fin:
30/06/2018
Importe concedido:
202.435,00€
Otros fondos:
-
Título:
Desarrollo de inmunoterapia del cáncer basada en mRNA (ARNMUNE)
Código de expediente:
0011-1411-2023-000101
Investigador principal:
Ignacio Javier Melero Bermejo
Financiador:
GOBIERNO DE NAVARRA
Convocatoria:
2023 GN PROYECTOS ESTRATEGICOS DE I+D 2023-2026
Fecha de inicio:
05/09/2023
Fecha fin:
31/12/2025
Importe concedido:
422.291,90€
Otros fondos:
Fondos FEDER
Título:
Transportadores de ADN/ARN de nueva generación:cápsides moleculares basadas en carbohidratos
Código de expediente:
PID2021-124247OB-C22
Investigador principal:
María de la Concepción Tros de Ilarduya Apaolaza
Financiador:
AGENCIA ESTATAL DE INVESTIGACION
Convocatoria:
2021 AEI Proyectos de Generación del Conocimiento
Fecha de inicio:
01/09/2022
Fecha fin:
31/08/2025
Importe concedido:
84.700,00€
Otros fondos:
Fondos FEDER
Título:
Identificación y desarrollo de candidato inhibidor de HDAC6 como tratamiento frente al cáncer de colon (COLON-HDAC6)
Código de expediente:
0011-1411-2021-000097
Investigador principal:
Ana Gloria Gil Royo
Financiador:
GOBIERNO DE NAVARRA
Convocatoria:
2021 GN PROYECTOS ESTRATEGICOS DE I+D 2021-2024
Fecha de inicio:
01/07/2021
Fecha fin:
31/12/2023
Importe concedido:
412.467,21€
Otros fondos:
-
Título:
Nueva Plataforma para el tratamiento personalizado del cáncer de colon ONCO-CEBRA-GEN
Código de expediente:
0011-1365-2020-000282
Financiador:
GOBIERNO DE NAVARRA
Convocatoria:
2020 GN I+D Transferencia del conocimiento (empresas)
Fecha de inicio:
01/04/2020
Fecha fin:
30/07/2022
Importe concedido:
145.126,12€
Otros fondos:
Fondos FEDER
Título:
Fármacos innovadores para el tratamiento de la Enfermedad de Alzheimer: Estudios preclínicos de eficacia y toxicidad bajo condiciones BPL por vía oral.
Código de expediente:
RTC-2017-5994-1
Financiador:
MINISTERIO DE CIENCIA E INNOVACIÓN
Convocatoria:
2017 MINECO RETOS COLABORACIÓN
Fecha de inicio:
01/01/2018
Fecha fin:
31/12/2020
Importe concedido:
86.118,00€
Otros fondos:
Fondos FEDER
Título:
IDP4SCLC Optimización de fármacos en nuevas dianas terapéuticas IDP (ASCL1) para el tratamiento de cáncer microcítico de pulmón.
Código de expediente:
RTC-2017-6585-1
Financiador:
MINISTERIO DE CIENCIA E INNOVACIÓN
Convocatoria:
2017 MINECO RETOS COLABORACIÓN
Fecha de inicio:
01/01/2018
Fecha fin:
30/11/2021
Importe concedido:
133.489,47€
Otros fondos:
Fondos FEDER
Otros (PIUNA, fundaciones, contratos…)
Título:
Desarrollo preclínico BPL de un producto para cancer
Fecha de inicio:
28/07/2020
Fecha fin:
31/12/2021
Importe:
195.414,50€
Otros fondos:
-
Título:
Desarrollo Preclínico de un tratamiento COMBINADO
Investigador principal:
Ana Gloria Gil Royo, María Jesús Garrido Cid
Fecha de inicio:
23/05/2018
Fecha fin:
31/12/2018
Importe:
7.410,00€
Otros fondos:
-
Título:
ESTUDIO ANTICUERPOS MACACOS
Investigador principal:
Ana Gloria Gil Royo
Fecha de inicio:
21/06/2021
Fecha fin:
31/12/2022
Importe:
186.025,00€
Otros fondos:
-
Título:
Tol. Local i.m y PK dos soluciones en conejo
Investigador principal:
Ana Gloria Gil Royo
Fecha de inicio:
15/07/2019
Fecha fin:
30/09/2019
Importe:
22.245,00€
Otros fondos:
-
Título:
Estudio de seguridad y eficacia en colirio
Investigador principal:
Ana Gloria Gil Royo, María Jesús Garrido Cid
Fecha de inicio:
14/03/2023
Fecha fin:
30/09/2023
Importe:
130.145,00€
Otros fondos:
-
Título:
Desarrollo toxicológico del producto en macaco
Fecha de inicio:
12/01/2021
Fecha fin:
31/08/2022
Importe:
115.775,00€
Otros fondos:
-
Título:
Desarrollo preclínico CAPRICORN
Fecha de inicio:
09/11/2020
Fecha fin:
30/04/2024
Importe:
209.110,00€
Otros fondos:
-
Título:
Evaluación farmacocinética del compuesta
Fecha de inicio:
07/06/2019
Fecha fin:
31/10/2019
Importe:
12.745,00€
Otros fondos:
-
Título:
Estudio I.m COnejo
Fecha de inicio:
05/10/2018
Fecha fin:
19/07/2019
Importe:
139.017,00€
Otros fondos:
-
Título:
Develop a model of the mecanisms immune-mediated tumor Kill
Investigador principal:
José Ignacio Fernández de Trocóniz Fernández, María Jesús Garrido Cid
Fecha de inicio:
04/10/2016
Fecha fin:
28/12/2021
Importe:
136.850,00€
Otros fondos:
-
Título:
¿Validation of bioanalútical method and Repeated dose
Investigador principal:
Ángel María Irigoyen Barrio, Ana Gloria Gil Royo
Fecha de inicio:
01/09/2019
Fecha fin:
30/03/2020
Importe:
36.380,00€
Otros fondos:
-