ABSTRACT
Physiologic barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduced metastasis, and increased both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (i) increase intratumoral drug accumulation by >10-fold, (ii) increase the duration of drug exposure above a critical therapeutic threshold, and (iii) attenuate surges in CD44 and CXCR4 expression, which mediate chemoresistance often observed after multicycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression, and drug resistance and to extend patient survival.Significance: A biophysical priming approach overcomes key treatment barriers, significantly reduces metastases, and prolongs survival in orthotopic models of human pancreatic cancer. Cancer Res; 78(2); 558-71. ©2017 AACR.
Subject(s)
Camptothecin/analogs & derivatives , Drug Delivery Systems , Liposomes/administration & dosage , Nanoparticles/administration & dosage , Pancreatic Neoplasms/drug therapy , Photochemotherapy , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biomarkers, Tumor/metabolism , Camptothecin/administration & dosage , Camptothecin/chemistry , Camptothecin/pharmacology , Cell Proliferation/drug effects , Humans , Irinotecan , Liposomes/chemistry , Male , Mice , Mice, Nude , Nanoparticles/chemistry , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Receptors, CXCR4/metabolism , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Liposomal irinotecan (irinotecan liposome injection, nal-IRI), a liposomal formulation of irinotecan, is designed for extended circulation relative to irinotecan and for exploiting discontinuous tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38. Sustained inhibition of topoisomerase 1 by extended SN-38 exposure as a result of delivery by nal-IRI is hypothesized to enable superior antitumor activity compared with traditional topoisomerase 1 inhibitors such as conventional irinotecan and topotecan. We evaluated the antitumor activity of nal-IRI compared with irinotecan and topotecan in preclinical models of small-cell lung cancer (SCLC) including in a model pretreated with carboplatin and etoposide, a first-line regimen used in SCLC. Nal-IRI demonstrated antitumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, and NCI-H1048 cell line-derived models as well as in three patient-derived xenograft models. The antitumor activity of nal-IRI was superior to that of topotecan in all models tested, which generally exhibited limited control of tumor growth and was superior to irinotecan in four out of five models. Further, nal-IRI demonstrated antitumor activity in tumors that progressed following treatment with topotecan or irinotecan, and demonstrated significantly greater antitumor activity than both topotecan and irinotecan in NCI-H1048 tumors that had progressed on previous carboplatin plus etoposide treatment. These results support the clinical development of nal-IRI in patients with SCLC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Camptothecin/analogs & derivatives , Small Cell Lung Carcinoma/drug therapy , Topoisomerase I Inhibitors/administration & dosage , Animals , Camptothecin/administration & dosage , Cell Line, Tumor , DNA Topoisomerases, Type I/metabolism , Female , Humans , Irinotecan , Liposomes/administration & dosage , Mice , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Random Allocation , Small Cell Lung Carcinoma/enzymology , Topotecan/administration & dosage , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE: To determine the pharmacokinetics and the antitumor activity in pediatric cancer models of MM-398, a nanoliposomal irinotecan (nal-IRI). EXPERIMENTAL DESIGN: Mouse plasma and tissue pharmacokinetics of nal-IRI and the current clinical formulation of irinotecan were characterized. In vivo activity of irinotecan and nal-IRI was compared in xenograft models (3 each in nu/nu mice) of Ewing's sarcoma family of tumors (EFT), neuroblastoma (NB), and rhabdomyosarcoma (RMS). SLFN11 expression was assessed by Affymetrix HuEx arrays, Taqman RT-PCR, and immunoblotting. RESULTS: Plasma and tumor concentrations of irinotecan and SN-38 (active metabolite) were approximately 10-fold higher for nal-IRI than for irinotecan. Two doses of NAL-IRI (10 mg/kg/dose) achieved complete responses maintained for >100 days in 24 of 27 EFT-xenografted mice. Event-free survival for mice with RMS and NB was significantly shorter than for EFT. High SLFN11 expression has been reported to correlate with sensitivity to DNA damaging agents; median SLFN11 mRNA expression was >100-fold greater in both EFT cell lines and primary tumors compared with NB or RMS cell lines or primary tumors. Cytotoxicity of SN-38 inversely correlated with SLFN11 mRNA expression in 20 EFT cell lines. CONCLUSIONS: In pediatric solid tumor xenografts, nal-IRI demonstrated higher systemic and tumor exposures to SN-38 and improved antitumor activity compared with the current clinical formulation of irinotecan. Clinical studies of nal-IRI in pediatric solid tumors (especially EFT) and correlative studies to determine if SLFN11 expression can serve as a biomarker to predict nal-IRI clinical activity are warranted.
