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1.
Proc Natl Acad Sci U S A ; 120(50): e2122178120, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38051771

RESUMO

Thrombocytopenia, hemorrhage, anemia, and infection are life-threatening issues following accidental or intentional radiation exposure. Since few therapeutics are available, safe and efficacious small molecules to mitigate radiation-induced injury need to be developed. Our previous study showed the synthetic TLR2/TLR6 ligand fibroblast stimulating lipopeptide (FSL-1) prolonged survival and provided MyD88-dependent mitigation of hematopoietic acute radiation syndrome (H-ARS) in mice. Although mice and humans differ in TLR number, expression, and function, nonhuman primate (NHP) TLRs are like those of humans; therefore, studying both animal models is critical for drug development. The objectives of this study were to determine the efficacy of FSL-1 on hematopoietic recovery in small and large animal models subjected to sublethal total body irradiation and investigate its mechanism of action. In mice, we demonstrate a lack of adverse effects, an easy route of delivery (subcutaneous) and efficacy in promoting hematopoietic progenitor cell proliferation by FSL-1. NHP given radiation, followed a day later with a single subcutaneous administration of FSL-1, displayed no adversity but showed elevated hematopoietic cells. Our analyses revealed that FSL-1 promoted red blood cell development and induced soluble effectors following radiation exposure. Cytologic analysis of bone marrow aspirates revealed a striking enhancement of mononuclear progenitor cells in FSL-1-treated NHP. Combining the efficacy of FSL-1 in promoting hematopoietic cell recovery with the lack of adverse effects induced by a single administration supports the application of FSL-1 as a viable countermeasure against H-ARS.


Assuntos
Síndrome Aguda da Radiação , Receptor 2 Toll-Like , Humanos , Camundongos , Animais , Receptor 6 Toll-Like , Ligantes , Síndrome Aguda da Radiação/tratamento farmacológico , Primatas , Fibroblastos
2.
Drug Metab Dispos ; 51(1): 130-141, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36273826

RESUMO

This article reports on an American Society of Pharmacology and Therapeutics, Division of Drug Metabolism and Disposition symposium held at Experimental Biology on April 2, 2022, in Philadelphia. As of July 2022, over 500 million people have been infected with SARS-CoV-2 (the virus causing COVID-19) and over 12 billion vaccine doses have been administered. Clinically significant interactions between viral infections and hepatic drug metabolism were first recognized over 40 years ago during a cluster of pediatric theophylline toxicity cases attributed to reduced hepatic drug metabolism amid an influenza B outbreak. Today, a substantive body of research supports that the activated innate immune response generally decreases hepatic cytochrome P450 activity. The interactions extend to drug transporters and other organs and have the potential to impact drug absorption, distribution, metabolism, and excretion (ADME). Based on this knowledge, altered ADME is predicted with SARS-CoV-2 infection or vaccination. The report begins with a clinical case exploring the possibility of SARS-CoV-2 vaccination increasing clozapine levels. This is followed by discussions of how SARS-CoV-2 infection or vaccines alter the metabolism and disposition of complex drugs, such as nanoparticles and biologics and small molecule therapies. The review concludes with a discussion of the effects of viral infections on placental amino acid transport and their potential to impact fetal development. The session improved our understanding of the impact of emerging viral infections and vaccine technologies on drug metabolism and disposition, which will help mitigate drug toxicity and improve drug and vaccine safety and effectiveness. SIGNIFICANCE STATEMENT: Altered pharmacokinetics of small molecule and complex molecule drugs and fetal brain distribution of amino acids following SARS-CoV-2 infection or immunization are possible. The proposed mechanisms involve decreased liver cytochrome P450 metabolism of small molecules, enhanced innate immune system metabolism of complex molecules, and altered placental and fetal blood-brain barrier amino acid transport, respectively. Future research is needed to understand the effects of these interactions on adverse drug responses, drug and vaccine safety, and effectiveness and fetal neurodevelopment.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Criança , Feminino , Humanos , Gravidez , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Placenta , SARS-CoV-2 , Vacinas
3.
Invest New Drugs ; 39(4): 1047-1056, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33594602

