Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Nanoscale ; 12(21): 11672-11683, 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32436925

RESUMO

B cell malignancies, such as B cell leukemia and lymphoma, have CD22 overexpression with ∼7% of patients. A short CD22 binding peptide (PV3) with a moderate affinity (Kd ∼ 9 µM) was identified by screening multiple peptide candidates determined through analysis of CD22-epratuzumab complex crystal structure. PV3 binding specificity was confirmed via competitive binding inhibition, then was used as the targeting moiety on CD22-targeted liposomal nanoparticle (TNPPV3) formulations. To maximize the potential therapeutic outcome of TNPPV3 formulation, nanoparticle design parameters, such as peptide hydrophilicity, ethylene glycol linker length, valency, and particle size were optimized for maximum selective cellular uptake by CD22+ malignant cancer cells. The effects of altering design parameters one at a time on TNP uptake were evaluated using flow cytometry, and the optimal parameters for TNPPV3 were determined to be 8% peptide density, EG18 linker, and 3 lysines of 100 nm nanoparticles. This optimally designed TNPPV3 achieved ∼4 and 40-fold enhancement of cellular uptake by CD22+ Raji cells over CD22- Jurkat and MOLT-4 cells, respectively, demonstrating selectivity for malignant cells with CD22 overexpression. Overall, this study establishes PV3 to be CD22 binding peptide with proven effectiveness as a targeting element. In future, the optimal TNPPV3 formulation will potentially achieve maximal in vivo therapeutic outcomes by efficiently targeting CD22+ blood cancer cells in vivo.


Assuntos
Linfoma de Células B/metabolismo , Nanopartículas/metabolismo , Peptídeos/metabolismo , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Desenho de Fármacos , Endocitose , Humanos , Lipossomos/química , Lipossomos/metabolismo , Linfoma de Células B/patologia , Nanopartículas/química , Peptídeos/química
2.
J Hematol Oncol ; 13(1): 145, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33138841

RESUMO

BACKGROUND: Drug-loaded nanoparticles have established their benefits in the fight against multiple myeloma; however, ligand-targeted nanomedicine has yet to successfully translate to the clinic due to insufficient efficacies reported in preclinical studies. METHODS: In this study, liposomal nanoparticles targeting multiple myeloma via CD38 or CD138 receptors are prepared from pre-synthesized, purified constituents to ensure increased consistency over standard synthetic methods. These nanoparticles are then tested both in vitro for uptake to cancer cells and in vivo for accumulation at the tumor site and uptake to tumor cells. Finally, drug-loaded nanoparticles are tested for long-term efficacy in a month-long in vivo study by tracking tumor size and mouse health. RESULTS: The targeted nanoparticles are first optimized in vitro and show increased uptake and cytotoxicity over nontargeted nanoparticles, with CD138-targeting showing superior enhancement over CD38-targeted nanoparticles. However, biodistribution and tumor suppression studies established CD38-targeted nanoparticles to have significantly increased in vivo tumor accumulation, tumor cell uptake, and tumor suppression over both nontargeted and CD138-targeted nanoparticles due to the latter's poor selectivity. CONCLUSION: These results both highlight a promising cancer treatment option in CD38-targeted nanoparticles and emphasize that targeting success in vitro does not necessarily translate to success in vivo.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Lipossomos/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Sindecana-1/metabolismo , ADP-Ribosil Ciclase 1/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Humanos , Lipossomos/química , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Simulação de Acoplamento Molecular , Mieloma Múltiplo/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Sindecana-1/química , Distribuição Tecidual
3.
Nanoscale ; 11(10): 4414-4427, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30801591

RESUMO

Targeted liposomal nanoparticles are commonly used drug delivery vehicles for targeting cancer cells that overexpress a particular cell surface receptor. However, typical target receptors are also expressed at variable levels in healthy tissue, leading to non-selective targeting and systemic toxicity. Here, we demonstrated that the selectivity of peptide-targeted liposomes for their target cells can be significantly enhanced by employing a dual-receptor targeted approach to simultaneously target multiple tumor cell surface receptors. The dual-receptor targeted approach can be tuned to create cooperativity in binding only for the cancer cells, therefore leaving the healthy cells and tissue unharmed. We evaluated this strategy in a multiple myeloma disease model where the liposomes were functionalized with two distinct peptide antagonists to target VLA-4 and LPAM-1, two receptors with increasing relevance in multiple myeloma. By employing a multifaceted strategy to synthesize dual-receptor targeted liposomes with high purity, reproducibility, and precisely controlled stoichiometry of functionalities, we identified optimal design parameters for enhanced selectivity via systematic analysis. Through control of the liposomal formulation and valency of each targeting peptide, we identified that the optimal dual-receptor targeted liposome consisted of a peptide density of 0.75% VLA4pep and 1% LPAM1pep, resulting in an 8-fold and 12-fold increased cellular uptake over VLA-4 and LPAM-1 single targeted liposomes respectively. This formulation resulted in a cooperative ratio of 4.3 and enhanced uptake for myeloma cells that simultaneously express both VLA-4 and LPAM-1 receptors, but displayed no increase in uptake for cells that express only one or neither of the receptors, resulting in a 28-fold selectivity of the dual-targeted liposomes for cells displaying both targeted receptors over cells displaying neither receptor. These results demonstrated that through refined design and well-characterized nanoparticle formulations, dual-receptor targeted liposomes have the potential to improve cancer therapy by providing enhanced selectivity over conventional single-receptor targeted approaches.


Assuntos
Integrina alfa4beta1 , Integrinas , Nanopartículas , Proteínas de Neoplasias , Neoplasias , Peptídeos , Humanos , Integrina alfa4beta1/antagonistas & inibidores , Integrina alfa4beta1/metabolismo , Integrinas/antagonistas & inibidores , Integrinas/metabolismo , Células Jurkat , Lipossomos , Nanopartículas/química , Nanopartículas/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Peptídeos/química , Peptídeos/farmacologia
4.
J Control Release ; 311-312: 190-200, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31473250

RESUMO

Despite ligand-targeted liposomes long garnering interest as drug delivery vehicles for cancer therapeutics, inconsistency in successful outcomes have hindered their translation into the clinic. This is in part due to discrepancies between in vitro design evaluations and final in vivo outcomes. By employing a multifaceted synthetic strategy to prepare peptide-targeted nanoparticles of high purity, reproducibility, and with precisely controlled quantity of functionalities, we systematically evaluated the individual roles that peptide-linker length, peptide hydrophilicity, peptide density, and nanoparticle size play on cancer cell uptake and tumor targeting both in vitro and in vivo, and how the results correlated and contrasted. These parameters were analyzed using a VLA-4-targeted liposome system in a multiple myeloma mouse xenograft model to evaluate in vivo biodistribution and tumor cell uptake. The results showed that using in vitro models to optimize targeted-nanoparticles for maximum cellular uptake was helpful in narrowing down the particle characteristics. However, in vitro optimization fell short of achieving enhanced results in animal models, rather had negative consequences for in vivo targeting. This outcome is not surprising considering that the receptor being targeted is also present on healthy lymphocytes and increasing targeting peptide valency on particle surfaces results in an increase in non-selective, off-target binding to healthy cells. Hence, further optimization using in vivo models was absolutely necessary, through which we were able to increase the uptake of peptide-targeted liposomes by cancerous cells overexpressing VLA-4 to 15-fold over that of non-targeted liposomes in vivo. The results highlighted the importance of creating a comprehensive understanding of the effect of each liposome design parameter on multifactorial biological endpoints including both in vitro and in vivo in determining the therapeutic potential of peptide-targeted liposomes.


Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Nanopartículas/administração & dosagem , Peptídeos/administração & dosagem , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Lipossomos , Camundongos SCID , Mieloma Múltiplo/metabolismo , Nanopartículas/química , Peptídeos/química
5.
Mol Cancer Ther ; 15(7): 1452-9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27196779

RESUMO

Here, we report the synthesis and evaluation of dual drug-loaded nanoparticles as an effective means to deliver carfilzomib and doxorubicin to multiple myeloma tumor cells at their optimal synergistic ratio. First, various molar ratios of carfilzomib to doxorubicin were screened against multiple myeloma cell lines to determine the molar ratio that elicited the greatest synergy using the Chou-Talalay method. The therapeutic agents were then incorporated into liposomes at the optimal synergistic ratio of 1:1 to yield dual drug-loaded nanoparticles with a narrow size range of 115 nm and high reproducibility. Our results demonstrated that the dual drug-loaded liposomes exhibited synergy in vitro and were more efficacious in inhibiting tumor growth in vivo than a combination of free drugs, while at the same time reducing systemic toxicity. Taken together, this study presents the synthesis and preclinical evaluation of dual drug-loaded liposomes containing carfilzomib and doxorubicin for enhanced therapeutic efficacy to improve patient outcome in multiple myeloma. Mol Cancer Ther; 15(7); 1452-9. ©2016 AACR.


Assuntos
Doxorrubicina/administração & dosagem , Lipossomos , Nanopartículas , Oligopeptídeos/administração & dosagem , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Doxorrubicina/química , Combinação de Medicamentos , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Lipossomos/química , Camundongos , Estrutura Molecular , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Nanopartículas/química , Oligopeptídeos/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Biomed Nanotechnol ; 11(8): 1418-30, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26295142

RESUMO

Ligand-targeted liposomes are increasingly used as drug delivery carriers for cancer therapy, yet have not consistently produced successful outcomes. Here, we demonstrated the significant enhancement in cellular uptake of peptide-targeted liposomes by simultaneously increasing the hydrophilicity of the targeting peptide, optimizing the EG peptide-linker length, and using appropriate peptide surface density. We analyzed these parameters in a HER2-overexpressing breast cancer model system where the liposomes were functionalized with one of four distinct HER2-antagonist peptides to evaluate cellular uptake. Our results demonstrated that including a short oligolysine chain adjacent to the targeting peptide sequence effectively improved cellular uptake -6-10 fold when using an EG6-EG18 linker depending on the selected antagonist peptide. Uptake efficiency reached a maximum and a plateau with -2% peptide density with higher observed sensitivity at lower peptide densities for the more hydrophilic peptides. Taken together, these findings demonstrated the importance of optimizing liposome design for improved cellular uptake.


Assuntos
Neoplasias da Mama/metabolismo , Lipossomos/química , Nanocápsulas/química , Peptídeos/farmacocinética , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Receptor ErbB-2/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Reagentes de Ligações Cruzadas/química , Etilenoglicol/química , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Teste de Materiais , Nanocápsulas/ultraestrutura , Tamanho da Partícula , Peptídeos/química
7.
Trends Biotechnol ; 32(1): 32-45, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24210498

RESUMO

Nanomedicine, particularly liposomal drug delivery, has expanded considerably over the past few decades, and several liposomal drugs are already providing improved clinical outcomes. Liposomes have now progressed beyond simple, inert drug carriers and can be designed to be highly responsive in vivo, with active targeting, increased stealth, and controlled drug-release properties. Ligand-targeted liposomes (LTLs) have the potential to revolutionize the treatment of cancer. However, these highly engineered liposomes generate new problems, such as accelerated clearance from circulation, compromised targeting owing to non-specific serum protein binding, and hindered tumor penetration. This article highlights recent challenges facing LTL strategies and describes the advanced design elements used to circumvent them.


