RESUMEN
Mammalian cell membranes are often incompatible with chemical modifications typically used to increase circulation half-life. Using cellular nanoghosts as a model, we show that proline-alanine-serine (PAS) peptide sequences expressed on the membrane surface can extend the circulation time of a cell membrane derived nanotherapeutic. Membrane expression of a PAS 40 repeat sequence decreased protein binding and resulted in a 90% decrease in macrophage uptake when compared with non-PASylated controls (Pâ¯≤â¯0.05). PASylation also extended circulation half-life (t1/2â¯=â¯37â¯h) compared with non-PASylated controls (t1/2â¯=â¯10.5â¯h) (Pâ¯≤â¯0.005), resulting in ~7-fold higher in vivo serum concentrations at 24â¯h and 48â¯h (Pâ¯≤â¯0.005). Genetically engineered membrane expression of PAS repeats may offer an alternative to PEGylation and provide extended circulation times for cellular membrane-derived nanotherapeutics.
Asunto(s)
Membrana Celular/metabolismo , Nanopartículas/uso terapéutico , Ingeniería de Proteínas , Adsorción , Animales , Proteínas Sanguíneas/metabolismo , Dispersión Dinámica de Luz , Células HEK293 , Humanos , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/ultraestructura , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Ratas , Propiedades de Superficie , Distribución TisularRESUMEN
In this study, a series of star-shaped polycarbonates are synthesized by metal-free organocatalytic ring-opening polymerization of benzyl chloride (BnCl) and mannose-functionalized cyclic carbonate monomers (MTC-BnCl and MTC-ipman) with heptakis-(2,3-di-O-acetyl)-ß-cyclodextrin (DA-ß-CD) as macroinitiator. The distributions and compositions of pendent benzyl chloride and protected mannose group (ipman) units are facilely modulated by varying the polymerization sequence and feed ratio of the monomers, allowing precise control over the molecular composition, and the resulting polymers have narrow molecular weight distribution. After deprotection of ipman groups and quaternization with various N,N-dimethylalkylamines, these star polymers with optimized compositions of cationic and mannose groups in block and random forms exhibit strong bactericidal activity and low hemolysis. Furthermore, the optimal mannose-functionalized polymer demonstrates mannose receptor-mediated intracellular bactericidal activity against BCG mycobacteria without inducing cytotoxicity on mammalian cells at the effective dose. Taken together, the materials designed in this study have potential use as antimicrobial agents against diseases such as tuberculosis, which is caused by intracellular bacteria.
Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/inmunología , Bacterias/efectos de los fármacos , Manosa/química , Cemento de Policarboxilato/química , Animales , Antiinfecciosos/farmacología , Cationes/química , Hemólisis/efectos de los fármacos , Hemólisis/inmunología , Mamíferos/inmunología , Mamíferos/microbiología , Polimerizacion , Polímeros/química , beta-Ciclodextrinas/química , beta-Ciclodextrinas/inmunología , beta-Ciclodextrinas/farmacologíaRESUMEN
AIM: Phenformin-loaded micelles (Phen M) were used in combination with gemcitabine-loaded micelles (Gem M) to study their combined effect against H460 human lung cancer cells and cancer stem cells (CSCs) in vitro and in vivo. MATERIALS & METHODS: Gem M and Phen M were prepared via self-assembly of a mixture of a diblock copolymer of PEG and urea-functionalized polycarbonate (PEG-PUC) and a diblock copolymer of PEG and acid-functionalized polycarbonate (PEG-PAC) through hydrogen bonding and ionic interactions. Gem M and Phen M were characterized and tested for efficacy both in vitro and in vivo against cancer cells and CSCs. RESULTS: The combination of Gem M/Phen M exhibited higher cytotoxicity against CSCs and non-CSCs than Gem M and Phen M alone, and showed significant cell cycle growth arrest in vitro. The combination therapy had superior tumor suppression and apoptosis in vivo without inducing toxicity to liver and kidney. CONCLUSION: The combination of Gem M and Phen M may be potentially used in lung cancer therapy.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Desoxicitidina/análogos & derivados , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Fenformina/administración & dosificación , Animales , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Sistemas de Liberación de Medicamentos , Sinergismo Farmacológico , Femenino , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , Neoplasias Pulmonares/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Micelas , Células Madre Neoplásicas/patología , Fenformina/farmacología , Fenformina/uso terapéutico , Cemento de Policarboxilato/química , Polietilenglicoles/química , Urea/análogos & derivados , GemcitabinaRESUMEN
Polymeric nanoparticles and liposomes have been the platform of choice for nanoparticle-based cancer drug delivery applications over the past decade, but extensive research has revealed their limitations as drug delivery carriers. A hybrid class of nanoparticles, aimed at combining the advantages of both polymeric nanoparticles and liposomes, has received attention in recent years. These core/shell type nanoparticles, frequently referred to as lipid-polymer hybrid nanoparticles (LPNs), possess several characteristics that make them highly suitable for drug delivery. This review introduces the formulation methods used to synthesize LPNs and discusses the strategies used to treat cancer, such as by targeting the tumor microenvironment or vasculature. Finally, it discusses the challenges that must be overcome to realize the full potential of LPNs in the clinic.
Asunto(s)
Antineoplásicos/farmacocinética , Portadores de Fármacos/química , Lípidos/química , Nanopartículas/química , Neoplasias/química , Polímeros/química , Sistemas de Liberación de Medicamentos , Humanos , Neoplasias/tratamiento farmacológico , Polímeros/metabolismoRESUMEN
Development of cancer resistance, cancer relapse and metastasis are attributed to the presence of cancer stem cells (CSCs). Eradication of this subpopulation has been shown to increase life expectancy of patients. Since the discovery of CSCs a decade ago, several strategies have been devised to specifically target them but with limited success. Nanocarriers have recently been employed to deliver anti-CSC therapeutics for reducing the population of CSCs at the tumor site with great success. This review discusses the different therapeutic strategies that have been employed using nanocarriers, their advantages, success in targeting CSCs and the challenges that are to be overcome. Exploiting this new modality of cancer treatment in the coming decade may improve outcomes profoundly with promise of effective treatment response and reducing relapse and metastasis.
Asunto(s)
Terapia Molecular Dirigida , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Humanos , Nanomedicina , Nanopartículas/química , Neoplasias/patología , Células Madre Neoplásicas/patología , Transducción de Señal/efectos de los fármacosRESUMEN
Conventional cancer chemotherapy often fails as most anti-cancer drugs are not effective against drug-resistant cancer stem cells. These surviving cancer stem cells lead to relapse and metastasis. In this study, an anti-diabetic drug, phenformin, capable of eliminating cancer stem cells was loaded into micelles via self-assembly using a mixture of a diblock copolymer of poly(ethylene glycol) (PEG) and urea-functionalized polycarbonate and a diblock copolymer of PEG and acid-functionalized polycarbonate through hydrogen bonding. The phenformin-loaded micelles, having an average diameter of 102 nm with narrow size distribution, were stable in serum-containing solution over 48 h and non-cytotoxic towards non-cancerous cells. More than 90% of phenformin was released from the micelles over 96 h. Lung cancer stem cells (side population cells, i.e. SP cells) and non-SP cells were sorted from H460 human lung cancer cell line, and treated with free phenformin and phenformin-loaded micelles. The results showed that the drug-loaded micelles were more effective in inhibiting the growth of both SP and non-SP cells. In vivo studies conducted in an H460 human lung cancer mouse model demonstrated that the drug-loaded micelles had greater anti-tumor efficacy, and reduced the population of SP cells in the tumor tissues more effectively than free phenformin. Liver function analysis was performed following drug treatments, and the results indicated that the drug-loaded micelles did not cause liver damage, a harmful side-effect of phenformin when used clinically. These phenformin-loaded micelles may be used to target both cancer cells and cancer stem cells in chemotherapy for the prevention of relapse and metastasis.
Asunto(s)
Antineoplásicos/farmacología , Micelas , Células Madre Neoplásicas/efectos de los fármacos , Fenformina/farmacología , Animales , Antineoplásicos/química , Línea Celular Tumoral , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fenformina/química , Cemento de Policarboxilato/química , Polietilenglicoles/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Polymeric micelles self-assembled from biodegradable amphiphilic block copolymers have been proven to be effective drug delivery carriers that reduce the toxicity and enhance the therapeutic efficacy of free drugs. Several reviews have been reported in the literature to discuss the importance of size/size distribution, stability and drug loading capacity of polymeric micelles for successful in vivo drug delivery. This review is focused on non-covalent and covalent interactions that are employed to enhance cargo loading capacity and in vivo stability, and to achieve nanosize with narrow size distribution. In particular, this review analyzes various non-covalent and covalent interactions and chemistry applied to introduce these interactions to the micellar drug delivery systems, as well as the effects of these interactions on micelle stability, drug loading capacity and release kinetics. Moreover, the factors that influence these interactions and the future research directions of polymeric micelles are discussed.