RESUMO

Background This was a phase I/IIa study to investigate the tolerability, efficacy and pharmacokinetics (PK)/ pharmacodynamics (PD) of CRLX301, CDP-based nanoparticle formulation of docetaxel. Methods The study was conducted in two parts. In part 1, dose-escalation using a standard 3 + 3 design was performed in two dosing schedules (every week (QW) and every 3 weeks (Q3W)). Part 2 was comprised of a dose expansion at 75 mg/m2 Q3W. PK studies were performed on both dosing schedules. Results Forty-two patients were recruited onto the study with a median age of 64(range 38-76); median number of prior systemic therapies was 5(range 0-10). Grade 3/4 treatment-related toxicities included: neutropenia (21.4 %), infusion related reaction (11.9 %), anemia (7.1 %), fatigue (4.8 %), diarrhea (4.8 %), and peripheral neuropathy (4.8 %). The maximum tolerated dose was 75 mg/m2 given on the Q3W schedule and was not determined on the QW schedule. In this heavily pre-treated population, four patients (12.9 %) achieved stable disease (SD) ≥ 4 months and 2 patients (6.5 %) achieved partial response (PR) for a clinical benefit rate (CBR) of 19.4 % (6/31 patients). The PRs were seen in prostate and breast adenocarcinoma (one each). CRLX301 exhibited some PK advantages over docetaxel including higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. Conclusions In this heavily pretreated patient population, the safety profile was acceptable for CRLX301 therapy. There was some evidence of preliminary tumor efficacy, but further work is necessary to find the optimal dose and schedule of this formulation.Clinicaltrials.gov trial registration number: NCT02380677 (Date of registration: March 2, 2015).


Assuntos
Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Nanopartículas , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Preparações de Ação Retardada , Docetaxel/efeitos adversos , Docetaxel/farmacocinética , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Resultado do Tratamento
4.
Int J Gynecol Cancer ; 29(1): 147-152, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30640697

RESUMO

INTRODUCTION: Intraperitoneal (IP) chemotherapy improves survival in ovarian cancer but its use has been limited by toxicity with cisplatin-based regimens. The primary objective of this study was to define the maximum tolerated dose and dose-limiting toxicity of intravenous (IV) oxaliplatin and IP docetaxel in women with recurrent ovarian, fallopian tube or peritoneal cancer. Secondary objectives were response rate, time to progression, symptom interference with quality of life, and pharmacokinetics. METHODS: Patients received a constant dose of oxaliplatin 75 mg/m2 IV on day 1 and docetaxel escalating from 50 mg/m2 IP on day 2 every 3 weeks using a 3 + 3 design. Treatment continued until disease progression, remission, or intolerable toxicity occurred. Plasma and IP samples were taken to determine drug concentrations. Patients completed the MD Anderson Symptom Inventory weekly. RESULTS: Twelve patients were included. The median number of cycles was 4 (range 2-6) with a median time to progression of 4.5 months. Among eight patients with measurable disease, the best responses were partial response in two patients, stable disease in five, and progressive disease in one. A total of 14 grade 3-4 toxicities were noted, most commonly hematologic. Four patients, all dose level 3, had six dose-limiting toxicities: two with prolonged neutropenia, one with infection, one with hyponatremia, and two with abdominal pain. Dose level 3 was therefore considered intolerable. The mean±SD ratio of docetaxel area under the curve (AUC) in IP fluid to AUC in plasma was 229±111. Symptom interference with life activities steadily decreased from cycle 1 to 5. CONCLUSIONS: Oxaliplatin 75 mg/m2 IV on day 1 and docetaxel 75 mg/m2 IP on day 2 was the maximum tolerated dose. Most patients had partial response or stable disease, even in a heavily pre-treated population. At this dose level, patient-reported outcomes demonstrate temporary but tolerable decrements in quality of life.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Qualidade de Vida , Administração Intravenosa , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Docetaxel/administração & dosagem , Neoplasias das Tubas Uterinas/patologia , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Oxaliplatina/administração & dosagem , Neoplasias Peritoneais/patologia , Prognóstico , Distribuição Tecidual
5.
Nanomedicine ; 21: 102076, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31394261