Assuntos
Biotecnologia , Sistemas de Liberação de Medicamentos , Lipossomos , Nanomedicina , Animais , Antineoplásicos , Linhagem Celular Tumoral , Humanos , Ligantes , Camundongos
8.
J Med Chem ; 57(12): 5282-92, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24897555

RESUMO

In this study, we describe the development of liposomal bortezomib nanoparticles, which was accomplished by synthesizing bortezomib prodrugs with reversible boronic ester bonds and then incorporating the resulting prodrugs into the nanoparticles via surface conjugation. Initially, several prodrug candidates were screened based upon boronic ester stability using isobutylboronic acid as a model boronic acid compound. The two most stable candidates were then selected to create surface conjugated bortezomib prodrugs on the liposomes. Our strategy yielded stable liposomal bortezomib nanoparticles with a narrow size range of 100 nm and with high reproducibility. These liposomal bortezomib nanoparticles demonstrated significant proteasome inhibition and cytotoxicity against multiple myeloma cell lines in vitro and remarkable tumor growth inhibition with reduced systemic toxicity compared to free bortezomib in vivo. Taken together, this study demonstrates the incorporation of bortezomib into liposomal nanoparticles via reversible boronic ester bond formation to enhance the therapeutic index for improved patient outcome.


Assuntos
Antineoplásicos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Pró-Fármacos/administração & dosagem , Pirazinas/administração & dosagem , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Bortezomib , Linhagem Celular Tumoral , Ésteres , Humanos , Lipossomos , Camundongos SCID , Mieloma Múltiplo/tratamento farmacológico , Nanopartículas , Transplante de Neoplasias , Pró-Fármacos/síntese química , Pró-Fármacos/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirazinas/síntese química , Pirazinas/química
9.
J Control Release ; 196: 113-21, 2014 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-25312543

RESUMO

Carfilzomib, a recently FDA-approved proteasome inhibitor, has remarkable anti-myeloma (MM) activity. However, its effectiveness is limited by associated severe side-effects, short circulation half-life, and limited solubility. Here, we report the engineering of liposomal carfilzomib nanoparticles to overcome these problems and enhance the therapeutic efficacy of carfilzomib by increasing tumoral drug accumulation while decreasing systemic toxicity. In our design, carfilzomib was loaded into the bilayer of liposomes to yield stable and reproducible liposomal nanoparticles. Liposomal carfilzomib nanoparticles were efficiently taken up by MM cells, demonstrated proteasome inhibition, induced apoptosis, and exhibited enhanced cytotoxicity against MM cells. In vivo, liposomal carfilzomib demonstrated significant tumor growth inhibition and dramatically reduced overall systemic toxicity compared to free carfilzomib. Finally, liposomal carfilzomib demonstrated enhanced synergy in combination with doxorubicin. Taken together, this study establishes the successful synthesis of liposomal carfilzomib nanoparticles that demonstrates improved therapeutic index and the potential to improve patient outcome in MM.


Assuntos
Antineoplásicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/farmacologia , Inibidores de Proteases/farmacologia , Animais , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Humanos , Integrina alfa4beta1/efeitos dos fármacos , Integrinas/biossíntese , Lipossomos/química , Camundongos , Camundongos SCID , Nanopartículas , Oligopeptídeos/administração & dosagem , Tamanho da Partícula , Inibidores de Proteases/administração & dosagem , Solubilidade , Ensaios Antitumorais Modelo de Xenoenxerto
10.
ACS Nano ; 7(4): 2935-47, 2013 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-23421406