Subject(s)
Antineoplastic Agents/administration & dosage , Camptothecin/analogs & derivatives , Gene Expression , Liposomes , Nuclear Proteins/genetics , Sarcoma, Ewing/genetics , Sarcoma, Ewing/pathology , Sucrose/analogs & derivatives , Animals , Antineoplastic Agents/pharmacokinetics , Camptothecin/administration & dosage , Camptothecin/pharmacokinetics , Cell Line, Tumor , Disease Models, Animal , Drug Combinations , Female , Humans , Irinotecan , Macrophages/immunology , Macrophages/pathology , Mice , Sarcoma, Ewing/drug therapy , Sarcoma, Ewing/mortality , Sucrose/administration & dosage , Sucrose/pharmacokinetics , Tissue Distribution , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
A major challenge in the clinical use of cytotoxic chemotherapeutics is maximizing efficacy in tumors while sparing normal tissue. Irinotecan is used for colorectal cancer treatment but the extent of its use is limited by toxic side effects. Liposomal delivery systems offer tools to modify pharmacokinetic and safety profiles of cytotoxic drugs. In this study, we defined parameters that maximize the antitumor activity of a nanoliposomal formulation of irinotecan (nal-IRI). In a mouse xenograft model of human colon carcinoma, nal-IRI dosing could achieve higher intratumoral levels of the prodrug irinotecan and its active metabolite SN-38 compared with free irinotecan. For example, nal-IRI administered at doses 5-fold lower than free irinotecan achieved similar intratumoral exposure of SN-38 but with superior antitumor activity. Tumor response and pharmacokinetic modeling identified the duration for which concentrations of SN-38 persisted above a critical intratumoral threshold of 120 nmol/L as determinant for antitumor activity. We identified tumor permeability and carboxylesterase activity needed for prodrug activation as critical factors in achieving longer duration of SN-38 in tumors. Simulations varying tumor permeability and carboxylesterase activity predicted a concave increase in tumor SN-38 duration, which was confirmed experimentally in 13 tumor xenograft models. Tumors in which higher SN-38 duration was achieved displayed more robust growth inhibition compared with tumors with lower SN-38 duration, confirming the importance of this factor in drug response. Overall, our work shows how liposomal encapsulation of irinotecan can safely improve its antitumor activity in preclinical models by enhancing accumulation of its active metabolite within the tumor microenvironment.
Subject(s)
Antineoplastic Agents/pharmacology , Camptothecin/analogs & derivatives , Colonic Neoplasms/drug therapy , Liposomes/pharmacology , Prodrugs/pharmacology , Animals , Camptothecin/pharmacology , Carcinoma/drug therapy , Female , HT29 Cells , Humans , Irinotecan , Mice , Mice, Inbred NOD , Mice, SCID , Tumor Cells, Cultured , Xenograft Model Antitumor Assays/methodsABSTRACT
OBJECTIVE: The NF-kappaB signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF-kappaB activity is regulated by the IKK-2 kinase during inflammatory responses. To elucidate how IKK-2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibody-induced arthritis. METHODS: ML120B, a potent, small molecule inhibitor of IKK-2, was administered to arthritic animals, and disease activity was monitored. NF-kappaB activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase-polymerase chain reaction was used to evaluate gene expression in joints. Protease-activated near-infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints. RESULTS: Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF-kappaB activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF-kappaB pathway, i.e., KC, epithelial neutrophil-activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor alpha, interleukin-1beta, interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints. CONCLUSION: Our data demonstrate that IKK-2 inhibition in the murine model of antibody-induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.
