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DectiSomes are anti-infective drug-loaded liposomes targeted to pathogenic cells by pathogen receptors including the Dectins. We have previously used C-type lectin (CTL) pathogen receptors Dectin-1, Dectin-2, and DC-SIGN to target DectiSomes to the extracellular oligoglycans surrounding diverse pathogenic fungi and kill them. Dectin-3 (also known as MCL, CLEC4D) is a CTL pathogen receptor whose known cognate ligands are partly distinct from other CTLs. We expressed and purified a truncated Dectin-3 polypeptide (DEC3) comprised of its carbohydrate recognition domain and stalk region. We prepared amphotericin B (AmB)-loaded pegylated liposomes (AmB-LLs) and coated them with this isoform of Dectin-3 (DEC3-AmB-LLs), and we prepared control liposomes coated with bovine serum albumin (BSA-AmB-LLs). DEC3-AmB-LLs bound to the exopolysaccharide matrices of Candida albicans, Rhizopus delemar (formerly known as R. oryzae), and Cryptococcus neoformans from one to several orders of magnitude more strongly than untargeted AmB-LLs or BSA-AmB-LLs. The data from our quantitative fluorescent binding assays were standardized using a CellProfiler program, AreaPipe, that was developed for this purpose. Consistent with enhanced binding, DEC3-AmB-LLs inhibited and/or killed C. albicans and R. delemar more efficiently than control liposomes and significantly reduced the effective dose of AmB. In conclusion, Dectin-3 targeting has the potential to advance our goal of building pan-antifungal DectiSomes.
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Antifúngicos , Criptococose , Humanos , Antifúngicos/farmacologia , Lipossomos/química , Lipossomos/farmacologia , Anfotericina B/farmacologia , Anfotericina B/química , Candida albicansRESUMO
Gene therapy and sonodynamic therapy, as emerging treatment methods, have great potential in cancer treatment. However, there are significant challenges in the in vivo delivery of genes and sonosensitizers during the treatment process, which ultimately affects the therapeutic outcome. In this study, an ultrasound-sensitive targeted liposome nanoparticle system (MLipsiBcl-2) is developed to deliver the sonosensitizers and siRNA for the synergistic treatment of hepatocellular carcinoma. Generation of reactive oxygen species (ROS) by MLipsiBcl-2 can be initiated through ultrasound stimulation, leading to liposome rupture and release of the sonosensitizer and small interfering RNA (siRNA). Furthermore, ROS can disrupt lysosomal membranes, facilitating gene release for downregulating overexpressed antiapoptotic protein levels in cancer cells. Experimental results from in vitro and in vivo studies demonstrated the efficacy of synergistic treatment on hepatocellular carcinoma cells and the high biocompatibility of MLipsiBcl-2 under ultrasound stimulation. The advancement of this ultrasound-sensitive targeted gene delivery system shows potential as a versatile therapeutic platform that is easily operable, presenting a prospect for a synergistic treatment approach across various cancer types.
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Triple-negative breast Cancer (TNBC) is one of the deadliest types, making up about 20% of all breast cancers. Chemotherapy is the traditional manner of progressed TNBC treatment; however, it has a short-term result with a high reversibility pace. The lack of targeted treatment limited and person-dependent treatment options for those suffering from TNBC cautions to be the worst type of cancer among breast cancer patients. Consequently, appropriate treatment for this disease is considered a major clinical challenge. Therefore, various treatment methods have been developed to treat TNBC, among which chemotherapy is the most common and well-known approach recently studied. Although effective methods are chemotherapies, they are often accompanied by critical limitations, especially the lack of specific functionality. These methods lead to systematic toxicity and, ultimately, the expansion of multidrug-resistant (MDR) cancer cells. Therefore, finding novel and efficient techniques to enhance the targeting of TNBC treatment is an essential requirement. Liposomes have demonstrated that they are an effective method for drug delivery; however, among a large number of liposome-based drug delivery systems annually developed, a small number have just received authorization for clinical application. The new approaches to using liposomes target their structure with various ligands to increase therapeutic efficiency and diminish undesired side effects on various body tissues. The current study describes the most recent strategies and research associated with functionalizing the liposomes' structure with different ligands as targeted drug carriers in treating TNBCs in preclinical and clinical stages.