RESUMO

PEGylated liposomes are attractive pharmaceutical nanocarriers; however, literature reports of ligand-targeted nanoparticles have not consistently shown successful results. Here, we employed a multifaceted synthetic strategy to prepare peptide-targeted liposomal nanoparticles with high purity, reproducibility, and precisely controlled stoichiometry of functionalities to evaluate the role of liposomal PEG coating, peptide EG-linker length, and peptide valency on cellular uptake in a systematic manner. We analyzed these parameters in two distinct disease models where the liposomes were functionalized with either HER2- or VLA-4-antagonistic peptides to target HER2-overexpressing breast cancer cells or VLA-4-overexpressing myeloma cells, respectively. When targeting peptides were tethered to nanoparticles with an EG45 (∼PEG2000) linker in a manner similar to a more traditional formulation, their cellular uptake was not enhanced compared to non-targeted versions regardless of the liposomal PEG coating used. Conversely, reduction of the liposomal PEG to PEG350 and the peptide linker to EG12 dramatically enhanced cellular uptake by ∼9 fold and ∼100 fold in the breast cancer and multiple myeloma cells, respectively. Uptake efficiency reached a maximum and a plateau with ∼2% peptide density in both disease models. Taken together, these results demonstrate the significance of using the right design elements such as the appropriate peptide EG-linker length in coordination with the appropriate liposomal PEG coating and optimal ligand density in efficient cellular uptake of liposomal nanoparticles.


Assuntos
Lipossomos/química , Nanocápsulas/química , Nanocápsulas/ultraestrutura , Neoplasias Experimentais/metabolismo , Peptídeos/química , Peptídeos/farmacocinética , Polietilenoglicóis/química , Linhagem Celular Tumoral , Materiais Revestidos Biocompatíveis/síntese química , Humanos , Teste de Materiais , Tamanho da Partícula
11.
Chem Commun (Camb) ; 49(42): 4809-11, 2013 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-23595166

RESUMO

Nanoparticles formed via electrostatic interactions between methoxy-polyethylene glycol-block-poly(glutamic acid) (MPEG-PGA) and a multinuclear platinum(II) drug, di-cisPt, exhibit efficient platinum loading, improved cellular uptake, in vitro cytotoxicity, and enhanced in vivo efficacy.


Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Portadores de Fármacos/química , Humanos , Micelas , Nanopartículas/química , Polietilenoglicóis/química , Ácido Poliglutâmico/química , Eletricidade Estática
12.
Clin Cancer Res ; 15(18): 5829-39, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19737962

RESUMO

PURPOSE: The increasing incidence of osteonecrosis of the jaw and its possible association with high cumulative doses of bisphosphonate led us to study the effects of high doses of zoledronic acid (ZA) on bone remodeling. EXPERIMENTAL DESIGN: Five-week-old C57BL6 mice were treated with saline or ZA weekly for 3 weeks at increasing doses (0.05-1 mg/Kg). Effects of ZA on bone remodeling were studied using standard assays. RESULTS: We observed an increase in bone mineral density and content in treated animals at doses of 0.05 mg/Kg, which was not further enhanced at higher doses of ZA. Trabecular bone volume at the proximal tibia and the distal femur assessed by histomorphometry and microCT, respectively, increased significantly in ZA-treated groups. There was however no difference between 0.5 and 1 mg/kg, suggesting a ceiling effect for ZA. ZA led to decreased numbers of osteoclasts and osteoblasts per bone perimeter that paralleled a significant reduction of serum levels of TRAC5b and osteocalcin in vivo. Effects on osteoblasts were confirmed in in vitro assays. Mechanical testing of the femur showed increased brittleness in ZA-treated mice. CONCLUSIONS: High doses of ZA inhibit both osteoclast and osteoblasts function and bone remodeling in vivo interfering with bone mechanical properties. No dose response was noted beyond 0.5 mg/kg suggesting that lower doses of ZA may be adequate in inhibiting bone resorption. Our data may help inform future studies of ZA use with respect to alternate and lower doses in the treatment of patients with cancer bone disease.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Linhagem da Célula/efeitos dos fármacos , Difosfonatos/administração & dosagem , Difosfonatos/farmacologia , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Osteoblastos/efeitos dos fármacos , Adulto , Animais , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/citologia , Osteoblastos/fisiologia , Células Tumorais Cultivadas , Ácido Zoledrônico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA