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PURPOSE: Most therapeutic agents have limitations owing to low selectivity and poor solubility, resulting in post-treatment side effects. Therefore, there is a need to improve solubility and develop new formulations to deliver therapeutic agents specifically to the target site. Gelatin is a natural protein that is composed of several amino acids. Previous studies revealed that gelatin contains arginyl-glycyl-aspartic acid (RGD) sequences that become ligands for the integrin receptors expressed on cancer cells. Thus, in this study, we aimed to increase the efficiency of drug delivery into cancer cells by coating drug-encapsulating liposomes with gelatin (gelatin-coated liposomes, GCLs). METHODS: Liposomes were coated with gelatin using electrostatic interaction and covalent bonding. GCLs were compared with PEGylated liposomes in terms of their size, zeta potential, encapsulation efficiency, stability, dissolution profile, and cell uptake. Results: Small-sized and physically stable GCLs were prepared, and they showed high drug-encapsulation efficiency. An in vitro dissolution study showed sustained release depending on the degree of gelatin coating. Cell uptake studies showed that GCLs were superior to PEGylated liposomes in terms of cancer cell-targeting ability. CONCLUSIONS: GCLs can be a novel and promising carrier system for targeted anticancer agent delivery. GCLs, which exhibited various characteristics depending on the coating degree, could be utilized in various ways in future studies.
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Antineoplásicos/administración & dosificación , Gelatina/química , Liposomas/química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Liberación de Fármacos , Células HeLa , Humanos , Polietilenglicoles/química , SolubilidadRESUMEN
Photodynamic therapy is a clinically approved treatment approach for cancer. However, it has limited applications owing to poor water solubility and the short wavelength absorption of the photosensitizer (PS). We selected a near-infrared photosensitizer, SiNC, and encapsulated into a gold nanocage (AuNC) in the presence of phase-changing material. Then, the PS-encapsulated nanocage was coated with glycol chitosan (GC) with a cleavable peptide linkage or stable cysteine linkage to protect the PS from premature release and to improve the biocompatibility of the nanocage. We obtained particles of GC-coated SiNC-encapsulated AuNC with a neutral surface charge and approximately 160â¯nm in size. The enzyme-cleavable peptide-linked GC formulation (GC-pep@SiNC-AuNC) showed stronger phototoxicity and tumor suppression efficacy in a glioblastoma model compared with free NIR-PS and stable cysteine-linked GC-AuNC (GC-cys@SiNC-AuNC). This polymer-coated SiNC-AuNC may be a promising agent for brain cancer phototherapy.
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Quitosano/química , Glioblastoma/terapia , Oro/química , Rayos Infrarrojos , Nanopartículas del Metal/química , Fármacos Fotosensibilizantes/uso terapéutico , Fototerapia , Animales , Línea Celular Tumoral , Quitosano/síntesis química , Endocitosis , Humanos , Nanopartículas del Metal/ultraestructura , Ratones Endogámicos BALB C , Ratones Desnudos , Péptidos/síntesis química , Péptidos/química , Espectroscopía de Protones por Resonancia Magnética , Distribución TisularRESUMEN
Gold nanoparticles are commonly used for medical applications such as drug delivery and as therapeutic and diagnostic materials because of their unique properties. In this study, we prepared docetaxel (DTX)-loaded hyaluronic acid-cleavable-peptide-gold nanoparticles for the treatment of cancer by selectively delivering DTX into the tumor and, thus, enhancing the therapeutic effect of DTX; further, we determined synergistic effects of the nanoparticles using laser treatment. The DTX-loaded hyaluronic acid-cleavable-peptide-gold nanoparticles prepared in this study had an average size of 75 nm and negative surface charge. The nanoparticles revealed greater cytotoxicity and higher tumor suppression efficacy in tumor models than free DTX under near-infrared laser irradiation. Therefore, the nanoparticle formulation prepared in this study could be utilized for targeted drug delivery and in combination with other cancer therapies.
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Catepsina B/química , Docetaxel/química , Oro/química , Ácido Hialurónico/química , Nanopartículas del Metal/química , Péptidos/química , Polímeros/química , Animales , Sistemas de Liberación de Medicamentos/métodos , HumanosRESUMEN
Despite potential applications of nucleic acid therapeutics, the lack of effective delivery systems hinders their clinical application. To overcome the barriers to nucleic acid delivery, we previously reported nanoparticles using phospholipid-polyethylenimine conjugates. However, toxicity of polyethylenimine remains as a problematic issue. Herein, we proposed to substitute the polyethylenimine with arginine-rich peptide to obtain a less-toxic carrier system. Nonaarginine was conjugated to the distal end of phospholipid hydrocarbon chains leading to phospholipid-nonaarginine conjugates (PL9R) and then lipid-peptide hybrid nanoparticles carrying oligonucleotide therapeutics (hNP) were constructed by self-assembly process. The hNP were further modified with cell penetrating Tat peptide (T-hNP) to enhance cellular uptake. The PL9R was less cytotoxic, and the hNP showed high loading capacity and colloidal stability. The T-hNP showed higher cellular uptake and transfection efficiency and effective accumulation to tumor tissue and silencing effect in tumor bearing mice. Altogether, T-hNP could provide a promising nanocarrier for nucleic acid therapeutics.
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Péptidos de Penetración Celular/administración & dosificación , Sistemas de Liberación de Medicamentos , Nanopartículas/administración & dosificación , Neoplasias/tratamiento farmacológico , Animales , Péptidos de Penetración Celular/química , Humanos , Hidrocarburos/química , Ratones , Nanopartículas/química , Neoplasias/genética , Neoplasias/patología , Oligopéptidos/administración & dosificación , Oligopéptidos/química , Ácidos Nucleicos de Péptidos/administración & dosificación , Ácidos Nucleicos de Péptidos/química , Fosfolípidos/administración & dosificación , Fosfolípidos/química , Transfección , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The objective of this study was to develop a mitochondria-targeted photosensitizer (PS) for photodynamic therapy (PDT). Herein, a porphyrin-derivative photosensitizer, pheophorbide-a (PheoA), was conjugated to carboxybutyltriphenylphosphonium (TPP) via a carbodiimide linkage to enhance mitochondrial targeting and TPP-PheoA conjugate was further loaded into folate-cholesteryl albumin (FA-chol-BSA) nanoparticles (NPs) to improve its biocompatibility. Cellular uptake results showed that TPP-PheoA and TPP-PheoA@FA-chol-BSA NPs were readily taken up by B16F10 and HeLa cells. Further in vitro studies exhibited that TPP-PheoA and its nanoparticle primarily accumulate in the mitochondria, greatly generate ROS, lead mitochondrial disruption and cell apoptosis, and have higher phototoxicity against cancer cells. In vivo bioimaging and the in vivo antitumor studies indicated that TPP-PheoA@FA-chol-BSA NP greatly accumulated in the tumor area and significantly suppress the tumor growth as compared to PheoA@FA-chol-BSA NP in tumor-bearing mice. Taken together, TPP-PheoA@FA-chol-BSA NP could be a promising mitochondria-targeted PS for image-guided PDT.
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Nanopartículas , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes , Albúminas , Animales , Clorofila/análogos & derivados , Ácido Fólico , Humanos , RatonesRESUMEN
In spite of the great potential of nucleic acids as therapeutic agents, the clinical application of nucleic acid therapeutics requires the development of effective systemic delivery strategies. In an effort to develop effective nucleic acid delivery systems suitable for clinical application, we previously reported a self-assembling micelle-like nanoparticle that was based on phospholipid-polyethylenimine conjugates, i.e., "micelle-like nanoparticles" (MNPs). In this study, we aimed to improve the system by enhancing the efficiency of intracellular delivery of the payload via pH-responsive detachment of the monolayer envelope and release of the nucleic acid therapeutics upon reaching the target tissues with an acidic pH, e.g., tumors. The acid-cleavable phospholipid-polyethylenimine conjugate was synthesized via hydrazone bond, and acid-cleavable MNPs were then prepared and characterized as before. We evaluated the acid-cleavable MNP construct for in vitro and in vivo nucleic acid delivery efficiency using cultured tumor cells and tumor-bearing mice. The acid-cleavable nanocarrier showed an enhanced cellular delivery at pH 6.5 as compared to pH 7.4, whereas the noncleavable nanocarrier did not show any differences. Tail vein injections also led to enhanced intracellular uptake of the acid-cleavable nanocarrier compared to the noncleavable nanocarrier into tumor cells of tumor-bearing mice although no significant difference was observed in total tumor accumulation.
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Técnicas de Transferencia de Gen , Melanoma Experimental/terapia , Nanopartículas/química , Oligonucleótidos/administración & dosificación , Fosforilcolina/química , Polietileneimina/química , Animales , Concentración de Iones de Hidrógeno , Masculino , Melanoma Experimental/genética , Ratones , Ratones Endogámicos C57BL , Micelas , Microscopía Fluorescente , Nanopartículas/administración & dosificación , Oligonucleótidos/farmacocinética , Fosforilcolina/metabolismo , Polietileneimina/metabolismo , Distribución TisularRESUMEN
PUSPOSE: We aimed to synthesize novel ceramide-chitosan (CS-CE) conjugate that forms stable polymeric nanoparticle capable of functioning as efficient carriers of hydrophobic drug such as Paclitaxel (PTX) for oral delivery. METHODS: Chitosan (3-5 kDa) was conjugated with ceramide by using a DSC coupling reagent to improve its hydrophobic drug entrapment capacity. The structure of the conjugate was determined by proton ((1)H) NMR and FT-IR spectrometry. Size distribution and zeta potential were measured by DLS and PTX content in the cells and plasma was determined by HPLC and LC-MS. RESULTS: Under suitable conditions, the CS-CE self assembled to form colloidally stable nanoparticles with a mean diameter of ~300 nm. Further, PTX was incorporated into the CS-CE nanoparticle with 96.9% loading efficiency and 12.1% loading capacity via an emulsion-solvent evaporation method. The PTX-loaded CS-CE (PTX-CS-CE) showed sustained release of PTX and a comparable cytotoxic efficacy to that of free PTX on B16F10 melanoma and MCF-7 human breast adenocarcinoma cell lines. The empty nanoparticles showed no toxicity, indicating that the copolymer is safe to use in drug delivery. In addition, higher cellular uptake and slightly better pharmacokinetic parameters were obtained for PTX-CS-CE nanoparticle compared to free PTX. CONCLUSION: The polymeric nanoparticle of CS-CE represents a promising nanocarrier of hydrophobic drug for oral delivery.
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Ceramidas/química , Quitosano/química , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/química , Administración Oral , Animales , Línea Celular Tumoral , Preparaciones de Acción Retardada/química , Sistemas de Liberación de Medicamentos/métodos , Emulsiones/química , Humanos , Células MCF-7 , Melanoma Experimental/tratamiento farmacológico , Ratones , Tamaño de la PartículaRESUMEN
We previously reported that a liposome encapsulating polyethylenimine/oligonucleotides is suitable for in vivo delivery of nucleic acid therapeutics. However, toxicity of polyethylenimine is an obstacle in clinical application. To develop a liposome encapsulating polyplexes applicable to clinical use, we proposed to replace polyethylenimine with chitosan and thus constructed the liposome encapsulating low-molecular weight chitosan (LMWC)/oligonucleotide (ODN) polyplexes [LS(CO)]. ODN was completely complexed to LMWC at pH 5.5 and an N/P ratio 10 with a positive zeta potential of 19.81 ± 1.11. The positively charged polyplexes were encapsulated into anionic liposome by membrane extrusion. Folate-targeted liposome encapsulating LMWC/ODN complex [FLS(CO)] was prepared by adding folate-conjugated phospholipid. The resulting LS(CO) and FLS(CO) were characterized with respect to size distribution, zeta potential, and colloidal stability. The LS(CO) and FLS(CO) were also evaluated for in vitro cellular uptake and cytotoxicity. The LS(CO) and FLS(CO) showed a narrow size distribution with a mean diameter of about 130 nm and neutral zeta potentials and remained stable for 7 days in 0.15-M NaCl at room temperature. FLS(CO) showed higher cellular uptake than LS(CO) in B16F10 murine melanoma cells. Furthermore, LS(CO) showed less toxicity as compared to liposome encapsulating polyethylenimine/oligonucleotides, representing a biocompatible nanocarrier of oligonucleotide therapeutics.
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Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Ácido Fólico/química , Liposomas/química , Oligonucleótidos/administración & dosificación , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Quitosano , Coloides/química , Composición de Medicamentos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Ratones , Oligonucleótidos/metabolismo , Oligonucleótidos/farmacología , Tamaño de la PartículaRESUMEN
Triple-negative breast cancer (TNBC), lacking specific receptors found in other breast cancer subtypes, poses significant treatment challenges due to limited therapeutic options. Therefore, it is necessary to develop novel treatment approaches for TNBC. In the last few decades, many attempts have been reported for alternative tools for TNBC treatment: immunotherapy, radiotherapy, targeted therapy, combination therapy, and nanotechnology-based therapy. Among them, combination therapy and nanotechnology-based therapy show the most promise for TNBC treatment. This review outlines recent advancements in these areas, highlighting the efficacy of combination therapy (immunotherapy paired with chemotherapy, targeted therapy, or radiotherapy) in both preclinical and clinical stages and nanotechnology-based therapies utilizing various nanoparticles loaded with anticancer agents, nucleic acids, immunotherapeutics, or CRISPRs in preclinical stages for TNBC treatment.
RESUMEN
Triple negative breast cancer (TNBC) has a negative expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2). The survival rate for TNBC is generally worse than other breast cancer subtypes. TNBC treatment has made significant advances, but certain limitations remain. Treatment for TNBC can be challenging since the disease has various molecular subtypes. A variety of treatment options are available, such as chemotherapy, immunotherapy, radiotherapy, and surgery. Chemotherapy is the most common of these options. TNBC is generally treated with systemic chemotherapy using drugs such as anthracyclines and taxanes in neoadjuvant or adjuvant settings. Developing resistance to anticancer drugs and off-target toxicity are the primary hindrances to chemotherapeutic solutions for cancer. It is imperative that researchers, clinicians, and pharmaceutical companies work together to develop effective treatment options for TNBC. Several studies have suggested nanotechnology as a potential solution to the problem of suboptimal TNBC treatment. In this review, we summarized possible treatment options for TNBC, including chemotherapy, immunotherapy, targeted therapy, combination therapy, and nanoparticle-based therapy, and some solutions for the treatment of TNBC in the future. Moreover, we gave general information about TNBC in terms of its characteristics and aggressiveness.
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Photodynamic therapy (PDT) is a promising cancer treatment approach. However, the photosensitizers (PS) used for PDT are often limited by their poor solubility and selectivity for tumors. The goal of this study is to improve water solubility and delivery of the photosensitizer 2-[1-hexyloxyethyl]-2-divinyl pyropheophorbide-a (HPPH) to breast cancer cells. An N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-HPPH photosensitizer conjugate is synthesized with heat shock receptor glucose-regulated protein 78 (GRP78), targeting to GRP78 receptors of MCF-7 cells, which are upregulated under mild hyperthermia. It is found that the uptake of the GRP78 targeted pep-HPMA-HPPH copolymer conjugate in MCF-7 cells is improved through heat induction. Under mild hyperthermia the targeted copolymers are more effective compared to free HPPH. These results show potential for the utility of mild hyperthermia and copolymer delivery vehicles to enhance the efficacy of photodynamic therapy.
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Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Endocitosis , Proteínas de Choque Térmico/metabolismo , Hipertermia Inducida , Metacrilatos/química , Fármacos Fotosensibilizantes/farmacología , Polímeros/química , Muerte Celular/efectos de los fármacos , Chaperón BiP del Retículo Endoplásmico , Femenino , Humanos , Células MCF-7 , Metacrilatos/síntesis química , Polímeros/síntesis químicaRESUMEN
The mitochondrion is an important intracellular organelle for drug targeting due to its key roles and functions in cellular proliferation and death. In the last few decades, several studies have revealed mitochondrial functions, attracting the focus of many researchers to work in this field over nuclear targeting. Mitochondrial targeting was initiated in 1995 with a triphenylphosphonium-thiobutyl conjugate as an antioxidant agent. The major driving force for mitochondrial targeting in cancer cells is the higher mitochondrial membrane potential compared with that of the cytosol, which allows some molecules to selectively target mitochondria. In this review, we discuss mitochondria-targeting ligand-conjugated anticancer agents and their in vitro and in vivo behaviors. In addition, we describe a mitochondria-targeting nanocarrier system for anticancer drug delivery. As previously reported, several agents have been known to have mitochondrial targeting potential; however, they are not sufficient for direct application for cancer therapy. Thus, many studies have focused on direct conjugation of targeting ligands to therapeutic agents to improve their efficacy. There are many variables for optimal mitochondria-targeted agent development, such as choosing a correct targeting ligand and linker. However, using the nanocarrier system could solve some issues related to solubility and selectivity. Thus, this review focuses on mitochondria-targeting drug conjugates and mitochondria-targeted nanocarrier systems for anticancer agent delivery.
RESUMEN
AIM: The objective of this study was to develop a mitochondria-targeted anticancer drug, docetaxel (DTX), for chemotherapy. MATERIALS & METHODS: The DTX was conjugated to 4-carboxybutyl triphenylphosphonium (TPP) to enhance mitochondrial targeting, and the TPP-DTX conjugate was further loaded into folate-cholesteryl albumin (FA-chol-BSA) nanoparticles (NPs) to improve its biocompatibility. RESULTS & CONCLUSION: In vitro studies showed that TPP-DTX and its NP primarily accumulated in the mitochondria; generated high reactive oxygen species, leading to mitochondrial disruption and cell apoptosis; and had a higher cytotoxicity against cancer cells. In vivo antitumor studies indicated that the NP significantly suppressed tumor growth compared with free drugs in xenograft tumor-bearing mice. Our results demonstrated that TPP-DTX@FA-chol-BSA NPs could be a promising mitochondria-targeted anticancer prodrug for chemotherapy.
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Docetaxel/administración & dosificación , Sistemas de Liberación de Medicamentos , Nanopartículas/administración & dosificación , Neoplasias/tratamiento farmacológico , Albúminas/administración & dosificación , Albúminas/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Línea Celular Tumoral , Docetaxel/química , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Nanopartículas/química , Neoplasias/patología , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/química , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Mitochondrial targeting is a promising approach for solving current issues in clinical application of chemotherapy and diagnosis of several disorders. Here, we discuss direct conjugation of mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated in vitro and in vivo, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors.
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BACKGROUND: RIPL peptide (IPLVVPLRRRRRRRRC)-conjugated nanostructured lipid carriers (RIPL-NLCs) can facilitate selective drug delivery to hepsin (Hpn)-expressing cancer cells, but they exhibit low stability in the blood. Generally, biocompatible and nontoxic poly(ethylene glycol) surface modification (PEGylation) can enhance NLC stability, although this may impair drug delivery and NLC clearance. To attain RIPL-NLC steric stabilization without impairing function, pH-sensitive cleavable PEG (cPEG) was grafted onto RIPL-NLCs (cPEG-RIPL-NLCs). METHODS: Various types of NLC formulations including RIPL-NLCs, PEG-RIPL-NLCs, and cPEG-RIPL-NLCs were prepared using the solvent emulsification-evaporation method and characterized for particle size, zeta potential (ZP), and cytotoxicity. The steric stabilization effect was evaluated by plasma protein adsorption and phagocytosis inhibition studies. pH-sensitive cleavage was investigated using the dialysis method under different pH conditions. Employing a fluorescent probe (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate [DiI]), in vitro drug delivery capacity of the cPEG-RIPL-NLCs under different pH conditions was also performed on Hpn-expressing SKOV3 cells and 3D-tumor spheroids. RESULTS: All prepared NLCs showed homogenous dispersion (<220 nm in size) with a negative ZP (-18 to -22 mV), except for positively charged RIPL-NLCs (~10 mV), revealing no significant cytotoxicity in either SKOV3 or RAW 264.7 cell lines. cPEG-RIPL-NLC protein adsorption was 1.75-fold less than that of RIPL-NLCs, and PEGylation significantly reduced the macrophage uptake. PEG detachment from the cPEG-RIPL-NLCs was pH-sensitive and time dependent. At 2 hours incubation, cPEG-RIPL-NLCs and PEG-RIPL-NLCs exhibited comparable cellular uptake at pH 7.4, whereas cPEG-RIPL-NLC uptake was increased over 2-fold at pH 6.5. 3D-spheroid penetration also demonstrated pH-sensitivity: at pH 7.4, cPEG-RIPL-NLCs could not penetrate deep into the spheroid core region during 2 hours, whereas at pH 6.5, high fluorescence intensity in the core region was observed for both cPEG-RIPL-NLC-and RIPL-NLC-treated groups. CONCLUSION: cPEG-RIPL-NLCs are good candidates for Hpn-selective drug targeting in conjunction with pH-responsive PEG cleavage.
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Portadores de Fármacos/química , Diseño de Fármacos , Lípidos/química , Nanoestructuras/química , Neoplasias Ováricas/tratamiento farmacológico , Fragmentos de Péptidos/farmacología , Polietilenglicoles/química , Células Cultivadas , Composición de Medicamentos , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Técnicas In Vitro , Macrófagos/citología , Macrófagos/efectos de los fármacos , Neoplasias Ováricas/patología , Fragmentos de Péptidos/química , Fagocitosis , Serina Endopeptidasas/química , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/patologíaRESUMEN
Gold nanoparticles are promising materials for many applications that include imaging, drug delivery, and photothermal therapy. However, AuNPs can be unstable and/or toxic. We purposed to improve the stability and reduce toxicity of gold nanorods (AuNR) upon coating with biocompatible polymer, chitosan-ceramide (CS-CE), without replacing the original layer, CTAB. CS-CE-coated AuNR was prepared by simple mixing for 24 h and purified by centrifugation. The coating was confirmed by UV-Vis absorption analysis and surface charge and size measurement. We prepared nanorods with CS or CS-CE coating at two different concentrations (5 and 10% AuNR), the resulting in larger nanorods with a more positive surface-charge than that of AuNR. We investigated the UV-absorption and protein adsorption of the polymer coated nanorods. Based on the protein adsorption, AuNR-CS-CE was found to be more stable under physiological conditions than AuNR-CS. The cell internalization assay revealed that Hela cells internalized higher amounts of AuNR-CS-CE than that of AuNR-CS. Cytotoxicity study revealed that AuNR-CS-CE has lower toxicity than AuNR against HeLa cells. The CS-CE coating improved the stability of AuNR under physiological conditions via the hydrophobic interactions between the AuNR lipid surface and the ceramide anchor in the CS backbone as well as.
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Materiales Biocompatibles/química , Materiales Biocompatibles/toxicidad , Ceramidas/química , Quitosano/química , Oro/química , Oro/toxicidad , Lípidos/química , Lípidos/toxicidad , Nanotubos/química , Nanotubos/toxicidad , Supervivencia Celular , Coloides/química , Células HeLa , Humanos , Unión Proteica , Espectrofotometría Ultravioleta , Propiedades de SuperficieRESUMEN
The objective of this study was to develop an active-targeted, pH-responsive albumin-photosensitizer-incorporated graphene oxide nanocomplex as an image-guided theranostic agent for dual therapies. Herein, bovine serum albumin (BSA)-cis-aconityl pheophorbide-a (c-PheoA) conjugate was complexed with graphene oxide (GO) at ratios of 1:1, 1:0.5, and 1:0.1 with the mean hydrodynamic diameter of the resulting complex being 100-200nm. Further, with the 1:0.5 ratio, we developed a folate-BSA-c-PheoA conjugate:GO complex incorporated free PheoA (PheoA+GO:FA-BSA-c-PheoA NC) with a mean hydrodynamic diameter of 182.0±33.2nm. The release study showed that the photosensitizer from the nanocomplex was released rapidly at pH5.5 compared to that at pH7.4 when incubated for 24h. Cellular uptake results showed that the PheoA+GO:FA-BSA-c-PheoA NCs was readily taken up by B16F10 and MCF7 cancer cells. In vitro phototoxicity results showed that PheoA+GO:FA-BSA-c-PheoA NC has a higher efficacy against cancer cells than free PheoA, thereby demonstrating the synergistic effect of PS and GO in response to a single laser of 670nm. In vivo and ex vivo bioimaging results showed that fluorescence signals of higher intensity were observed in the tumor area of mice treated with PheoA+GO:FA-BSA-c-PheoA NC than those in the tumor of mice treated with free PheoA, thereby suggesting that the targeted nanocomplex selectively accumulated in the tumor area compared to free PheoA. Through antitumor study, PheoA+GO:FA-BSA-c-PheoA NC showed a synergistic effect in tumor-bearing mice by a single 671nm laser treatment. These results demonstrate that our prepared PheoA+GO:FA-BSA-c-PheoA NC can be used as a theranostic agent in phototherapies and for the photodiagnosis of cancer.
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Clorofila/análogos & derivados , Ácido Fólico/química , Grafito/química , Nanoconjugados/química , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/química , Albúmina Sérica Bovina/química , Ácido Aconítico/análogos & derivados , Ácido Aconítico/química , Animales , Clorofila/química , Clorofila/farmacocinética , Clorofila/uso terapéutico , Liberación de Fármacos , Humanos , Rayos Láser , Células MCF-7 , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/terapia , Ratones , Ratones Desnudos , Microscopía Confocal , Óxidos , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The objective of this study was to develop an active-targeted, pH-responsive albumin-photosensitizer conjugate as a theranostic agent. Herein, a porphyrin derivative photosensitizer, pheophorbide-a (PheoA), was conjugated to bovine serum albumin (BSA) via a cis-aconityl linkage, and the conjugate was then linked with polyethylene glycosylated folate to improve targeting ability. Further, BSA-c-PheoA and folate (FA)-BSA-c-PheoA at a ratio of 2 : 1 were self-assembled to form nanoparticles with a mean hydrodynamic diameter of 121.47 ± 11.60 nm. The release study exhibited that the photosensitizer was released 4.5-fold faster at pH 5.0 than at pH 7.4 when incubated for 24 h. Cellular uptake results showed that the FA-BSA-c-PheoA nanoparticles were readily taken up by B16F10 and MCF7 cancer cells. In vitro phototoxicity results showed that FA-BSA-c-PheoA NPs have higher efficacy on cancer cells compared to simple BSA-c-PheoA NPs. In vivo bioimaging results exhibited that FA-BSA-c-PheoA NPs greatly accumulated into the tumor area as compared to free PheoA. These results show that our prepared FA-BSA-c-PheoA NPs have the potential to be applied as theranostic agents in photodynamic therapy and photodiagnosis of cancer.
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The objective of this study was to develop an albumin nanoparticle with improved stability and drug loading capacity. Generation of nanomaterials having physiologically stable and high potential for drug delivery is still challenging. Herein we synthesized cholesteryl albumin conjugate using N,N-disuccinimidyl carbonate coupling reagent and prepared paclitaxel-loaded cholesteryl albumin nanoparticle (PTX-Chol-BSA) by self-assembly with the mean hydrodynamic diameter of 147.6±1.6nm and with high loading capacity. PTX-Chol-BSA nanoparticle showed much higher colloidal stability than a simple complex of PTX and BSA (PTX-BSA) and sustained release profile. PTX-Chol-BSA nanoparticles exhibited greater cellular uptake and cytotoxicity in B16F10 and MCF-7 cancer cell lines, as compared with PTX in Cremophor EL/ethanol (PTX-Cre/EtOH) and PTX-BSA formulations. A pharmacokinetic study in tumor-bearing mice showed that the area under the concentration-time curve (AUC0-8 h) following the administration of PTX-Chol-BSA was 1.6-2-fold higher than those following the administration of PTX-Cre/EtOH and PTX-BSA. In addition, the tumor AUC0-8 h of PTX-Chol-BSA was around 2-fold higher than that of PTX-BSA. Furthermore, in vivo antitumor efficacy results revealed that PTX-Chol-BSA nanoparticles have greater antitumor efficacy. In conclusion, we demonstrated the potential of PTX-Chol-BSA nanoparticles for anti-tumor chemotherapy, with enhanced in vitro and in vivo behaviors, as compared to PTX-BSA and PTX-Cre/EtOH.
Asunto(s)
Albúminas/química , Antineoplásicos/administración & dosificación , Colesterol/química , Portadores de Fármacos/química , Nanopartículas/química , Neoplasias Experimentales/metabolismo , Paclitaxel/administración & dosificación , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Área Bajo la Curva , Supervivencia Celular/efectos de los fármacos , Composición de Medicamentos , Liberación de Fármacos , Estabilidad de Medicamentos , Endocitosis/efectos de los fármacos , Humanos , Células MCF-7 , Masculino , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Paclitaxel/sangre , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Tamaño de la Partícula , Albúmina Sérica Bovina/química , Distribución TisularRESUMEN
Chitosan has been widely explored as one of the most favorable biomaterials for various pharmaceutical applications due to its biodegradability and biocompatibility. Here, we report novel PEGylated-chitosan-ceramide (PEG-CS-CE) that forms stable polymeric nanoparticles capable of functioning as efficient carriers of hydrophobic drug molecules. The chitosan-ceramide conjugate (CS-CE) was linked with amine-polyethyleneglycol (NH2-PEG2000) by using dicyclohexylcarbodiimide/N-hydroxysuccinimide (DCC-NHS) to obtain PEG-CS-CE that could exhibit steric stabilization in biological environments. The structure of the conjugate was determined by proton ((1)H) NMR and FT-IR spectrometry. Under suitable conditions, the PEG-CS-CE self-assembled to form colloidally stable nanoparticles with a mean diameter of â¼ 200 nm. Further, hydrophobic anti-tumor agent paclitaxel (PTX) was incorporated into the polymeric nanoparticle with 90% loading efficiency and 11.3% loading capacity via an emulsion-solvent evaporation method. The PTX-loaded PEG-CS-CE nanoparticle showed sustained release and exhibited higher cellular uptake and a comparable cytotoxic efficacy to that of free PTX on B16F10 melanoma and MCF-7 human breast adenocarcinoma cell lines. The empty nanoparticle showed no toxicity, indicating that the co-polymer is safe to use in drug delivery. The polymeric nanoparticle PEG-CS-CE developed by us represent promising nanocarriers of hydrophobic drug molecules.