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Targeted liposomes, as a promising carrier, have received tremendous attention in COVID-19 vaccines, molecular imaging, and cancer treatment, due to their enhanced cellular uptake and payload accumulation at target sites. However, the conventional methods for preparing targeted liposomes still suffer from limitations, including complex operation, time-consuming, and poor reproducibility. Herein, a facile and scalable strategy is developed for one-step construction of targeted liposomes using a versatile microfluidic mixing device (MMD). The engineered MMD provides an advanced synthesis platform for multifunctional liposome with high production rate and controllability. To validate the method, a programmed death-ligand 1 (PD-L1)-targeting aptamer modified indocyanine green (ICG)-liposome (Apt-ICG@Lip) is successfully constructed via the MMD. ICG and the PD-L1-targeting aptamer are used as model drug and targeting moiety, respectively. The Apt-ICG@Lip has high encapsulation efficiency (89.9 ± 1.4%) and small mean diameter (129.16 ± 5.48 nm). In vivo studies (PD-L1-expressing tumor models) show that Apt-ICG@Lip can realize PD-L1 targeted photoacoustic imaging, fluorescence imaging, and photothermal therapy. To verify the versatility of this approach, various targeted liposomes with different functions are further prepared and investigated. These experimental results demonstrate that this method is concise, efficient, and scalable to prepare multifunctional targeted liposomal nanoplatforms for molecular imaging and disease theranostics.
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COVID-19 , Lipossomos , Humanos , Antígeno B7-H1 , Microfluídica , Vacinas contra COVID-19 , Reprodutibilidade dos Testes , Verde de Indocianina , Linhagem Celular TumoralRESUMO
Cerebral malaria (CM) is a life-threatening neurological complication caused by Plasmodium falciparum. About 627,000 patients died of malaria in 2020. Currently, artemisinin and its derivatives are the front-line drugs used for the treatment of cerebral malaria. However, they cannot target the brain, which decreases their effectiveness. Therefore, increasing their ability to target the brain by the nano-delivery system with brain-targeted materials is of great significance for enhancing the effects of antimalarials and reducing CM mortality. This study used glucose transporter 1 (GLUT1) on the blood-brain barrier as a target for a synthesized cholesterol-undecanoic acid-glucose conjugate. The molecular dynamics simulation found that the structural fragment of glucose in the conjugate faced the outside the phospholipid bilayers, which was conducive to the recognition of brain-targeted liposomes by GLUT1. The fluorescence intensity of the brain-targeted liposomes (na-ATS/TMP@lipoBX) in the mouse brain was significantly higher than that of the non-targeted liposomes (na-ATS/TMP@lipo) in vivo (P < 0.001) after intranasal administration. The infection and recurrence rate of the mice receiving na-ATS/TMP@lipoBX treatment were significantly decreased, which had more advantages than those of other administration groups. The analysis of pharmacokinetic data showed that na-ATS/TMP@lipoBX could enter the brain in both systemic circulation and nasal-brain pathway to treat malaria. Taken together, these results in this study provide a new approach to the treatment of cerebral malaria.
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Malária Cerebral , Nanocompostos , Animais , Glucose/química , Transportador de Glucose Tipo 1 , Lipossomos/química , Malária Cerebral/tratamento farmacológico , CamundongosRESUMO
Brain tumors are hard to treat with the currently available therapy. The major obstacle in the treatment of brain tumors is the lack of therapeutic strategies capable to penetrate the blood-brain barrier (BBB). The BBB is an endothelial interface that separates the brain from the circulatory blood system and prevents the exposure of the central nervous system (CNS) to circulating toxins and potentially harmful compounds. Unfortunately, the BBB prevents also the penetration of therapeutic compounds into the brain. We present here a drug-delivery liposomal carrier, conjugated to a peptide inserted in the liposomal membrane, which is putatively recognized by BBB transporters. The peptide is a short sequence of 5 amino acids (RERMS) present in the amyloid precursor protein (APP). This APP-targeted liposomal system was designed specifically for transporting compounds with anti-cancer activity via the BBB into the brain in an effective manner. This drug-delivery liposomal carrier loaded with the anti-cancer compounds temozolomide (TMZ), curcumin, and doxorubicin crossed the BBB in an in vitro model as well as in vivo (mice model). In the in vitro model, the targeted liposomes crossed the BBB model fourfold higher than the non-targeted liposomes. Labeled targeted liposomes penetrated the brain in vivo 35% more than non-targeted liposomes. Treatment of mice that underwent intracranial injection of human U87 glioblastoma, with the targeted liposomes loaded with the three tested anti-cancer agents, delayed the tumor growth and prolonged the mice survival in a range of 45% -70%. It appears that the targeted liposomal drug-delivery system enables better therapeutic efficacy in a SCID mouse model of glioblastoma compared to the corresponding non-targeted liposomes and the free compounds.
