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1.
Biomed Chromatogr ; 36(3): e5289, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34846750

RESUMO

The Bcl-2 family small molecule inhibitor navitoclax is being clinically evaluated to treat multiple cancers including lymphoid malignancies and small cell lung cancer. A sensitive and reliable method was developed to quantitate navitoclax in human plasma using liquid chromatography with tandem mass spectrometry with which to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of navitoclax and the internal standard, navitoclax-d8, was achieved with a Waters Acquity UPLC BEH C18 column using isocratic flow over a 3 min total analytical run time. A SCIEX 4500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for the detection of navitoclax. The assay range was 5-5,000 ng/ml and proved to be accurate (89.5-104.9%) and precise (CV ≤ 11%). Long-term frozen plasma stability for navitoclax at -70°C was at least 34 months. The method was applied for the measurement of total plasma concentration of navitoclax in a patient receiving a 250 mg daily oral dose.


Assuntos
Compostos de Anilina , Sulfonamidas , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
2.
Biomed Chromatogr ; 36(11): e5467, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35895384

RESUMO

Navtemadlin is an orally bioavailable small molecule that blocks the protein-protein interaction between murine double minute 2 protein (MDM2) and the tumor suppressor protein p53, leading to p53-mediated cell cycle arrest and apoptosis. It is being evaluated in clinical trials for a variety of malignancies, both as a single agent and in combination regimens. A sensitive, robust LC-tandem mass spectrometry (LC-MS/MS) method was developed to quantitate navtemadlin in plasma, and this method was also validated using brain tissue homogenate. Sample preparation involved protein precipitation of plasma or brain tissue homogenate using acetonitrile. Navtemadlin, navtemadlin glucuronide, and the internal standard, D6 -navtemadlin, were separated from microsomal incubation extracts using gradient elution and a ZORBAX XDB C18 column. Analytes were detected using a SCIEX 5500 triple quadrupole mass spectrometer in positive electrospray ionization mode. The assay range of 1-1000 ng/mL was shown to be accurate (96.1-102.0% and 95.7-104%) and precise (coefficient of variation ≤ 10.6% and ≤ 6.6%) in plasma and brain tissue homogenate, respectively. An 8000 ng/mL navtemadlin sample diluted 1:10 (v/v) with plasma was also accurately quantitated. Navtemadlin has been stable in frozen plasma at -70°C for at least 20 months. This validated LC-MS/MS method was applied to determine navtemadlin concentrations in plasma and brain tissue samples from two separate patients receiving 120 mg/day navtemadlin on protocol ABTC1604.


Assuntos
Espectrometria de Massas em Tandem , Proteína Supressora de Tumor p53 , Acetonitrilas , Animais , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Glucuronídeos/metabolismo , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Proteína Supressora de Tumor p53/metabolismo
4.
Nat Commun ; 14(1): 2509, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-37130851

RESUMO

Sustained drug delivery strategies have many potential benefits for treating a range of diseases, particularly chronic diseases that require treatment for years. For many chronic ocular diseases, patient adherence to eye drop dosing regimens and the need for frequent intraocular injections are significant barriers to effective disease management. Here, we utilize peptide engineering to impart melanin binding properties to peptide-drug conjugates to act as a sustained-release depot in the eye. We develop a super learning-based methodology to engineer multifunctional peptides that efficiently enter cells, bind to melanin, and have low cytotoxicity. When the lead multifunctional peptide (HR97) is conjugated to brimonidine, an intraocular pressure lowering drug that is prescribed for three times per day topical dosing, intraocular pressure reduction is observed for up to 18 days after a single intracameral injection in rabbits. Further, the cumulative intraocular pressure lowering effect increases ~17-fold compared to free brimonidine injection. Engineered multifunctional peptide-drug conjugates are a promising approach for providing sustained therapeutic delivery in the eye and beyond.


Assuntos
Sistemas de Liberação de Medicamentos , Melaninas , Animais , Coelhos , Tartarato de Brimonidina , Peptídeos , Aprendizado de Máquina
5.
J Control Release ; 362: 371-380, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37657693

RESUMO

Effective eye drop delivery systems for treating diseases of the posterior segment have yet to be clinically validated. Further, adherence to eye drop regimens is often problematic due to the difficulty and inconvenience of repetitive dosing. Here, we describe a strategy for topically dosing a peptide-drug conjugate to achieve effective and sustained therapeutic sunitinib concentrations to protect retinal ganglion cells (RGCs) in a rat model of optic nerve injury. We combined two promising delivery technologies, namely, a hypotonic gel-forming eye drop delivery system, and an engineered melanin binding and cell-penetrating peptide that sustains intraocular drug residence time. We found that once daily topical dosing of HR97-SunitiGel provided up to 2 weeks of neuroprotection after the last dose, effectively doubling the therapeutic window observed with SunitiGel. For chronic ocular diseases affecting the posterior segment, the convenience of an eye drop combined with intermittent dosing frequency could result in greater patient adherence, and thus, improved disease management.

6.
J Pharm Biomed Anal ; 209: 114525, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34906921

RESUMO

The global transcription inhibitor terameprocol is being evaluated clinically as an oral formulation to treat high-grade glioma. A sensitive, reliable method was developed to quantitate terameprocol using LC-MS/MS to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of terameprocol and the internal standard, Sorafenib-methyl-d3, was achieved with a Zorbax XDB C18 column (2.1 × 50 mm, 3.5 µm) and gradient elution over a 2-minute total analytical run time. A SCIEX 4500 or SCIEX 5500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for terameprocol detection. The assay range of 5-1000 ng/mL was demonstrated to be accurate (92.7-107.4%) and precise (CV ≤ 11.3%). A sample diluted 1:10 (v/v) was accurately quantitated. Terameprocol in plasma has been proven stable for at least 20 months when stored at -70 °C. The method was applied to the measurement of total plasma concentrations of terameprocol in a patient with a high-grade glioma receiving a 300 mg oral dose.


Assuntos
Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Masoprocol/análogos & derivados , Reprodutibilidade dos Testes
7.
Drug Deliv Transl Res ; 12(4): 826-837, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-33900546

RESUMO

While eye drops are the most common ocular dosage form, eye drops for treating diseases of the posterior segment (retina, choroid, optic nerve) have yet to be developed. In glaucoma, eye drops are used extensively for delivering intraocular pressure (IOP)-lowering medications to the anterior segment. However, degeneration of retinal ganglion cells (RGCs) in the retina may progress despite significant IOP lowering, suggesting that a complementary neuroprotective therapy would improve glaucoma management. Here, we describe a hypotonic, thermosensitive gel-forming eye drop for effective delivery of sunitinib, a protein kinase inhibitor with activity against the neuroprotective targets dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK), to enhance survival of RGCs after optic nerve injury. Further, binding of sunitinib to melanin in the pigmented cells in the choroid and retinal pigment epithelium (RPE) led to prolonged intraocular residence time, including therapeutically relevant concentrations in the non-pigmented retinal tissue where the RGCs reside. The combination of enhanced intraocular absorption provided by the gel-forming eye drop vehicle and the intrinsic melanin binding properties of sunitinib led to significant protection of RGCs with only once weekly eye drop dosing. For a chronic disease such as glaucoma, an effective once weekly eye drop for neuroprotection could result in greater patient adherence, and thus, greater disease management and improved patient quality of life.


Assuntos
Glaucoma , Melaninas , Animais , Modelos Animais de Doenças , Glaucoma/tratamento farmacológico , Humanos , Pressão Intraocular , Melaninas/metabolismo , Soluções Oftálmicas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Qualidade de Vida , Células Ganglionares da Retina/metabolismo , Sunitinibe/metabolismo , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico
8.
Pharmaceutics ; 13(5)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062883

RESUMO

Glaucoma is the leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is one of the major risk factors for glaucoma onset and progression, and available pharmaceutical interventions are exclusively targeted at IOP lowering. However, degeneration of retinal ganglion cells (RGCs) may continue to progress despite extensive lowering of IOP. A complementary strategy to IOP reduction is the use of neuroprotective agents that interrupt the process of cell death by mechanisms independent of IOP. Here, we describe an ion complexation approach for formulating microcrystals containing ~50% loading of a protein kinase inhibitor, sunitinib, to enhance survival of RGCs with subconjunctival injection. A single subconjunctival injection of sunitinib-pamoate complex (SPC) microcrystals provided 20 weeks of sustained retina drug levels, leading to neuroprotection in a rat model of optic nerve injury. Furthermore, subconjunctival injection of SPC microcrystals also led to therapeutic effects in a rat model of corneal neovascularization. Importantly, therapeutically relevant retina drug concentrations were achieved with subconjunctival injection of SPC microcrystals in pigs. For a chronic disease such as glaucoma, a formulation that provides sustained therapeutic effects to complement IOP lowering therapies could provide improved disease management and promote patient quality of life.

9.
Nat Biomed Eng ; 4(11): 1053-1062, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32895514

RESUMO

Eye-drop formulations should hold as high a concentration of soluble drug in contact with ocular epithelium for as long as possible. However, eye tears and frequent blinking limit drug retention on the ocular surface, and gelling drops typically form clumps that blur vision. Here, we describe a gelling hypotonic solution containing a low concentration of a thermosensitive triblock copolymer for extended ocular drug delivery. On topical application, the hypotonic formulation forms a highly uniform and clear thin layer that conforms to the ocular surface and resists clearance from blinking, increasing the intraocular absorption of hydrophilic and hydrophobic drugs and extending the drug-ocular-epithelium contact time with respect to conventional thermosensitive gelling formulations and commercial eye drops. We also show that the conformal gel layer allows for therapeutically relevant drug delivery to the posterior segment of the eyeball in pigs. Our findings highlight the importance of formulations that conform to the ocular surface before viscosity enhancement for increased and prolonged ocular surface contact and drug absorption.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Olho/efeitos dos fármacos , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/síntese química , Administração Tópica , Animais , Olho/diagnóstico por imagem , Feminino , Géis/administração & dosagem , Géis/química , Soluções Hipotônicas/administração & dosagem , Soluções Hipotônicas/química , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Nanopartículas/química , Polímeros/administração & dosagem , Polímeros/química , Coelhos , Ratos Sprague-Dawley , Suínos
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