RESUMO

Pretargeting is an increasingly explored strategy to improve nanoparticle targeting, in which pretargeting molecules that bind both selected epitopes on target cells and nanocarriers are first administered, followed by the drug-loaded nanocarriers. Bispecific antibodies (bsAb) represent a promising class of pretargeting molecules, but how different bsAb formats may impact the efficiency of pretargeting remains poorly understood, in particular Fab valency and Fc receptor (FcR)-binding of bsAb. We found the tetravalent bsAb markedly enhanced PEGylated nanoparticle binding to target HER2+ cells relative to the bivalent bsAb in vitro. Pretargeting with tetravalent bsAb with abrogated FcR binding increased tumor accumulation of PEGylated liposomal doxorubicin (PLD) 3-fold compared to passively targeted PLD alone, and 5-fold vs pretargeting with tetravalent bsAb with normal FcR binding in vivo. Our work demonstrates that multivalency and elimination of FcRn recycling are both important features of pretargeting molecules, and further supports pretargeting as a promising nanoparticle delivery strategy.


Assuntos
Anticorpos Biespecíficos , Antineoplásicos Imunológicos , Portadores de Fármacos , Neoplasias Experimentais , Polietilenoglicóis , Receptor ErbB-2/antagonistas & inibidores , Animais , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/farmacologia , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Feminino , Humanos , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , ômega-Cloroacetofenona
6.
Proc Natl Acad Sci U S A ; 113(8): 2200-5, 2016 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-26858448

RESUMO

Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, Ki-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Carcinoma Ductal Pancreático/tratamento farmacológico , Bombas de Infusão Implantáveis , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/efeitos dos fármacos , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Humanos , Iontoforese/instrumentação , Leucovorina/administração & dosagem , Leucovorina/farmacocinética , Camundongos , Camundongos Nus , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacocinética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Nano Lett ; 17(1): 242-248, 2017 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-27966988

RESUMO

Novel treatment strategies, including nanomedicine, are needed for improving management of triple-negative breast cancer. Patients with triple-negative breast cancer, when considered as a group, have a worse outcome after chemotherapy than patients with breast cancers of other subtypes, a finding that reflects the intrinsically adverse prognosis associated with the disease. The aim of this study was to improve the efficacy of docetaxel by incorporation into a novel nanoparticle platform for the treatment of taxane-resistant triple-negative breast cancer. Rod-shaped nanoparticles encapsulating docetaxel were fabricated using an imprint lithography based technique referred to as Particle Replication in Nonwetting Templates (PRINT). These rod-shaped PLGA-docetaxel nanoparticles were tested in the C3(1)-T-antigen (C3Tag) genetically engineered mouse model (GEMM) of breast cancer that represents the basal-like subtype of triple-negative breast cancer and is resistant to therapeutics from the taxane family. This GEMM recapitulates the genetics of the human disease and is reflective of patient outcome and, therefore, better represents the clinical impact of new therapeutics. Pharmacokinetic analysis showed that delivery of these PLGA-docetaxel nanoparticles increased docetaxel circulation time and provided similar docetaxel exposure to tumor compared to the clinical formulation of docetaxel, Taxotere. These PLGA-docetaxel nanoparticles improved tumor growth inhibition and significantly increased median survival time. This study demonstrates the potential of nanotechnology to improve the therapeutic index of chemotherapies and rescue therapeutic efficacy to treat nonresponsive cancers.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Ácido Láctico/química , Nanopartículas/química , Ácido Poliglicólico/química , Taxoides/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Células A549 , Animais , Antineoplásicos/farmacocinética , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Sobrevivência Celular , Docetaxel , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos Nus , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Propriedades de Superfície , Taxoides/química , Taxoides/metabolismo , Taxoides/farmacocinética , Neoplasias de Mama Triplo Negativas/genética
8.
J Oncol Pharm Pract ; 23(2): 103-115, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26673538

