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1.
Mol Pharm ; 20(5): 2352-2361, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-37014806

RESUMEN

Current antibody (Ab) therapies require development of stable formulations and an optimal delivery system. Here, we present a new strategy to create a single-administration long-lasting Ab-delivery microarray (MA) patch, which can carry high doses of thermally stabilized Abs. The MA fabricated by an additive three-dimensional manufacturing technology can be fully embedded into the skin via a single application to deliver doses of Abs at multiple programmable time points, thus sustaining Ab concentrations in systemic circulation. We developed an MA formulation that stabilized and delivered human immunoglobulins (hIg) in a time-controlled manner while maintaining their structure and functionality. As an example, the b12 Ab─a broadly neutralizing Ab against HIV-1─maintained antiviral activity in vitro after MA manufacturing and heat exposure. Pharmacokinetic studies of MA patch-delivered hIg in rats successfully provided a proof of concept for concurrent and time-delayed Ab delivery. These MA patches codeliver different Abs, providing a tool for expanded protection against viral infections or combination HIV therapy and prevention.


Asunto(s)
Anticuerpos , Infecciones por VIH , Humanos , Ratas , Animales , Piel , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control
2.
Proc Natl Acad Sci U S A ; 117(1): 214-220, 2020 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-31871178

RESUMEN

Piezoelectric materials, a type of "smart" material that generates electricity while deforming and vice versa, have been used extensively for many important implantable medical devices such as sensors, transducers, and actuators. However, commonly utilized piezoelectric materials are either toxic or nondegradable. Thus, implanted devices employing these materials raise a significant concern in terms of safety issues and often require an invasive removal surgery, which can damage directly interfaced tissues/organs. Here, we present a strategy for materials processing, device assembly, and electronic integration to 1) create biodegradable and biocompatible piezoelectric PLLA [poly(l-lactic acid)] nanofibers with a highly controllable, efficient, and stable piezoelectric performance, and 2) demonstrate device applications of this nanomaterial, including a highly sensitive biodegradable pressure sensor for monitoring vital physiological pressures and a biodegradable ultrasonic transducer for blood-brain barrier opening that can be used to facilitate the delivery of drugs into the brain. These significant applications, which have not been achieved so far by conventional piezoelectric materials and bulk piezoelectric PLLA, demonstrate the PLLA nanofibers as a powerful material platform that offers a profound impact on various medical fields including drug delivery, tissue engineering, and implanted medical devices.


Asunto(s)
Implantes Absorbibles , Sistemas Microelectromecánicos/instrumentación , Nanofibras/química , Transductores , Sistemas de Liberación de Medicamentos , Electricidad , Electrónica , Diseño de Equipo , Monitoreo Fisiológico/instrumentación , Presión , Prótesis e Implantes , Ingeniería de Tejidos , Ultrasonido
3.
J Biol Chem ; 296: 100251, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33361107

RESUMEN

Poly-ADP-ribosyltransferases play a critical role in DNA repair and cell death, and poly(ADP-ribosyl) polymerase 1 (PARP1) is a particularly important therapeutic target for the treatment of breast cancer because of its synthetic lethal relationship with breast cancer susceptibility proteins 1 and 2. Numerous PARP1 inhibitors have been developed, and their efficacy in cancer treatment is attributed to both the inhibition of enzymatic activity and their ability to trap PARP1 on to the damaged DNA, which is cytotoxic. Of the clinical PARP inhibitors, talazoparib is the most effective at trapping PARP1 on damaged DNA. Biochemically, talazoparib is also suspected to be a potent inhibitor of PARP5a/b (tankyrase1/2 [TNKS1/2]), which is an important regulator of Wnt/ß-catenin pathway. Here we show using competition experiments in cell lysate that, at a clinically relevant concentration, talazoparib can potentially bind and engage TNKS1. Using surface plasmon resonance, we measured the dissociation constants of talazoparib, olaparib, niraparib, and veliparib for their interaction with PARP1 and TNKS1. The results show that talazoparib has strong affinity for PARP1 as well as uniquely strong affinity for TNKS1. Finally, we used crystallography and hydrogen deuterium exchange mass spectroscopy to dissect the molecular mechanism of differential selectivity of these PARP1 inhibitors. From these data, we conclude that subtle differences between the ligand-binding sites of PARP1 and TNKS1, differences in the electrostatic nature of the ligands, protein dynamics, and ligand conformational energetics contribute to the different pharmacology of these PARP1 inhibitors. These results will help in the design of drugs to treat Wnt/ß-catenin pathway-related cancers, such as colorectal cancers.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Poli(ADP-Ribosa) Polimerasa-1/genética , Tanquirasas/genética , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Sitios de Unión/efectos de los fármacos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Daño del ADN/efectos de los fármacos , Reparación del ADN/genética , Femenino , Humanos , Indazoles/farmacología , Ligandos , Ftalazinas/farmacología , Piperidinas/farmacología , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Vía de Señalización Wnt/efectos de los fármacos
4.
Sci Adv ; 9(24): eadg6075, 2023 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-37315129

RESUMEN

Amino acid crystals are an attractive piezoelectric material as they have an ultrahigh piezoelectric coefficient and have an appealing safety profile for medical implant applications. Unfortunately, solvent-cast films made from glycine crystals are brittle, quickly dissolve in body fluid, and lack crystal orientation control, reducing the overall piezoelectric effect. Here, we present a material processing strategy to create biodegradable, flexible, and piezoelectric nanofibers of glycine crystals embedded inside polycaprolactone (PCL). The glycine-PCL nanofiber film exhibits stable piezoelectric performance with a high ultrasound output of 334 kPa [under 0.15 voltage root-mean-square (Vrms)], which outperforms the state-of-the-art biodegradable transducers. We use this material to fabricate a biodegradable ultrasound transducer for facilitating the delivery of chemotherapeutic drug to the brain. The device remarkably enhances the animal survival time (twofold) in mice-bearing orthotopic glioblastoma models. The piezoelectric glycine-PCL presented here could offer an excellent platform not only for glioblastoma therapy but also for developing medical implantation fields.


Asunto(s)
Glioblastoma , Nanofibras , Animales , Ratones , Aminoácidos , Glicina , Encéfalo
5.
Drug Deliv Transl Res ; 12(11): 2613-2633, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35538189

RESUMEN

Gene therapy is a critical constituent of treatment approaches for genetic diseases and has gained tremendous attention. Treating and preventing diseases at the genetic level using genetic materials such as DNA or RNAs could be a new avenue in medicine. However, delivering genes is always a challenge as these molecules are sensitive to various enzymes inside the body, often produce systemic toxicity, and suffer from off-targeting problems. In this regard, transdermal delivery has emerged as an appealing approach to enable a high efficiency and low toxicity of genetic medicines. This review systematically summarizes outstanding transdermal gene delivery methods for applications in skin cancer treatment, vaccination, wound healing, and other therapies.


Asunto(s)
Sistemas de Liberación de Medicamentos , Agujas , Administración Cutánea , Sistemas de Liberación de Medicamentos/métodos , Terapia Genética/métodos , Piel
6.
Adv Mater Technol ; : 2200905, 2022 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-36714215

RESUMEN

The necessity for multiple injections and cold-chain storage has contributed to suboptimal vaccine utilization, especially in pandemic situations. Thermally-stable and single-administration vaccines hold a great potential to revolutionize the global immunization process. Here, a new approach to thermally stabilize protein-based antigens is presented and a new high-throughput antigen-loading process is devised to create a single-administration, pulsatile-release microneedle (MN) patch which can deliver a recombinant SARS-CoV-2 S1-RBD protein-a model for the COVID-19 vaccine. Nearly 100% of the protein antigen could be stabilized at temperatures up to 100 °C for at least 1 h and at an average human body temperature (37 °C) for up to 4 months. Arrays of the stabilized S1-RBD formulations can be loaded into the MN shells via a single-alignment assembly step. The fabricated MNs are administered at a single time into the skin of rats and induce antibody response which could neutralize authentic SARS-CoV-2 viruses, providing similar immunogenic effect to that induced by multiple bolus injections of the same antigen stored in conventional cold-chain conditions. The MN system presented herein could offer the key solution to global immunization campaigns by avoiding low patient compliance, the requirement for cold-chain storage, and the need for multiple booster injections.

