Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 58
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Sci Rep ; 9(1): 16099, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31695100

RESUMO

Traumatic brain injury (TBI) is a leading cause of injury-related death worldwide, yet there are no approved neuroprotective therapies that improve neurological outcome post-injury. Transient opening of the blood-brain barrier following injury provides an opportunity for passive accumulation of intravenously administered nanoparticles through an enhanced permeation and retention-like effect. However, a thorough understanding of physicochemical properties that promote optimal uptake and retention kinetics in TBI is still needed. In this study, we present a robust method for magnetic resonance imaging of nanoparticle uptake and retention kinetics following intravenous injection in a controlled cortical impact mouse model of TBI. Three contrast-enhancing nanoparticles with different hydrodynamic sizes and relaxivity properties were compared. Accumulation and retention were monitored by modelling the permeability coefficient, Ktrans, for each nanoparticle within the reproducible mouse model. Quantification of Ktrans for different nanoparticles allowed for non-invasive, multi-time point assessment of both accumulation and retention kinetics in the injured tissue. Using this method, we found that 80 nm poly(lactic-co-glycolic acid) nanoparticles had maximal Ktrans in a TBI when injected 3 hours post-injury, showing significantly higher accumulation kinetics than the small molecule, Gd-DTPA. This robust method will enable optimization of administration time and nanoparticle physicochemical properties to achieve maximum delivery.

2.
Mol Pharm ; 16(7): 2872-2883, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150251

RESUMO

Although the prognosis of patients with breast cancer continues to improve, breast cancer metastasis to bones remains high in incidence and challenging to manage. Here, we report the development of bone-homing alendronate (ALN)-anchored biodegradable polymeric micelles for the targeted treatment of metastatic cancer to bone. These micelles exhibited bone protective capacity including the recruitment, differentiation, and resorption activity of the osteoclasts. Encapsulation of docetaxel (DTX), the first-line chemotherapeutic for treatment of metastatic breast cancer, in ALN-modified micelles results in a sustained release, enhanced cytotoxicity, and improved pharmacokinetics. In the syngeneic animal model of late-stage disseminated breast cancer bone metastasis, the treatment with targeted DTX-loaded micelles attenuated the tumorigenesis and significantly improved animal lifespan compared to the conventional surfactant-based formulation (free DTX). These findings indicate potential applications of the osteotropic nanomedicines for bone metastasis treatment.

3.
J Control Release ; 306: 149-164, 2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31121280

RESUMO

Proteasome inhibitors (PIs) have markedly improved response rates as well as the survival of multiple myeloma (MM) patients over the past decade and have become an important foundation in the treatment of MM patients. Unfortunately, the majority of patients either relapses or becomes refractory to proteasome inhibition. This report describes that both PI sensitive and resistant MM cells display enhanced sensitivity to PI in the presence of synthetic amphiphilic block copolymers, Pluronics (SP1017). SP1017 effectively overcomes both acquired resistance and tumor microenvironment-mediated resistance to PIs. The combination of bortezomib and SP1017 augments accumulation of ubiquitinated proteins, increases markers of proteotoxic and ER stress, and ultimately induces both the intrinsic and extrinsic drug-induced apoptotic pathways in MM cells. Notably, co-treatment of bortezomib and SP1017 intensifies SP1017-induced disorganization of the Golgi complex and significantly reduces secretion of paraproteins. Using a human MM/SCID mice model, the combination of bortezomib and SP1017 exerted enhanced antitumor efficacy as compared to bortezomib alone, delaying disease progression, but without additional toxicity. Collectively, these findings provide proof of concept for the utility of combining PI with SP1017 and present a new approach to enhance the efficacy of current treatment options for MM patients.