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Precursor de Proteína beta-Amiloide/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Fragmentos de Peptídeos/administração & dosagem , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Animais Recém-Nascidos , Antineoplásicos/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Portadores de Fármacos/metabolismo , Humanos , Lipossomos , Camundongos , Camundongos SCID , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Wistar , Suínos , Resultado do TratamentoRESUMO
Gastric cancer is one of the leading causes of cancer-related death worldwide with a poor prognosis. Gastric cancer is usually treated with surgery and chemotherapy, accompanied by a high rate of metastasis and recurrence. In this paper, R8 (RRRRRRRR) modified vinorelbine plus schisandrin B liposomes had been successfully constructed for treating gastric cancer. In the liposomes, R8 was used to enhance the intracellular uptake, schisandrin B was incorporated into liposomes for inhibiting tumor cells metastasis, and vinorelbine was encapsulated into liposomes as antitumor drugs. Studies were performed on BGC-823 cells in vitro and were verified in the BGC-823 cell xenografts nude mice in vivo. Results in vitro demonstrated that the targeting liposomes could induce BGC-823 cells apoptosis, inhibit the metastasis of tumor cells, and increase targeting effects to tumor cells. Meanwhile, action mechanism studies showed that the targeting liposomes could down-regulate VEGF, VE-Cad, HIF-1a, PI3K, MMP-2, and FAK to inhibit tumor metastasis. In vivo results exhibited that the targeting liposomes displayed an obvious antitumor efficacy by accumulating selectively in tumor site and induce tumor cell apoptosis. Hence, R8 modified vinorelbine plus schisandrin B liposomes might provide a safe and efficient therapy strategy for gastric cancer.
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Lipossomos , Neoplasias Gástricas , Vinorelbina/química , Animais , Apoptose , Linhagem Celular Tumoral , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Lignanas/química , Lignanas/farmacologia , Camundongos , Camundongos Nus , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Vinorelbina/farmacologiaRESUMO
Tumor invasion and metastasis are the nodus of anti-tumor. Epithelial cell-mesenchymal transition is widely regarded as one of the key steps in the invasion and metastasis of breast cancer. In this study, GGP modified daunorubicin plus dioscin liposomes are constructed and characterized. GGP modified daunorubicin plus dioscin liposome has suitable particle size, narrow PDI, zeta potential of about -5 mV, long cycle effect, and enhanced cell uptake due to surface modification of GGP making the liposome could enter the inside of the tumor to fully exert its anti-tumor effect. The results of in vitro experiments show that the liposome has superior killing effect on tumor cells and invasion. In vivo results indicate that the liposome prolongs the drug's prolonged time in the body and accumulates at the tumor site with little systemic toxicity. In short, the targeted liposome can effectively inhibit tumor invasion and may provide a new strategy for the treatment of invasive breast cancer.