7.
Sci Transl Med ; 14(627): eabi7282, 2022 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-35020409

RESUMEN

More than 32.5 million American adults suffer from osteoarthritis, and current treatments including pain medicines and anti-inflammatory drugs only alleviate symptoms but do not cure the disease. Here, we have demonstrated that a biodegradable piezoelectric poly(L-lactic acid) (PLLA) nanofiber scaffold under applied force or joint load could act as a battery-less electrical stimulator to promote chondrogenesis and cartilage regeneration. The PLLA scaffold under applied force or joint load generated a controllable piezoelectric charge, which promoted extracellular protein adsorption, facilitated cell migration or recruitment, induced endogenous TGF-ß via calcium signaling pathway, and improved chondrogenesis and cartilage regeneration both in vitro and in vivo. Rabbits with critical-sized osteochondral defects receiving the piezoelectric scaffold and exercise treatment experienced hyaline-cartilage regeneration and completely healed cartilage with abundant chondrocytes and type II collagen after 1 to 2 months of exercise (2 to 3 months after surgery including 1 month of recovery before exercise), whereas rabbits treated with nonpiezoelectric scaffold and exercise treatment had unfilled defect and limited healing. The approach of combining biodegradable piezoelectric tissue scaffolds with controlled mechanical activation (via physical exercise) may therefore be useful for the treatment of osteoarthritis and is potentially applicable to regenerating other injured tissues.


Asunto(s)
Cartílago Articular , Osteoartritis , Animales , Cartílago , Condrogénesis/fisiología , Osteoartritis/terapia , Conejos , Regeneración/fisiología , Ingeniería de Tejidos , Andamios del Tejido
8.
Nat Biomed Eng ; 5(9): 998-1007, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33230304

RESUMEN

Repeated bolus injections are associated with higher costs and poor compliance and can hinder the implementation of global immunization campaigns. Here, we report the development and preclinical testing of patches of transdermal core-shell microneedles-which were fabricated by the micromoulding and alignment of vaccine cores and shells made from poly(lactic-co-glycolic acid) with varying degradability kinetics-for the preprogrammed burst release of vaccine payloads over a period of a few days to more than a month from a single administration. In rats, microneedles loaded with a clinically available vaccine (Prevnar-13) against the bacterium Streptococcus pneumoniae induced immune responses that were similar to immune responses observed after multiple subcutaneous bolus injections, and led to immune protection against a lethal bacterial dose. Microneedle patches delivering preprogrammed doses may offer an alternative strategy to prophylactic and therapeutic protocols that require multiple injections.


Asunto(s)
Agujas , Vacunas , Administración Cutánea , Animales , Sistemas de Liberación de Medicamentos , Ratas , Vacunación
9.
Cancer Cell ; 39(10): 1404-1421.e11, 2021 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-34520734

RESUMEN

The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.


Asunto(s)
Ciclo Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Femenino , Humanos , Masculino , Neoplasias/inmunología
10.
Bioorg Med Chem Lett ; 20(24): 7429-34, 2010 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-21036042

RESUMEN

HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the ß-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series.


Asunto(s)
Inhibidores de Integrasa VIH/química , Integrasa de VIH/química , VIH-1/enzimología , Ácidos Hidroxámicos/química , Indoles/química , Administración Oral , Animales , Perros , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/toxicidad , Semivida , Hepatocitos/efectos de los fármacos , Humanos , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/toxicidad , Relación Estructura-Actividad
11.
J Med Chem ; 54(9): 3393-417, 2011 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-21446745

RESUMEN

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the synthesis of orally bioavailable azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. Here we disclose the design and synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones as potent, orally bioavailable HIV-1 integrase inhibitors displaying excellent ligand and lipophilic efficiencies.


Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , VIH-1/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Naftiridinas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Permeabilidad de la Membrana Celular , Células Cultivadas , Perros , Diseño de Fármacos , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/farmacología , VIH-1/enzimología , Hepatocitos/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Hígado/metabolismo , Conformación Molecular , Naftiridinas/farmacocinética , Naftiridinas/farmacología , Relación Estructura-Actividad
12.
J Med Chem ; 52(22): 7211-9, 2009 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-19873974

RESUMEN

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication. Recently, HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Herein, we report the discovery of azaindole carboxylic acids and azaindole hydroxamic acids as potent inhibitors of the HIV-1 IN enzyme and their structure-activity relationships. Several 4-fluorobenzyl substituted azaindole hydroxamic acids showed potent antiviral activities in cell-based assays and offered a structurally simple scaffold for the development of novel HIV-1 IN inhibitors.


Asunto(s)
Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , VIH-1/enzimología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores de Integrasa VIH/síntesis química , VIH-1/efectos de los fármacos , Ácidos Hidroxámicos/síntesis química , Concentración 50 Inhibidora , Ligandos , Magnesio/metabolismo , Picolinas/química
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