Subject(s)
Antirheumatic Agents/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Carbolines/pharmacology , Enzyme Inhibitors/pharmacology , I-kappa B Kinase/antagonists & inhibitors , Niacinamide/analogs & derivatives , Spectroscopy, Near-Infrared/methods , Administration, Oral , Animals , Arthritis, Experimental/enzymology , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/enzymology , Arthritis, Rheumatoid/pathology , Dose-Response Relationship, Drug , Female , Gene Expression/drug effects , I-kappa B Kinase/metabolism , Joints/drug effects , Joints/metabolism , Joints/pathology , Mice , Mice, Inbred BALB C , NF-kappa B/genetics , NF-kappa B/metabolism , Niacinamide/pharmacology , RNA, Messenger/metabolism , Spectrometry, Fluorescence/methods , Up-Regulation/drug effectsABSTRACT
In the present study we have characterized T cell-driven immune function in mice that are genetically deficient in PKC theta. In response to simple immunologic stimulation invoked by in vivo T cell receptor (TCR) cross-linking, these mice showed significantly depressed plasma cytokine levels for IL-2, IL-4, IFNgamma, and TNFalpha compared to wild-type (WT) mice. In parallel, spleen mRNA levels for these cytokines were reduced, and NF-kappaB activation was also reduced in PKC theta knockouts (KO). Injection of allogeneic cells into the footpad of PKC theta deficient mice provoked a significantly diminished local T cell response compared to WT mice similarly challenged. Unlike comparable cells from wild type mice, CD45RBhi T cells harvested from PKC theta deficient mice failed to induce colitis in the SCID-CD45RB cell transfer model of IBD. In another T cell-dependent model of inflammatory disease, PKC theta deficient animals developed far less severe neurologic signs and reduced spinal cord inflammatory cell infiltrate compared to WT controls in the MOG-induced EAE model. A fundamental role for PKC theta in T cell activation and in the development of T cell-mediated inflammatory diseases is indicated by these results.
Subject(s)
Inflammation/immunology , Isoenzymes/genetics , Protein Kinase C/genetics , Receptors, Antigen, T-Cell/immunology , Animals , CD4 Antigens/immunology , Cell Proliferation , Cytokines/blood , Cytokines/metabolism , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Enzyme Activation , Female , Inflammation/pathology , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/pathology , Isoenzymes/immunology , Leukocyte Common Antigens/immunology , Lymph Nodes/immunology , Lymph Nodes/pathology , Lymphocyte Activation , Mice , Mice, Knockout , Mice, SCID , NF-kappa B/metabolism , Protein Kinase C/immunology , Protein Kinase C-theta , RNA, Messenger/blood , RNA, Messenger/metabolism , Spinal Cord/immunology , Spinal Cord/pathology , Spleen/metabolismABSTRACT
Una de las principales responsabilidades del administrador o Regente farmacéutico institucional es la de asegurar que haya la suficiente cantidad de medicamentos esenciales primarios en unidades y dosis completas disponibles, para proveer al paciente la medicación prescrita y funcionar correctamente. La adquisión, almacenaje y movimiento de productos es conocido como "Administración de Medicamentos o Insumos Médicos" En el presente artículo, se ha intentado presentar los métodos básicos que ayuden al farmacéutico a cumplir con estos objetivos a través de las estrategias de adquisición organizada y del control de inventario. Estos deberán utilizarse cuando se estime apropiado, considerando que el ingrediente primordial de un programa es el compromiso de lograr el éxito y que este es una función esencial que no debe tratarse superficialmente
Subject(s)
Catalogs, Drug as Topic , Drug Administration Routes , Education, Pharmacy , Pharmacists/standardsABSTRACT
En el presente texto se exponen los valores normales de los distintos servicios de laboratorio, que servirán para uniformar criterios no sólo dentro del Hospital Militar Central, sino también en los otros centros hospitalarios de la ciudad, ya que se toma en cuenta la altura de la ciudad de La Paz.