4.
J Pharmacol Exp Ther ; 370(3): 682-694, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30796131

RESUMO

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer-related death in the United States, is highly aggressive and resistant to both chemo- and radiotherapy. It remains one of the most difficult-to-treat cancers, not only due to its unique pathobiological features such as stroma-rich desmoplastic tumors surrounded by hypovascular and hypoperfused vessels limiting the transport of therapeutic agents, but also due to problematic early detection, which renders most treatment options largely ineffective, resulting in extensive metastasis. To elevate therapeutic effectiveness of treatments and overt their toxicity, significant enthusiasm was generated to exploit new strategies for combating PDAC. Combination therapy targeting different barriers to mitigate delivery issues and reduce tumor recurrence and metastasis has demonstrated optimal outcomes in patients' survival and quality of life, providing possible approaches to overcome therapeutic challenges. This paper aims to provide an overview of currently explored multimodal therapies using either conventional therapy or nanomedicines along with rationale, up-to-date progress, as well as the key challenges that must be overcome. Understanding the future directions of the field may assist in the successful development of novel treatment strategies for enhancing therapeutic efficacy in PDAC.

5.
J Pharmacol Exp Ther ; 370(3): 894-901, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30683666

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. A combination of cisplatin (CDDP) and gemcitabine (Gem) treatment has shown favorable clinical results for metastatic disease; both are limited by toxicities and nontargeted delivery. More than 80% of PDAC aberrantly expresses the sialyl Tn (STn) antigen due to the loss of function of the core 1ß3-Gal-T-specific molecular chaperone, a specific chaperone for the activity of core 1 ß3-galactosyltransferase or C1GalT. Here, we report the development of polymeric nanogels (NGs) loaded with CDDP and coated with an anti-STn antigen-specific antibody (TKH2 monoclonal antibody) for the targeted treatment of PDAC. TKH2-functionalized, CDDP-loaded NGs delivered a significantly higher amount of platinum into the cells and tumors expressing STn antigens. We also confirmed that a synergistic cytotoxic effect of sequential exposure of pancreatic cancer cells to Gem followed by CDDP can be mimicked by the codelivery of CDDP-loaded NGs (NG/CDDP) and free Gem. In a murine orthotopic model of PDAC, combined simultaneous treatment with Gem and targeted NG/CDDP significantly attenuated tumor growth with no detectable acute toxicity. Altogether, these results suggest that combination therapy consisting of Gem followed by TKH2-conjugated CDDP NGs induces highly synergistic therapeutic efficacy against pancreatic cancer. Our results offer the basis for development of combination drug regimens using targeted nanomedicines to increase treatment effectiveness and improve outcomes of PDAC therapy.

6.
Adv Drug Deliv Rev ; 148: 252-289, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30421721

RESUMO

The discipline of neurotheranostics was forged to improve diagnostic and therapeutic clinical outcomes for neurological disorders. Research was facilitated, in largest measure, by the creation of pharmacologically effective multimodal pharmaceutical formulations. Deployment of neurotheranostic agents could revolutionize staging and improve nervous system disease therapeutic outcomes. However, obstacles in formulation design, drug loading and payload delivery still remain. These will certainly be aided by multidisciplinary basic research and clinical teams with pharmacology, nanotechnology, neuroscience and pharmaceutic expertise. When successful the end results will provide "optimal" therapeutic delivery platforms. The current report reviews an extensive body of knowledge of the natural history, epidemiology, pathogenesis and therapeutics of neurologic disease with an eye on how, when and under what circumstances neurotheranostics will soon be used as personalized medicines for a broad range of neurodegenerative, neuroinflammatory and neuroinfectious diseases.

7.
ACS Nano ; 12(8): 7663-7681, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-29965725

RESUMO

Nephritis is one of the major complications of systemic lupus erythematosus. While glucocorticoids (GCs) are frequently used as the first-line treatment for lupus nephritis (LN), long-term GC usage is often complicated by severe adverse effects. To address this challenge, we have developed a polyethylene glycol-based macromolecular prodrug (ZSJ-0228) of dexamethasone, which self-assembles into micelles in aqueous media. When compared to the dose equivalent daily dexamethasone 21-phosphate disodium (Dex) treatment, monthly intravenous administration of ZSJ-0228 for two months significantly improved the survival of lupus-prone NZB/W F1 mice and was much more effective in normalizing proteinuria, with clear histological evidence of nephritis resolution. Different from the dose equivalent daily Dex treatment, monthly ZSJ-0228 administration has no impact on the serum anti-double-stranded DNA (anti-dsDNA) antibody level but can significantly reduce renal immune complex deposition. No significant systemic toxicities of GCs ( e. g., total IgG reduction, adrenal gland atrophy, and osteopenia) were found to be associated with ZSJ-0228 treatment. In vivo imaging and flow cytometry studies revealed that the fluorescent-labeled ZSJ-0228 primarily distributed to the inflamed kidney after systemic administration, with renal myeloid cells and proximal tubular epithelial cells mainly responsible for its kidney retention. Collectively, these data suggest that the ZSJ-0228's potent local anti-inflammatory/immunosuppressive effects and improved safety may be attributed to its nephrotropicity and cellular sequestration at the inflamed kidney tissues. Pending further optimization, it may be developed into an effective and safe therapy for improved clinical management of LN.


Assuntos
Dexametasona/farmacologia , Glucocorticoides/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/tratamento farmacológico , Micelas , Pró-Fármacos/farmacologia , Animais , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/química , Modelos Animais de Doenças , Feminino , Glucocorticoides/efeitos adversos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos NZB , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química
8.
Theranostics ; 8(1): 256-276, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29290806

RESUMO

RATIONALE: Long-acting slow effective release antiretroviral therapy (LASER ART) was developed to improve patient regimen adherence, prevent new infections, and facilitate drug delivery to human immunodeficiency virus cell and tissue reservoirs. In an effort to facilitate LASER ART development, "multimodal imaging theranostic nanoprobes" were created. These allow combined bioimaging, drug pharmacokinetics and tissue biodistribution tests in animal models. METHODS: Europium (Eu3+)- doped cobalt ferrite (CF) dolutegravir (DTG)- loaded (EuCF-DTG) nanoparticles were synthesized then fully characterized based on their size, shape and stability. These were then used as platforms for nanoformulated drug biodistribution. RESULTS: Folic acid (FA) decoration of EuCF-DTG (FA-EuCF-DTG) nanoparticles facilitated macrophage targeting and sped drug entry across cell barriers. Macrophage uptake was higher for FA-EuCF-DTG than EuCF-DTG nanoparticles with relaxivities of r2 = 546 mM-1s-1 and r2 = 564 mM-1s-1 in saline, and r2 = 850 mM-1s-1 and r2 = 876 mM-1s-1 in cells, respectively. The values were ten or more times higher than what was observed for ultrasmall superparamagnetic iron oxide particles (r2 = 31.15 mM-1s-1 in saline) using identical iron concentrations. Drug particles were detected in macrophage Rab compartments by dual fluorescence labeling. Replicate particles elicited sustained antiretroviral responses. After parenteral injection of FA-EuCF-DTG and EuCF-DTG into rats and rhesus macaques, drug, iron and cobalt levels, measured by LC-MS/MS, magnetic resonance imaging, and ICP-MS were coordinate. CONCLUSION: We posit that these theranostic nanoprobes can assess LASER ART drug delivery and be used as part of a precision nanomedicine therapeutic strategy.


Assuntos
Imagem por Ressonância Magnética/métodos , Imagem Multimodal/métodos , Nanomedicina Teranóstica/métodos , Animais , Sistemas de Liberação de Medicamentos/métodos , Európio/química , Európio/farmacocinética , Ácido Fólico/química , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Macaca mulatta , Macrófagos/metabolismo , Microscopia Confocal , Nanopartículas/química
10.
Oncotarget ; 7(9): 10522-35, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26859680

RESUMO

Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance receptor endocytosis and lysosomal routing can provide a novel strategy to significantly improve therapy with ANPs and ADCs.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Imunoconjugados/farmacologia , Maitansina/análogos & derivados , Receptor ErbB-2/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Maitansina/farmacologia , Camundongos , Camundongos Nus , Nanopartículas , Trastuzumab , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Control Release ; 240: 109-126, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-26571000