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Neoplasias da Mama , Daunorrubicina/química , Diosgenina/análogos & derivados , Transição Epitelial-Mesenquimal , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Diosgenina/química , Humanos , LipossomosRESUMO
BACKGROUND: Liver cancer is a common malignant tumor worldwide, and its morbidity and mortality increase each year. The disease has a short course and high mortality, making it a serious threat to human health. PURPOSE: The objective of this study was to create novel liver-targeting nanoliposomes to encapsulate cantharidin (CTD) as a potential treatment for hepatic carcinoma. METHODS: 3-Galactosidase-30-stearyl deoxyglycyrrhetinic acid (11-DGA-3-O-Gal)-modified liposomes (11-DGA-3-O-Gal-CTD-lip) for the liver-targeted delivery of CTD were prepared via the film-dispersion method and characterized. In vitro analyses of the effects on cellular cytotoxicity, cell migration, cell cycle, and cell apoptosis were carried out and an in vivo pharmacokinetics study and tissue distribution analysis were performed. RESULTS: Compared with unmodified liposomes (CTD-lip), 11-DGA-3-O-Gal-CTD-lip showed higher cytotoxicity and increased the inhibition of HepG2 cell migration, but they did not increase the apoptotic rate of cells. The inhibition mechanism of 11-DGA-3-O-Gal-CTD-lip on hepatocellular carcinoma was partly through cell cycle arrest at the S phase. Analysis of pharmacokinetic parameters indicated that 11-DGA-3-O-Gal-CTD-lip were eliminated more rapidly than CTD-lip. Regarding tissue distribution, the targeting efficiency of 11-DGA-3-O-Gal-CTD-lip to the liver was (41.15 ± 3.28)%, relative targeting efficiency was (1.53 ± 0.31)%, relative uptake rate was( 1.69 ± 0.37)%, and peak concentration ratio was (2.68 ± 0.12)%. CONCLUSION: 11-DGA-3-O-Gal-CTD-lip represent a promising nanocarrier for the liver-targeted delivery of antitumor drugs to treat hepatocellular carcinoma.
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Antineoplásicos/administração & dosagem , Antineoplásicos/química , Cantaridina/administração & dosagem , Cantaridina/química , Galactosidases/química , Ácido Glicirretínico/química , Lipossomos , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Cantaridina/síntese química , Cantaridina/farmacocinética , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Sobrevivência Celular , Técnicas de Química Sintética , Portadores de Fármacos , Composição de Medicamentos , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas , Masculino , Estrutura Molecular , Ratos , Distribuição TecidualRESUMO
BACKGROUND: Liposomes, used to improve the therapeutic index of new and established drugs, have advanced with the insertion of active targeting. The lectin from Lotus tetragonolobus (LTL), which binds glycans containing alpha-1,2-linked fucose, reveals surface regionalized glycoepitopes in highly proliferative cells not detectable in normally growing cells. In contrast, other lectins localize the corresponding glycoepitopes all over the cell surface. LTL also proved able to penetrate the cells by an unconventional uptake mechanism. METHODS: We used confocal laser microscopy to detect and localize LTL-positive glycoepitopes and lectin uptake in two cancer cell lines. We then constructed doxorubicin-loaded liposomes functionalized with LTL. Intracellular delivery of the drug was determined in vitro and in vivo by confocal and electron microscopy. RESULTS: We confirmed the specific localization of Lotus binding sites and the lectin uptake mechanism in the two cell lines and determined that LTL-functionalized liposomes loaded with doxorubicin greatly increased intracellular delivery of the drug, compared to unmodified doxorubicin-loaded liposomes. The LTL-Dox-L mechanism of entry and drug delivery was different to that of Dox-L and other liposomal preparations. LTL-Dox-L entered the cells one by one in tiny tubules that never fused with lysosomes. LTL-Dox-L injected in mice with melanoma specifically delivered loaded Dox to the cytoplasm of tumor cells. CONCLUSIONS: Liposome functionalization with LTL promises to broaden the therapeutic potential of liposomal doxorubicin treatment, decreasing non-specific toxicity. GENERAL SIGNIFICANCE: Doxorubicin-LTL functionalized liposomes promise to be useful in the development of new cancer chemotherapy protocols.