RESUMO

Background Even while following best practices, surface exposures of hazardous drugs (HDs) are high and numerous. Thus, it is important to develop new products to reduce the surface contamination of HDs. Hazardous Drug Clean (HDClean™) was developed to decontaminate and remove HDs from various types of surfaces and overcome the problems associated with other cleaning products. Methods HDClean was evaluated to remove mock surface exposures of HDs (docetaxel, paclitaxel, ifosfamide, cyclophosphamide, 5-FU, and cisplatin) from various types of surfaces. In two separate cancer centers, studies were performed to evaluate HDClean in reducing surface contamination of HDs in the pharmacy departments where no closed system transfer device (CSTD) was used. In a third cancer center, studies were performed comparing the effectiveness of a CSTD + Surface Safe compared with CSTD + HDClean to remove HDs. Results HDClean was able to completely remove mock exposures of a wide range of HDs from various surfaces (4 and 8 sq ft areas). Daily use of HDClean was equal to or more effective in reducing surface contamination of HDs in two pharmacies compared with a CSTD. HDClean was significantly more effective in removing HDs, especially cisplatin, compared with Surface Safe and does not have the problems associated with decontamination solutions that contain sodium hypochlorite. Conclusion These studies support HDClean as an effective decontaminating product, that HDClean is more effective than Surface Safe in removing HDs and is equal to or more effective than CSTD in controlling HD surface exposures.


Assuntos
Antineoplásicos/efeitos adversos , Descontaminação/métodos , Desinfetantes/química , Contaminação de Equipamentos , Substâncias Perigosas/efeitos adversos , Exposição Ocupacional/prevenção & controle , Hipoclorito de Sódio/química , Antineoplásicos/química , Composição de Medicamentos/instrumentação , Composição de Medicamentos/normas , Substâncias Perigosas/química , Humanos , Enfermeiras e Enfermeiros , Farmacêuticos , Serviço de Farmácia Hospitalar/normas , Guias de Prática Clínica como Assunto , Equipamentos de Proteção
9.
Nanomedicine ; 13(2): 471-482, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27720926

RESUMO

The mononuclear phagocyte system (MPS) has previously been shown to significantly affect the clearance, tumor delivery, and efficacy of nanoparticles (NPs). This study profiled MPS cell infiltration in murine preclinical tumor models and evaluated how these differences may affect tumor disposition of PEGylated liposomal doxorubicin (PLD) in models sensitive and resistant to PLD. Significant differences in MPS presence existed between tumor types (e.g. ovarian versus endometrial), cell lines within the same tumor type, and location of tumor implantation (i.e. flank versus orthotopic xenografts). Further, the differences in MPS presence of SKOV-3 ovarian and HEC1A endometrial orthotopic cancer models may account for the 2.6-fold greater PLD tumor exposure in SKOV-3, despite similar plasma, liver and spleen exposures. These findings suggest that profiling the presence of MPS cells within and between tumor types is important in tumor model selection and in tumor types and patients likely to respond to NP treatment.


Assuntos
Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacologia , Macrófagos/efeitos dos fármacos , Polietilenoglicóis , Animais , Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Camundongos , Modelos Biológicos , Nanopartículas , Neoplasias/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Fosfolipídeos/uso terapêutico
10.
Mol Pharm ; 13(6): 1996-2009, 2016 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-27170232