RESUMO

Nanogels have emerged as a versatile hydrophilic platform for encapsulation of guest molecules with a capability to respond to external stimuli that can be used for a multitude of applications. These are soft materials capable of holding small molecular therapeutics, biomacromolecules, and inorganic nanoparticles within their crosslinked networks, which allows them to find applications for therapy as well as imaging of a variety of disease conditions. Their stimuli-responsive behavior can be easily controlled by selection of constituent polymer and crosslinker components to achieve a desired response at the site of action, which imparts nanogels the ability to participate actively in the intended function of the carrier system rather than being passive carriers of their cargo. These properties not only enhance the functionality of the carrier system but also help in overcoming many of the challenges associated with the delivery of cargo molecules, and this review aims to highlight the distinct and unique capabilities of nanogels as carrier systems for the delivery of an array of cargo molecules over other nanomaterials. Despite their obvious usefulness, nanogels are still not a commonplace occurrence in clinical practice. We have also made an attempt to highlight some of the major challenges that need to be overcome to advance nanogels further in the field of biomedical applications.


Assuntos
Tecnologia Biomédica/métodos , Sistemas de Liberação de Medicamentos/métodos , Polietilenoglicóis/química , Polietilenoimina/química , Animais , Tecnologia Biomédica/tendências , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Humanos , Polietilenoglicóis/administração & dosagem , Polietilenoimina/administração & dosagem
12.
Ther Deliv ; 6(11): 1279-96, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26599420

RESUMO

During the last decades increasing attention has been paid to peptides as potential therapeutics. However, clinical applications of peptide drugs suffer from susceptibility to degradation, rather short circulation half-life, limited ability to cross physiological barriers and potential immunogenicity. These challenges can be addressed by using polymeric materials as peptide delivery systems, owing to their versatile structures and properties. A number of polymer-based vehicles have been developed to stabilize the peptides and to control their release rates. Unfortunately, no single polymer or formulation strategy has been considered ideal for all types of peptide drugs. In this review, currently used and potential polymer-based systems for the peptide delivery will be discussed.


Assuntos
Química Farmacêutica , Sistemas de Liberação de Medicamentos/métodos , Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Polímeros/administração & dosagem , Polímeros/química , Humanos
13.
J Control Release ; 220(Pt B): 651-9, 2015 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-26381902

RESUMO

Biodegradable polypeptide-based nanogels have been developed from amphiphilic block copolymers, poly(ethylene glycol)-b-poly(L-glutamic acid)-b-poly(L-phenylalanine), which effectively co-incorporate cisplatin and paclitaxel, the clinically used drug combination for the treatment of advanced ovarian cancer. In order to target both drugs selectively to the tumor cells, we explored the benefits of ligand-mediated drug delivery by targeting folate receptors, which are overexpressed in most ovarian cancers. Drug-loaded nanogels were surface-functionalized with folic acid (FA) with the help of a PEG spacer without affecting the ligand binding affinity and maintaining the stability of the carrier system. FA-decorated nanogels significantly suppressed the growth of intraperitoneal ovarian tumor xenografts outperforming their nontargeted counterparts without extending their cytotoxicity to the normal tissues. We also confirmed that synchronized co-delivery of the platinum-taxane drug combination via single carrier to the same targeted cells is more advantageous than a combination of targeted single drug formulations administered at the same drug ratio. Lastly, we demonstrated that the same platform can also be used for localized chemotherapy. Our data indicate that intraperitoneal administration can be more effective in the context of targeted combination therapy. Our findings suggest that multifunctional nanogels are promising drug delivery carriers for improvement of current treatment for ovarian cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Portadores de Fármacos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Polímeros/química , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/química , Linhagem Celular Tumoral , Química Farmacêutica , Cisplatino/química , Feminino , Ácido Fólico/química , Ácido Fólico/metabolismo , Transportadores de Ácido Fólico/metabolismo , Géis , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Camundongos Nus , Nanopartículas , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Paclitaxel/química , Peptídeos/química , Polietilenoglicóis/química , Ácido Poliglutâmico/química , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Biomaterials ; 70: 37-47, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26298393

RESUMO

Great success in HCV therapy was achieved by the development of direct-acting antivirals (DAA). However, the unsolved issues such as high cost and genotype dependency drive us to pursue additional therapeutic agents to be used instead or in combination with DAA. The cationic peptide p41 is one of such candidates displaying submicromolar anti-HCV potency. By electrostatic coupling of p41 with anionic poly(amino acid)-based block copolymers, antiviral peptide nanocomplexes (APN) platform was developed to improve peptide stability and to reduce cytotoxicity associated with positive charge. Herein, we developed a facile method to prepare galactosylated Gal-APN and tested their feasibility as liver-specific delivery system. In vitro, Gal-APN displayed specific internalization in hepatoma cell lines. Even though liver-targeted and non-targeted APN displayed comparable antiviral activity, Gal-APN offered prominent advantages to prevent HCV association with lipid droplets and suppress intracellular expression of HCV proteins. Moreover, in vivo preferential liver accumulation of Gal-APN was revealed in the biodistribution study. Altogether, this work illustrates the potential of Gal-APN as a novel liver-targeted therapy against HCV.


Assuntos
Antivirais/uso terapêutico , Sistemas de Liberação de Medicamentos , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Fígado/metabolismo , Nanopartículas/química , Peptídeos/uso terapêutico , Sequência de Aminoácidos , Animais , Antivirais/farmacologia , Linhagem Celular Tumoral , Cromatografia em Gel , Química Click , Galactose/química , Humanos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/farmacologia , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polimerização , Espectroscopia de Prótons por Ressonância Magnética , Distribuição Tecidual/efeitos dos fármacos
15.
Int J Nanomedicine ; 10: 3779-90, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26082630

RESUMO

Regimen adherence, systemic toxicities, and limited drug penetrance to viral reservoirs are obstacles limiting the effectiveness of antiretroviral therapy (ART). Our laboratory's development of the monocyte-macrophage-targeted long-acting nanoformulated ART (nanoART) carriage provides a novel opportunity to simplify drug-dosing regimens. Progress has nonetheless been slowed by cumbersome, but required, pharmacokinetic (PK), pharmacodynamics, and biodistribution testing. To this end, we developed a small magnetite ART (SMART) nanoparticle platform to assess antiretroviral drug tissue biodistribution and PK using magnetic resonance imaging (MRI) scans. Herein, we have taken this technique a significant step further by determining nanoART PK with folic acid (FA) decorated magnetite (ultrasmall superparamagnetic iron oxide [USPIO]) particles and by using SMART particles. FA nanoparticles enhanced the entry and particle retention to the reticuloendothelial system over nondecorated polymers after systemic administration into mice. These data were seen by MRI testing and validated by comparison with SMART particles and direct evaluation of tissue drug levels after nanoART. The development of alendronate (ALN)-coated magnetite thus serves as a rapid initial screen for the ability of targeting ligands to enhance nanoparticle-antiretroviral drug biodistribution, underscoring the value of decorated magnetite particles as a theranostic tool for improved drug delivery.


Assuntos
Antirretrovirais/farmacocinética , Imagem por Ressonância Magnética/métodos , Nanopartículas de Magnetita , Alendronato/química , Animais , Sulfato de Atazanavir/farmacocinética , Dextranos , Sistemas de Liberação de Medicamentos/métodos , Ácido Fólico/química , Ácido Fólico/farmacocinética , Macrófagos/efeitos dos fármacos , Nanopartículas de Magnetita/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular/métodos , Sistema Fagocitário Mononuclear/efeitos dos fármacos , Nanomedicina/métodos , Reprodutibilidade dos Testes , Distribuição Tecidual
16.
J Control Release ; 208: 59-66, 2015 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-25660204