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Proliferação de Células/efeitos dos fármacos , Fabaceae/metabolismo , Lectinas/administração & dosagem , Lectinas/química , Lipossomos/administração & dosagem , Lipossomos/química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Citoplasma/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos , Epitopos/administração & dosagem , Epitopos/química , Humanos , Lisossomos/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , CamundongosRESUMO
We describe the use of bioactive peptides to drive liposomal drugs on target receptors overexpressed in cancer cells. A detailed description for several targeting liposomes derivatized with different peptides and thus able to target relevant receptors for cancer therapy is reported. Even if the development of peptide-targeted liposomes represents a great advance in the use of liposomal drugs for cancer therapy, many critical issues are still unsolved in the development of these innovative drug delivery systems. Advantages and drawbacks of the peptide-mediated active targeting are discussed.
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Sistemas de Liberação de Medicamentos , Lipossomos/química , Peptídeos/química , Humanos , Receptor ErbB-2/metabolismoRESUMO
The special bilayer structure of mitochondrion is a promising therapeutic target in the diagnosis and treatment of diseases such as cancer and metabolic diseases. Nanocarriers such as liposomes modified with mitochondriotropic moieties can be developed to send therapeutic molecules to mitochondria. In this study, DSPE-PEG-TPP polymer conjugate was synthesized and used to prepare mitochondria-targeted liposomes (TPPLs) to improve the therapeutic index of chemotherapeutic agents functioning in mitochondria and reduce their side effects. Doxorubicin (Dox) loaded-TPPL and non-targeted PEGylated liposomes (PPLs) were prepared and compared based on physicochemical properties, morphology, release profile, cellular uptake, mitochondrial localization, and anticancer effects. All formulations were spherically shaped with appropriate size, dispersity, and zeta potential. The stability of the liposomes was favorable for two months at 4 °C. TPPLs localize to mitochondria, whereas PPLs do not. The empty TPPLs and PPLs were not cytotoxic to HCT116 cells. The release kinetics of Dox-loaded liposomes showed that Dox released from TPPLs was higher at pH 5.6 than at pH 7.4, which indicates a higher accumulation of the released drug in the tumor environment. The half-maximal inhibitory concentration of Dox-loaded TPPLs and PPLs was 1.62-fold and 1.17-fold lower than that of free Dox due to sustained drug release, respectively. The reactive oxygen species level was significantly increased when HCT116 cells were treated with Dox-loaded TPPLs. In conclusion, TPPLs may be promising carriers for targeted drug delivery to tumor mitochondria.
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Novel therapeutics for the treatment of ischemic stroke remains to be the unmet clinical needs. Previous studies have indicated that salvianolic acid A (SAA) is a promising candidate for the treatment of the brain diseases. However, SAA has poor absolute bioavailability and does not efficiently cross the intact blood-brain barrier (BBB), which limit its efficacy. To this end we developed a brain-targeted liposomes for transporting SAA via the BBB by incorporating the liposomes to a transport receptor, insulin-like growth factor-1 receptor (IGF1R). The liposomes were prepared by ammonium sulfate gradients loading method. The prepared SAA-loaded liposomes (Lipo/SAA) were modified with IGF1R monoclonal antibody to generate IGF1R antibody-conjugated Lipo/SAA (IGF1R-targeted Lipo/SAA). The penetration of IGF1R-targeted Lipo/SAA into the brain was confirmed by labeling with Texas Red, and their efficacy were evaluate using middle cerebral artery occlusion (MCAO) model. The results showed that IGF1R-targeted Lipo/SAA are capable of transporting SAA across the BBB into the brain, accumulation in brain tissue, and sustained releasing SAA for several hours. Administration o IGF1R-targeted Lipo/SAA notably reduced infarct size and neuronal damage, improved neurological function and inhibited cerebral inflammation, which had much higher efficiency than no-targeted SAA.
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AVC Isquêmico , Lipossomos , Animais , AVC Isquêmico/tratamento farmacológico , Masculino , Ácidos Cafeicos/administração & dosagem , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Receptor IGF Tipo 1/metabolismo , Camundongos , Lactatos/administração & dosagem , Lactatos/química , Infarto da Artéria Cerebral Média/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Ratos Sprague-Dawley , Ratos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacosRESUMO
Background: 2',3'-cGAMP (2',3'-cyclic AMP-GMP) has been reported as an agonist of the STING (stimulator of interferon genes) signaling pathway. However, cGAMP has poor membrane permeability and can be hydrolyzed by ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), limiting its ability to activate the STING-IRF3 pathway. This study aimed to investigate that the folate-targeted liposomal cGAMP could overcome the defects of free cGAMP to enhance the antitumor effect. Materials and Methods: cGAMP was encapsulated in PEGylated folic acid-targeted liposomes to construct a carrier-delivered formulation. The particle size and morphology were detected by dynamic light scattering and transmission electron microscopy. The sustained-release ability was measured by drug release and pharmacokinetics. Animal models were applied to evaluate the tumor inhibition efficiency in vivo. Flow cytometry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction were used to detect the expression of immune cells, secreted cytokines, and target genes. The activation of the STING-IRF3 pathway was evaluated by immunofluorescence. Results: Physical characters of liposomes revealed that the prepared liposomes were stable in neutral humoral environments and released more internal drugs in acidic tumor tissues. Systemic therapy with liposomes on Colorectal 26 tumor-bearing mice in vivo effectively inhibited tumor growth via stimulating the expression of CD8+ T cells and reversed the immunosuppressed tumor microenvironment (TME). Conclusions: The study suggests that the folic acid-targeted cGAMP-loaded liposomes deliver drugs to the TME to enhance the STING agonist activity, improving the efficiency of tumor therapy via the cGAMP-STING-IRF3 pathway.
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Lipossomos , Neoplasias , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Proteínas de Membrana/genética , Neoplasias/patologia , Microambiente TumoralRESUMO
Pseudomonas aeruginosa is the leading nosocomial and community-acquired pathogen causing a plethora of acute and chronic infections. The Centers for Disease Control and Prevention has designated multidrug-resistant isolates of P. aeruginosa as a serious threat. A novel delivery vehicle capable of specifically targeting â¯P. aeruginosa, and encapsulating antimicrobials, may address the challenges associated with these infections. We have developed hetero-multivalent targeted liposomes functionalized with host cell glycans to increase the delivery of antibiotics to the site of infection. Previously, we have demonstrated that compared with monovalent liposomes, these hetero-multivalent liposomes bind with higher affinity to P. aeruginosa. Here, compared with nontargeted liposomes, we have shown that greater numbers of targeted liposomes are found in the circulation, as well as at the site of P. aeruginosa (PAO1) infection in the thighs of CD-1 mice. No significant difference was found in the uptake of targeted, nontargeted, and PEGylated liposomes by J774.A1 macrophages. Ciprofloxacin-loaded liposomes were formulated and characterized for size, encapsulation, loading, and drug release. In vitro antimicrobial efficacy was assessed using CLSI broth microdilution assays and time-kill kinetics. Lastly, PAO1-inoculated mice treated with ciprofloxacin-loaded, hetero-multivalent targeted liposomes survived longer than mice treated with ciprofloxacin-loaded, monovalent targeted, or nontargeted liposomes and free ciprofloxacin. Thus, liposomes functionalized with host cell glycans target P. aeruginosa resulting in increased retention of the liposomes in the circulation, accumulation at the site of infection, and increased survival time in a mouse surgical site infection model. Consequently, this formulation strategy may improve outcomes in patients infected with P. aeruginosa.
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Anti-Infecciosos , Infecções por Pseudomonas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Ciprofloxacina , Lipossomos , Camundongos , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosaRESUMO
Combination therapy has gained a lot of attention thanks to its superior activity against cancer. In the present study, we report a cRGD-targeted liposomal preparation for co-delivery of programmed cell death ligand 1 (PD-L1) small interfering RNA (siRNA) and anemoside B4 (AB4)âAB4/siP-c-Lâand evaluate its anticancer efficiency in mouse models of LLC and 4T1 tumors. AB4/siP-c-L showed a particle size of (180.7 ± 7.3) nm and a ζ-potential of (32.8 ± 1.5) mV, with high drug encapsulation, pH-sensitive release properties, and good stability in serum. AB4/siP-c-L demonstrated prolonged blood circulation and increased tumor accumulation. Elevated cellular uptake was dependent on the targeting ligand cRGD. This combination induced significant tumor inhibition in LLC xenograft tumor-bearing mice by downregulating PD-L1 protein expression and modulating the immunosuppressive microenvironment. Liposomes favored the antitumor T-cell response with long-term memory, without obvious toxicity. A similar tumor growth inhibition was also demonstrated in the 4T1 tumor model. In summary, our results indicate that cRGD-modified and AB4- and PD-L1 siRNA-coloaded liposomes have potential as an antitumor preparation, and this approach may lay a foundation for the development of a new targeted drug delivery system.
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Antígeno B7-H1 , Lipossomos , Animais , Linhagem Celular Tumoral , Humanos , Imunoterapia , Ligantes , Camundongos , RNA Interferente Pequeno , SaponinasRESUMO
BACKGROUND AND AIM: A photosensitizer (PS) delivery and comprehensive tumor targeting platform was developed that is centered on the photosensitization of key pharmacological targets in solid tumors (cancer cells, tumor vascular endothelium, and cellular and non-cellular components of the tumor microenvironment) before photodynamic therapy (PDT). Interstitially targeted liposomes (ITLs) encapsulating zinc phthalocyanine (ZnPC) and aluminum phthalocyanine (AlPC) were formulated for passive targeting of the tumor microenvironment. In previous work it was established that the PEGylated ITLs were taken up by cultured cholangiocarcinoma cells. The aim of this study was to verify previous results in cancer cells and to determine whether the ITLs can also be used to photosensitize cells in the tumor microenvironment and vasculature. Following positive results, rudimentary in vitro and in vivo experiments were performed with ZnPC-ITLs and AlPC-ITLs as well as their water-soluble tetrasulfonated derivatives (ZnPCS4 and AlPCS4) to assemble a research dossier and bring this platform closer to clinical transition. METHODS: Flow cytometry and confocal microscopy were employed to determine ITL uptake and PS distribution in cholangiocarcinoma (SK-ChA-1) cells, endothelial cells (HUVECs), fibroblasts (NIH-3T3), and macrophages (RAW 264.7). Uptake of ITLs by endothelial cells was verified under flow conditions in a flow chamber. Dark toxicity and PDT efficacy were determined by cell viability assays, while the mode of cell death and cell cycle arrest were assayed by flow cytometry. In vivo systemic toxicity was assessed in zebrafish and chicken embryos, whereas skin phototoxicity was determined in BALB/c nude mice. A PDT efficacy pilot was conducted in BALB/c nude mice bearing human triple-negative breast cancer (MDA-MB-231) xenografts. RESULTS: The key findings were that (1) photodynamically active PSs (i.e., all except ZnPCS4) were able to effectively photosensitize cancer cells and non-cancerous cells; (2) following PDT, photodynamically active PSs were highly toxic-to-potent as per anti-cancer compound classification; (3) the photodynamically active PSs did not elicit notable systemic toxicity in zebrafish and chicken embryos; (4) ITL-delivered ZnPC and ZnPCS4 were associated with skin phototoxicity, while the aluminum-containing PSs did not exert detectable skin phototoxicity; and (5) ITL-delivered ZnPC and AlPC were equally effective in their tumor-killing capacity in human tumor breast cancer xenografts and superior to other non-phthalocyanine PSs when appraised on a per mole administered dose basis. CONCLUSIONS: AlPC(S4) are the safest and most effective PSs to integrate into the comprehensive tumor targeting and PS delivery platform. Pending further in vivo validation, these third-generation PSs may be used for multi-compartmental tumor photosensitization.
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Colangiocarcinoma , Compostos Organometálicos , Fotoquimioterapia , Animais , Linhagem Celular Tumoral , Embrião de Galinha , Células Endoteliais , Humanos , Lipossomos , Camundongos , Camundongos Nus , Compostos Organometálicos/farmacologia , Compostos Organometálicos/uso terapêutico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Microambiente Tumoral , Peixe-ZebraRESUMO
Triple-negative breast cancers (TNBCs) are highly aggressive and recurrent. Standard cytotoxic chemotherapies are currently the main treatment options, but their clinical efficacies are limited and patients usually suffer from severe side effects. The goal of this study was to develop and evaluate targeted liposomes-delivered combined chemotherapies to treat TNBCs. Specifically, the IC50 values of the microtubule polymerization inhibitor mertansine (DM1), mitotic spindle assembly defecting taxane (paclitaxel, PTX), DNA synthesis inhibitor gemcitabine (GC), and DNA damage inducer doxorubicin (AC) were tested in both TNBC MDA-MB-231 and MDA-MB-468 cells. Then we constructed the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) tagged liposomes and confirmed its TNBC cell surface binding using flow cytometry, internalization with confocal laser scanning microscopy, and TNBC xenograft targeting in NSG female mice using In Vivo Imaging System. The safe dosage of anti-EGFR liposomal chemotherapies, i.e., <20% body weight change, was identified. Finally, the in vivo anti-tumor efficacy studies in TNBC cell line-derived xenograft and patient-derived xenograft models revealed that the targeted delivery of chemotherapies (mertansine and gemcitabine) can effectively inhibit tumor growth. This study demonstrated that the targeted liposomes enable the new formulations of combined therapies that improve anti-TNBC efficacy.
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PURPOSE: Chronic pancreatitis (CP) is an inflammatory disorder of the pancreas that leads to impaired pancreatic function. The limited therapeutic options and the lack of molecular targeting ligands or non-serum-based biomarkers hinder the development of target-specific drugs. Thus, there is a need for an unbiased, comprehensive discovery and evaluation of pancreatitis-specific ligands. METHODS: This study utilized a computational-guided in vivo phage display approach to select peptide ligands selective for cellular components in the caerulein-induced mouse model of CP. The identified peptides were conjugated to pegylated DOPC liposomes via the reverse-phase evaporation method, and the in vivo specificity and pharmacokinetics were determined. As proof of concept, CP-targeted liposomes were used to deliver an antifibrotic small molecular drug, apigenin. Antifibrotic effects determined by pancreatic histology, fibronectin expression, and collagen deposition were evaluated. RESULTS: We have identified five peptides specific for chronic pancreatitis and demonstrated selectivity to activated pancreatic stellate cells, acinar cells, macrophages, and extracellular matrix, respectively. MDLSLKP-conjugated liposomes demonstrated an increased particle accumulation by 1.3-fold in the inflamed pancreas compared to the control liposomes. We also observed that targeted delivery of apigenin resulted in improved acini preservation, a 37.2% and 33.1% respective reduction in collagen and fibronectin expression compared to mice receiving the free drug, and reduced oxidative stress in the liver. CONCLUSION: In summary, we have developed a systematic approach to profile peptide ligands selective for cellular components of complex disease models and demonstrated the biomedical applications of the identified peptides to improve tissue remodeling in the inflamed pancreas.
Assuntos
Pancreatite Crônica , Animais , Ceruletídeo , Ligantes , Camundongos , Pâncreas , Células Estreladas do Pâncreas , Pancreatite Crônica/tratamento farmacológicoRESUMO
The use of targeted liposomes encapsulating chemotherapy drugs enhances the specific targeting of cancer cells, thus reducing the side effects of these drugs and providing patient-friendly chemotherapy treatment. Targeted pegylated (stealth) liposomes have the ability to safely deliver their loaded drugs to the cancer cells by targeting specific receptors overly expressed on the surface of these cells. Applying ultrasound as an external stimulus will safely trigger drug release from these liposomes in a controlled manner. In this study, we investigated the release kinetics of the model drug "calcein" from targeted liposomes sonicated with low-frequency ultrasound (20 kHz). Our results showed that pegylated liposomes were more sonosensitive compared to nonpegylated liposomes. A comparison of the effect of three targeting moieties conjugated to the surface of pegylated liposomes, namely human serum albumin (HSA), transferrin (Tf) and arginylglycylaspartic acid (RGD), on calcein release kinetics was conducted. The fluorescent results showed that HSA-PEG and Tf-PEG liposomes were more sonosensitive (showing higher calcein release following the exposure to pulsed LFUS) compared to the control pegylated liposomes, thus adding more acoustic benefits to their targeting efficacy.