RESUMO

Platinum (Pt) based chemotherapy is widely used to treat many types of cancer. Pt therapy faces challenges such as dose limiting toxicities, cumulative side effects, and multidrug resistance. Nanoemulsions (NEs) have tremendous potential in overcoming these challenges as they can be designed to improve circulation time, limit non-disease tissue uptake, and enhance tumor uptake by surface modification. We designed novel synthesis of three difattyacid platins, dimyrisplatin, dipalmiplatin, and distearyplatin, suitable for encapsulation in the oil core of an NE. The dimyrisplatin, dipalmiplatin, and distearyplatin were synthesized, characterized, and loaded into the oil core of our NEs, NMI-350, NMI-351, and NMI-352 respectively. Sequestration of the difattyacid platins was accomplished through high energy microfluidization. To target the NE, FA-PEG3400-DSPE was incorporated into the surface during microfluidization. The FA-NEs selectively bind the folate receptor α (FR-α) and utilize receptor mediated endocytosis to deliver Pt past cell surface resistance mechanisms. FR-α is overexpressed in a number of oncological conditions including ovarian cancer. The difattyacid platins, lipidated Gd-DTPA, and lipidated folate were characterized by nuclear magnetic resonance (NMR), mass spectrometry (MS), and elemental analysis. NEs were synthesized using high shear microfluidization process and characterized for size, zeta-potential, and loading efficiency. In vitro cytotoxicity was determined using KB-WT (Pt-sensitive) and KBCR-1000 (Pt-resistant) cancer cells and measured by MTT assay. Pharmacokinetic profiles were studied in CD-1 mice. NEs loaded with difattyacid platins are highly stable and had size distribution in the range of ∼120 to 150 nm with low PDI. Cytotoxicity data indicates the longer the fatty acid chains, the less potent the NEs. The inclusion of C6-ceramide, an apoptosis enhancer, and surface functionalization with folate molecules significantly increased in vitro potency. Pharmacokinetic studies show that the circulation time for all three difattyacid platins encapsulated in NE remained identical, thus indicating that chain length did not influence circulation time. A stable NMI-350 family of NEs were successfully designed, formulated, and characterized. The Pt-resistance in KBCR-1000 cells was reversed with the NMI-350 family. Dimyrisplatin loaded NE (NMI-350) was most potent in vitro. The NMI-350 family demonstrated identical pharmacokinetic profiles to one another and circulated much longer than cisplatin. These data indicate that NMI-350 warrants further preclinical and clinical development as a replacement for current Pt regimens especially for those afflicted with multi drug resistant cancers.


Assuntos
Emulsões/administração & dosagem , Emulsões/química , Ácido Fólico/administração & dosagem , Ácido Fólico/química , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/química , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Feminino , Receptor 1 de Folato/metabolismo , Gadolínio DTPA/química , Células HeLa , Humanos , Camundongos , Neoplasias Ovarianas/metabolismo , Tamanho da Partícula , Polietilenoglicóis/química , Nanomedicina Teranóstica/métodos
11.
Nanomedicine ; 12(7): 2007-2017, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27288666

RESUMO

Nanoparticles (NP) including liposomes are cleared by phagocytes of the mononuclear phagocyte system. High inter-patient variability in pharmacokinetics of PEGylated liposomal doxorubicin (PLD) has been reported. We hypothesized that genetic factors may be associated with the variable disposition of PLD. We evaluated plasma and tissue disposition of doxorubicin after administration of PLD at 6mg/kg IV ×1 via tail vein in 23 different male inbred mouse strains. An approximately 13-fold difference in plasma clearance of PLD was observed among inbred strains. We identified a correlation between strain-specific differences in PLD clearance and genetic variation within a genomic region encoding GULP1 (PTB domain containing engulfment adapter 1) protein using haplotype associated mapping and the efficient mixed-model association algorithms. Our results also show that Gulp1 expression in adipose tissue was associated with PLD disposition in plasma. Our findings suggest that genetic variants may be associated with inter-individual pharmacokinetic differences in NP clearance.


Assuntos
Doxorrubicina , Nanopartículas , Proteínas Adaptadoras de Transdução de Sinal , Animais , Humanos , Cinética , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos , Variantes Farmacogenômicos , Polietilenoglicóis
12.
Gynecol Oncol ; 138(3): 548-53, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26111788

RESUMO

OBJECTIVE: The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of IV docetaxel and IP oxaliplatin in women with recurrent ovarian (OV), fallopian tube (FT) or peritoneal (PP) cancer. Secondary objectives included response rate, time to progression, pharmacokinetics (PK) and quality of life (QoL). METHODS: Patients received docetaxel 75mg/m(2) IV day (d) 1 and oxaliplatin escalating from 50mg/m(2) IP d2 every 3weeks using a 3+3 design. Treatment continued until disease progression, remission, or intolerable toxicity. Plasma and IP samples were taken to determine drug concentrations. MD Anderson Symptom Inventory and symptom interference scale were completed weekly. RESULTS: Thirteen patients were included. Median number of cycles was 6 (range 1-10). Ten patients had measureable disease. Best response was partial response (PR-2), stable disease (SD-7), and progressive disease (PD-1). Twenty-one Grades 3-4 toxicities were noted, commonly hematologic. Two patients had DLTs: prolonged neutropenia (1) and abdominal pain (1). MTD was d1 docetaxel 75mg/m(2) IV and d2 oxaliplatin 50mg/m(2) IP. Symptom burden peaked week one and returned to baseline by week two of each cycle on dose level 1. Dose level 2 had persistently high symptom burden and interference. At IP oxaliplatin doses of 50mg/m(2), total unbound drug exposure (AUC) averaged 8 times larger and Cmax reached concentrations 50-fold greater in IP fluid compared to plasma. CONCLUSIONS: Docetaxel 75mg/m(2) IV d1 and oxaliplatin 50mg/m(2) IP d2 is the MTD. Most patients had PR or SD. Patient-reported outcomes demonstrate temporary but tolerable decrements in QoL. IP oxaliplatin provides PK advantages over IV administration.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Docetaxel , Relação Dose-Resposta a Droga , Esquema de Medicação , Neoplasias das Tubas Uterinas/metabolismo , Feminino , Humanos , Infusões Intravenosas , Infusões Parenterais , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/farmacocinética , Oxaliplatina , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Taxoides/farmacocinética
13.
Nanomedicine ; 11(7): 1797-807, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26093057

RESUMO

Nanoparticles (NPs) are cleared by monocytes and macrophages. Chemokines CCL2 and CCL5 are key mediators for recruitment of these immune cells into tumors and tissues. The purpose of this study was to investigate effects of CCL2 and CCL5 on the pharmacokinetics (PKs) of NPs. Mice deficient in CCL2 or CCL5 demonstrated altered clearance and tissue distribution of polyethylene glycol tagged liposomal doxorubicin (PLD) compared to control mice. The PK studies using mice bearing SKOV3 ovarian cancer xenografts revealed that the presence of tumor cells and higher expression of chemokines were significantly associated with greater clearance of PLD compared to non-tumor bearing mice. Plasma exposure of encapsulated liposomal doxorubicin positively correlated with the total exposure of plasma CCL2 and CCL5 in patients with recurrent epithelial ovarian cancer treated with PLD. These data emphasize that the interplay between PLD and chemokines may have an important role in optimizing PLD therapy. FROM THE CLINICAL EDITOR: The use of nanoparticles as drug delivery carriers is gaining widespread acceptance in the clinical setting. However, the underlying pharmacokinetics of these novel drugs has not really been elucidated. In this interesting article, the authors carried out experiments using mice deficient in CCL2 or CCL5 to study the clearance of liposomal system. They showed the important role the immune system played and would enable better designs of future drug delivery systems.


Assuntos
Quimiocina CCL2/sangue , Quimiocina CCL5/sangue , Doxorrubicina/análogos & derivados , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Animais , Carcinoma Epitelial do Ovário , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Distribuição Tecidual/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nano Lett ; 14(3): 1472-6, 2014 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-24552251

RESUMO

Delivery systems designed to have triggered release after passively targeting the tumor may improve small molecule chemotherapeutic delivery. Particle replication in nonwetting templates was used to prepare nanoparticles to passively target solid tumors in an A549 subcutaneous xenograft model. An acid labile prodrug was delivered to minimize systemic free docetaxel concentrations and improve tolerability without compromising efficacy.


Assuntos
Portadores de Fármacos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Pró-Fármacos , Taxoides , Animais , Docetaxel , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Humanos , Camundongos , Nanopartículas/ultraestrutura , Neoplasias/patologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Taxoides/química , Taxoides/farmacologia , Molhabilidade , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Mol Pharm ; 11(4): 1250-8, 2014 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-24521246

RESUMO

Coating nanoparticles with polyethylene glycol (PEG), which reduces particle uptake and clearance by immune cells, is routinely used to extend the circulation times of nanoparticle therapeutics. Nevertheless, due to technical hurdles in quantifying the extent of PEG grafting, as well as in generating very dense PEG coatings, few studies have rigorously explored the precise PEG grafting density necessary to achieve desirable "stealth" properties. Here, using polymeric nanoparticles with precisely tunable PEG grafting, we found that, for a wide range of PEG lengths (0.6-20 kDa), PEG coatings at densities substantially exceeding those required for PEG to adopt a "brush" conformation are exceptionally resistant to uptake by cultured human macrophages, as well as primary peripheral blood leukocytes. Less than 20% of these nanoparticles were cleared from the blood after 2 h (t1/2 ∼ 14 h) in BALB/c mice, whereas slightly less densely PEGylated and uncoated control particles were both virtually eliminated within 2 h. Our results suggest that the stealth properties of PEG-coated nanoparticles are critically dependent on achieving PEG grafting at densities exceeding those required for brush conformation.


Assuntos
Sistemas de Liberação de Medicamentos , Leucócitos/imunologia , Nanopartículas/química , Polietilenoglicóis/química , Animais , Células Cultivadas , Feminino , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C
16.
Nanomedicine ; 10(1): 109-17, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23891988

RESUMO

A meta-analysis was conducted to evaluate the inter-patient pharmacokinetic (PK) variability of liposomal and small molecule (SM) anticancer agents. Inter-patient PK variability of 9 liposomal and SM formulations of the same drug was evaluated. PK variability was measured as coefficient of variance (CV%) of area under the plasma concentration versus time curve (AUC) and the fold-difference between AUCmax and AUCmin (AUC range). CV% of AUC and AUC ranges were 2.7-fold (P<0.001) and 16.7-fold (P=0.13) greater, respectively, for liposomal compared with SM drugs. There was an inverse linear relationship between the clearance (CL) of liposomal agents and PK variability with a lower CL associated with greater PK variability (R(2)=0.39). PK variability of liposomal agents was greater when evaluated from 0-336 h compared with 0-24h. PK variability of liposomes is significantly greater than SM. The factors associated with the PK variability of liposomal agents need to be evaluated. FROM THE CLINICAL EDITOR: In this meta-analysis, the inter-patient pharmacokinetic variability of 9 liposomal and small molecule anti-cancer agents was studied. The authors determined that several parameters are in favor of the liposomal formulation; however, the PK variability of the formulation was higher compared with small molecule agents, the reason for which remains to be determined in future studies.


Assuntos
Antineoplásicos/farmacocinética , Lipossomos/administração & dosagem , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/química , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/sangue , Camptotecina/farmacocinética , Humanos , Lipossomos/sangue , Lipossomos/química , Neoplasias/sangue
17.
Proc Natl Acad Sci U S A ; 108(2): 586-91, 2011 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-21220299

RESUMO

It has long been hypothesized that elastic modulus governs the biodistribution and circulation times of particles and cells in blood; however, this notion has never been rigorously tested. We synthesized hydrogel microparticles with tunable elasticity in the physiological range, which resemble red blood cells in size and shape, and tested their behavior in vivo. Decreasing the modulus of these particles altered their biodistribution properties, allowing them to bypass several organs, such as the lung, that entrapped their more rigid counterparts, resulting in increasingly longer circulation times well past those of conventional microparticles. An 8-fold decrease in hydrogel modulus correlated to a greater than 30-fold increase in the elimination phase half-life for these particles. These results demonstrate a critical design parameter for hydrogel microparticles.


Assuntos
Eritrócitos/citologia , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Animais , Materiais Biocompatíveis/química , Biomimética , Portadores de Fármacos/química , Desenho de Equipamento , Feminino , Cinética , Teste de Materiais , Camundongos , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência/métodos , Tamanho da Partícula , Polímeros/química , Fatores de Tempo , Distribuição Tecidual
18.
J Pharmacol Exp Ther ; 347(3): 599-606, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24042160

RESUMO

As nanoparticles (NPs) are cleared via phagocytes of the mononuclear phagocyte system (MPS), we hypothesized that the function of circulating monocytes and dendritic cells (MO/DC) in blood can predict NP clearance (CL). We measured MO/DC phagocytosis and reactive oxygen species (ROS) production in mice, rats, dogs, and patients with refractory solid tumors. Pharmacokinetic studies of polyethylene glycol (PEG)-encapsulated liposomal doxorubicin (PEGylated liposomal doxirubicin [PLD]), CKD-602 (S-CKD602), and cisplatin (SPI-077) were performed at the maximum tolerated dose. MO/DC function was also evaluated in patients with recurrent epithelial ovarian cancer (EOC) administered PLD. Across species, a positive association was observed between cell function and CL of PEGylated liposomes. In patients with EOC, associations were observed between PLD CL and phagocytosis (R(2) = 0.43, P = 0.04) and ROS production (R(2) = 0.61, P = 0.008) in blood MO/DC. These findings suggest that probes of MPS function may help predict PEGylated liposome CL across species and PLD CL in patients with EOC.


Assuntos
Antineoplásicos/administração & dosagem , Lipossomos/farmacologia , Sistema Fagocitário Mononuclear/efeitos dos fármacos , Adulto , Idoso , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Área Sob a Curva , Células Dendríticas/efeitos dos fármacos , Cães , Composição de Medicamentos , Feminino , Meia-Vida , Humanos , Camundongos , Pessoa de Meia-Idade , Nanopartículas , Neoplasias Ovarianas/tratamento farmacológico , Fagocitose/efeitos dos fármacos , Farmacocinética , Fenótipo , Polietilenoglicóis , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Pesquisa Translacional Biomédica
19.
Eur J Clin Pharmacol ; 69(12): 2073-81, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23989300

RESUMO

PURPOSE: To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK. METHODS: Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was administered as a 1 h IV infusion with doses ranging from 3.5 to 210 mg/m(2). Plasma concentrations of encapsulated CPT-11, released CPT-11 and SN-38 were used to develop a population PK model using NONMEM®. RESULTS: PK of encapsulated CPT-11 was described by 1-compartment model with nonlinear clearance and PK of released CPT-11 was described by a 1-compartment model with linear clearance for all patients. PK of the active metabolite SN-38 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that gender was a significant covariate for volume of distribution of encapsulated CPT-11. Vencap in male patients is 1.5-fold higher compared with female patients. CONCLUSIONS: The developed population PK modeling approach is useful to predict PK exposures of encapsulated and released drug and can be applied to the more than 300 other nanoparticle formulations of anticancer agents that are currently in development. The effect of gender on PK of IHL-305 needs to be further evaluated.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Modelos Biológicos , Neoplasias/sangue , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Camptotecina/administração & dosagem , Camptotecina/sangue , Camptotecina/farmacocinética , Feminino , Humanos , Infusões Intravenosas , Irinotecano , Lipossomos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Polietilenoglicóis/química
20.
Nanomedicine ; 9(5): 686-93, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23219874

RESUMO

The particle fabrication technique PRINT® was used to fabricate monodisperse size and shape specific poly(lactide-co-glycolide) particles loaded with the chemotherapeutic Docetaxel. The pharmacokinetics of two cylindrical shaped particles with diameter=80nm; height=320nm (PRINT-Doc-80×320) and d=200nm; h=200nm (PRINT-Doc-200×200) were compared to Docetaxel in mice bearing human ovarian carcinoma SKOV-3 flank xenografts. The Docetaxel plasma exposure was ~20-fold higher for both particles compared to docetaxel. Additionally, the volume of distribution (Vd) of Docetaxel in PRINT formulations was ~18-fold (PRINT-Doc-80×320) and ~33-fold (PRINT-Doc-200×200) lower than Docetaxel. The prolonged duration of Docetaxel in plasma when dosed with PRINT formulations subsequently led to increased tumor exposure of Docetaxel from 0 to 168h (~53% higher for PRINT-Doc-80×320 and ~76% higher for PRINT-Doc-200×200 particles). PRINT-Doc-80×320 had lower exposures in the liver, spleen and lung compared with PRINT-Doc-200×200. Thus, the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system. FROM THE CLINICAL EDITOR: In this study, the plasma, tumor, and tissue pharmacokinetics of different Docetaxel nanoparticles of precise shape and size were characterized in mice with human ovarian carcinoma xenograft. It is concluded that the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system.


Assuntos
Carcinoma/tratamento farmacológico , Nanopartículas/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Taxoides/administração & dosagem , Animais , Carcinoma/sangue , Carcinoma/patologia , Linhagem Celular Tumoral , Docetaxel , Feminino , Humanos , Camundongos , Nanopartículas/química , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Tamanho da Partícula , Taxoides/sangue , Taxoides/farmacocinética , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
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