RESUMO

ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin™; Genentech), with chemotherapy is the current standard of treatment. Novel agents and strategies continue to be explored, given the challenges posed by Trastuzumab-resistance development in most patients. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which induces ErbB2 degradation and attenuates downstream oncogenic signaling, is one such agent that showed significant promise in early phase I and II clinical trials. Its low water solubility, potential toxicities and undesirable side effects observed in patients, partly due to the Cremophor-based formulation, have been discouraging factors in the advancement of this promising drug into clinical use. Encapsulation of 17-AAG into polymeric nanoparticle formulations, particularly in synergistic combination with conventional chemotherapeutics, represents an alternative approach to overcome these problems. Herein, we report an efficient co-encapsulation of 17-AAG and doxorubicin, a clinically well-established and effective modality in breast cancer treatment, into biodegradable and biocompatible polypeptide-based nanogels. Dual drug-loaded nanogels displayed potent cytotoxicity in a breast cancer cell panel and exerted selective synergistic anticancer activity against ErbB2-overexpressing breast cancer cell lines. Analysis of ErbB2 degradation confirmed efficient 17-AAG release from nanogels with activity comparable to free 17-AAG. Furthermore, nanogels containing both 17-AAG and doxorubicin exhibited superior antitumor efficacy in vivo in an ErbB2-driven xenograft model compared to the combination of free drugs. These studies demonstrate that polypeptide-based nanogels can serve as novel nanocarriers for encapsulating 17-AAG along with other chemotherapeutics, providing an opportunity to overcome solubility issues and thereby exploit its full potential as an anti-cancer agent.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Benzoquinonas/administração & dosagem , Benzoquinonas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Lactamas Macrocíclicas/administração & dosagem , Lactamas Macrocíclicas/farmacologia , Nanoestruturas/química , Receptor ErbB-2/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica , Composição de Medicamentos , Sinergismo Farmacológico , Feminino , Géis , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Am J Pathol ; 184(1): 101-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24200850

RESUMO

Human-specific HIV-1 and hepatitis co-infections significantly affect patient management and call for new therapeutic options. Small xenotransplantation models with human hepatocytes and hematolymphoid tissue should facilitate antiviral/antiretroviral drug trials. However, experience with mouse strains tested for dual reconstitution is limited, with technical difficulties such as risky manipulations with newborns and high mortality rates due to metabolic abnormalities. The best animal strains for hepatocyte transplantation are not optimal for human hematopoietic stem cell (HSC) engraftment, and vice versa. We evaluated a new strain of highly immunodeficient nonobese diabetic/Shi-scid (severe combined immunodeficiency)/IL-2Rγc(null) (NOG) mice that carry two copies of the mouse albumin promoter-driven urokinase-type plasminogen activator transgene for dual reconstitution with human liver and immune cells. Three approaches for dual reconstitution were evaluated: i) freshly isolated fetal hepatoblasts were injected intrasplenically, followed by transplantation of cryopreserved HSCs obtained from the same tissue samples 1 month later after treosulfan conditioning; ii) treosulfan conditioning is followed by intrasplenic simultaneous transplantation of fetal hepatoblasts and HSCs; and iii) transplantation of mature hepatocytes is followed by mismatched HSCs. The long-term dual reconstitution was achieved on urokinase-type plasminogen activator-NOG mice with mature hepatocytes (not fetal hepatoblasts) and HSCs. Even major histocompatibility complex mismatched transplantation was sustained without any evidence of hepatocyte rejection by the human immune system.


Assuntos
Coinfecção , Modelos Animais de Doenças , Transplante de Células-Tronco Hematopoéticas/métodos , Hepatócitos/transplante , Animais , Antineoplásicos Alquilantes/farmacologia , Bussulfano/análogos & derivados , Bussulfano/farmacologia , Infecções por HIV , Hepatite C , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Transgenes , Ativador de Plasminogênio Tipo Uroquinase/genética
18.
Adv Drug Deliv Rev ; 65(13-14): 1667-85, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24113520

RESUMO

Platinum based anticancer drugs have revolutionized cancer chemotherapy, and continue to be in widespread clinical use especially for management of tumors of the ovary, testes, and the head and neck. However, several dose limiting toxicities associated with platinum drug use, partial anti-tumor response in most patients, development of drug resistance, tumor relapse, and many other challenges have severely limited the patient quality of life. These limitations have motivated an extensive research effort towards development of new strategies for improving platinum therapy. Nanocarrier-based delivery of platinum compounds is one such area of intense research effort beginning to provide encouraging preclinical and clinical results and may allow the development of the next generation of platinum chemotherapy. This review highlights current understanding on the pharmacology and limitations of platinum compounds in clinical use, and provides a comprehensive analysis of various platinum-polymer complexes, micelles, dendrimers, liposomes and other nanoparticles currently under investigation for delivery of platinum drugs.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Resistencia a Medicamentos Antineoplásicos , Nanopartículas/química , Compostos Organoplatínicos/administração & dosagem , Compostos de Platina/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Estrutura Molecular , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacocinética , Compostos Organoplatínicos/uso terapêutico , Compostos de Platina/química , Compostos de Platina/farmacocinética , Compostos de Platina/uso terapêutico
19.
J Drug Target ; 21(10): 981-93, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23998716

RESUMO

Polymer nanogels have gained considerable attention as a potential platform for drug delivery applications. Here we describe the design and synthesis of novel polypeptide-based nanogels with hydrophobic moieties in the cross-linked ionic cores. Diblock copolymer, poly(ethylene glycol)-b-poly(L-glutamic acid), hydrophobically modified with L-phenylalanine methyl ester moieties was used for controlled template synthesis of nanogels with small size (ca. 70 nm in diameter) and narrow particle size distribution. Steady-state and time-resolved fluorescence studies using coumarin C153 indicated the existence of hydrophobic domains in the ionic cores of the nanogels. Stable doxorubicin-loaded nanogels were prepared at high drug capacity (30 w/w%). We show that nanogels are enzymatically-degradable leading to accelerated drug release under simulated lysosomal acidic pH. Furthermore, we demonstrate that the nanogel-based formulation of doxorubicin is well tolerated and exhibit an improved antitumor activity compared to a free doxorubicin in an ovarian tumor xenograft mouse model. Our results signify the point to a potential of these biodegradable nanogels as attractive carriers for delivery of chemotherapeutics.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/toxicidade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Reagentes para Ligações Cruzadas/química , Doxorrubicina/farmacologia , Doxorrubicina/toxicidade , Portadores de Fármacos/química , Feminino , Géis , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Camundongos , Nanopartículas , Neoplasias Ovarianas/patologia , Tamanho da Partícula , Fenilalanina/análogos & derivados , Fenilalanina/química , Polietilenoglicóis/química , Ácido Poliglutâmico/química , Polímeros/química , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Mol Pharm ; 10(10): 3913-21, 2013 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-23957812

RESUMO

Targeted drug delivery using multifunctional polymeric nanocarriers is a modern approach for cancer therapy. Our purpose was to prepare targeted nanogels for selective delivery of chemotherapeutic agent cisplatin to luteinizing hormone-releasing hormone (LHRH) receptor overexpressing tumor in vivo. Building blocks of such delivery systems consisted of innovative soft block copolymer nanogels with ionic cores serving as a reservoir for cisplatin (loading 35%) and a synthetic analogue of LHRH conjugated to the nanogels via poly(ethylene glycol) spacer. Covalent attachment of (D-Lys6)-LHRH to nanogels was shown to be possible without loss in either the ligand binding affinity or the nanogel drug incorporation ability. LHRH-nanogel accumulation was specific to the LHRH-receptor positive A2780 ovarian cancer cells and not toward LHRH-receptor negative SKOV-3 cells. The LHRH-nanogel cisplatin formulation was more effective and less toxic than equimolar doses of free cisplatin or untargeted nanogels in the treatment of receptor-positive ovarian cancer xenografts in mice. Collectively, the study indicates that LHRH mediated nanogel-cisplatin delivery is a promising formulation strategy for therapy of tumors that express the LHRH receptor.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Cisplatino/administração & dosagem , Cisplatino/química , Neoplasias Ovarianas/tratamento farmacológico , Polietilenoglicóis/química , Polietilenoimina/química , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Feminino , Citometria de Fluxo , Humanos , Camundongos Nus , Microscopia Confocal , Nanopartículas/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA