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1.
Acta Biomater ; 136: 508-518, 2021 12.
Article in English | MEDLINE | ID: mdl-34626819

ABSTRACT

Drug-based chemotherapy is associated with serious side effects. We developed a chemotherapeutic system comprising a chitosan hydrogel (CH-HG) containing gold cluster-labeled liposomal doxorubicin (DOX) (CH-HG-GLDOX) as an injectable drug depot system. CH-HG-GLDOX can be directly injected into tumor tissue without a surgical procedure, allowing this system to act as a reservoir for liposomal DOX. CH-HG-GLDOX enhanced the retention time of DOX in tumor tissue and controlled its release in response to near-infrared (NIR) irradiation, resulting in significant inhibition of tumor growth and reduced DOX-related toxicity. The combined effect of CH-HG-GLDOX and poly (D,L-lactide-co-glycolic acid) nanoparticle-based vaccines increased cytotoxic CD8+ T cell immunity, leading to enhanced synergistic therapeutic efficacy. CH-HG-GLDOX provides an advanced therapeutic approach for local drug delivery and controlled release of DOX, resulting in reduced toxicity. Here, we suggest a combination strategy for chemo- and immunotherapies, as well as in nanomedicine applications. STATEMENT OF SIGNIFICANCE: We developed an injectable hydrogel containing gold cluster-labeled liposomes for sustained drug release at the tumor site. Moreover, we demonstrated the combined therapeutic efficacy of a hydrogel system and a nanoparticle-based immunotherapeutic vaccine for melanoma cancer. Thus, we show a potential combination approach for chemo- and immunotherapies for cancer treatment.


Subject(s)
Liposomes , Melanoma , Cell Line, Tumor , Doxorubicin/pharmacology , Drug Delivery Systems , Drug Liberation , Humans , Hydrogels
2.
Int J Nanomedicine ; 15: 8427-8436, 2020.
Article in English | MEDLINE | ID: mdl-33149585

ABSTRACT

BACKGROUND: Epithelial ovarian cancer (EOC) is a fatal gynecologic malignancy that is usually treated with chemotherapy after surgery. However, patients who receive chemotherapy experience severe side effects because of the inherent toxicity and high dose of chemotherapeutics. To overcome these issues, we suggest a combination therapeutic strategy using liposomes encapsulating linalool nanoemulsions (LN-NEs) and doxorubicin (DOX), a chemotherapeutic drug, to increase their synergistic antitumor efficacy and reduce the incidence of side effects from chemotherapeutics for EOC. METHODS: The physical properties of LN-NE-DOX-liposomes were characterized by light scattering with a particle size analyzer. Cell viability was determined by MTT assay. Therapeutic efficacy was evaluated in a mouse HeyA8 EOC tumor model of ovarian carcinoma. Additionally, biochemical toxicity was analyzed for levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood urea nitrogen (BUN) using BALB/c nude mice. RESULTS: The size of the liposomes encapsulating LN-NEs and DOX (LN-NE-DOX-liposomes) was 267.0 ± 4.6 nm, with a loading efficiency of 55.1 ± 3.1% and 27.2 ± 0.9% for linalool and DOX, respectively. Cell viability after treatment with LN-NE-DOX-liposomes was significantly decreased compared to that of cells treated with DOX liposomes, and apoptosis was significantly increased. Additionally, LN-NE-DOX-liposomes significantly inhibited HeyA8 EOC tumor growth compared to that of the control (p < 0.01) and DOX-liposome-treated groups (p < 0.05), while decreasing cell proliferation (Ki67) and microvessel density (CD31), and promoting apoptosis (caspase-3) compared to the control (p < 0.05). Moreover, the liposomal formulations induced no significant differences in biochemical toxicity (AST, ALT, and BUN) compared to healthy control mice, indicating that the liposomal formulations showed no overt toxicity in mice. CONCLUSION: This study demonstrates that the production of LN-NE-DOX-liposomes is a pivotal approach for EOC treatment, suggesting a novel combination therapeutic strategy.


Subject(s)
Acyclic Monoterpenes/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Doxorubicin/analogs & derivatives , Drug Carriers/chemistry , Acyclic Monoterpenes/pharmacology , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Combined Modality Therapy , Doxorubicin/therapeutic use , Emulsions/chemistry , Female , Humans , Liposomes/chemistry , Mice, Inbred BALB C , Mice, Nude , Nanoparticles/chemistry , Particle Size , Polyethylene Glycols/therapeutic use , Treatment Outcome
3.
ACS Appl Bio Mater ; 2(6): 2481-2489, 2019 Jun 17.
Article in English | MEDLINE | ID: mdl-35030704

ABSTRACT

Dendritic cell (DC)-based cancer immunotherapies have been studied extensively. In cancer immunotherapy, the initial key step is the delivery of tumor-specific antigens, leading to the maturation and activation of DCs. To promote effective antigen delivery, liposome-based delivery systems for tumor-specific antigens have been investigated, and although promising, a triggered release of the antigen from the liposome is required to attain an optimum immune response. In this study, we developed CO2-bubble-generating thermosensitive liposomes (BG-TSLs) that encapsulate whole tumor cell lysates (TCLs). The release of the lysate from BG-TSLs can be triggered using near-infrared (NIR) irradiation. We also developed BG-TSLs able to encapsulate doxorubicin (DOX) for combination therapy. The DOX-BG-TSLs and TCL-BG-TSLs have a mean particle size of 114.17 ± 8.28 nm and 123.8 ± 10.2 nm and a surface charge of -22.56 ± 1.3 mV and -28.9 ± 0.8 mV, respectively. CO2 bubble generation within TCL-BG-TSLs and DOX-BG-TSLs by NIR irradiation led to the burst release of TCL or DOX. TCL release from TCL-BG-TSLs promoted dendritic cell maturation and activation, leading to the emergence of antigen-specific cytotoxic CD8+ T cells. The combination of TCL-BG-TSLs with DOX-BG-TSLs showed a significantly greater antitumor efficacy in B16F10 tumor-bearing mice compared to that seen in the control mice (P < 0.001). Taken together, our liposomal delivery system, combined with NIR irradiation, could enhance the therapeutic efficacy of cancer immunotherapies.

4.
Cancer Res ; 78(21): 6247-6256, 2018 11 01.
Article in English | MEDLINE | ID: mdl-30115698

ABSTRACT

Chemotherapy is commonly used in the treatment of ovarian cancer, yet most ovarian cancers harbor inherent resistance or develop acquired resistance. Therefore, novel therapeutic approaches to overcome chemoresistance are required. In this study, we developed a hyaluronic acid-labeled poly(d,l-lactide-co-glycolide) nanoparticle (HA-PLGA-NP) encapsulating both paclitaxel (PTX) and focal adhesion kinase (FAK) siRNA as a selective delivery system against chemoresistant ovarian cancer. The mean size and zeta potential of the HA-PLGA-NP were 220 nm and -7.3 mV, respectively. Incorporation efficiencies for PTX and FAK siRNA in the HA-PLGA-NPs were 77% and 85%, respectively. HA-PLGA-NP showed higher binding efficiency for CD44-positive tumor cells as compared with CD44-negative cells. HA-PLGA (PTX+FAK siRNA)-NP caused increased cytotoxicity and apoptosis in drug-resistant tumor cells. Treatment of human epithelial ovarian cancer tumor models HeyA8-MDR (P < 0.001) and SKOV3-TR (P < 0.001) with HA-PLGA (PTX+FAK siRNA)-NP resulted in significant inhibition of tumor growth. Moreover, in a drug-resistant, patient-derived xenograft (PDX) model, HA-PLGA (PTX+FAK siRNA)-NP significantly inhibited tumor growth compared with PTX alone (P < 0.002). Taken together, HA-PLGA-NP acts as an effective and selective delivery system for both the chemotherapeutic and the siRNA in order to overcome chemoresistance in ovarian carcinoma.Significance: These findings demonstrate the efficacy of a novel, selective, two-in-one delivery system to overcome chemoresistance in epithelial ovarian cancer. Cancer Res; 78(21); 6247-56. ©2018 AACR.


Subject(s)
Carcinoma, Ovarian Epithelial/metabolism , Focal Adhesion Kinase 1/metabolism , Hyaluronan Receptors/chemistry , Nanoparticles/chemistry , Paclitaxel/pharmacology , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , RNA, Small Interfering/metabolism , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Carcinoma, Ovarian Epithelial/drug therapy , Cell Line, Tumor , Cell Survival , Drug Carriers/chemistry , Drug Resistance, Neoplasm , Female , Gene Silencing , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism
5.
Drug Deliv ; 25(1): 1394-1402, 2018 Nov.
Article in English | MEDLINE | ID: mdl-29890852

ABSTRACT

Angiogenesis plays an essential role in the growth and metastasis of tumor cells, and the modulation of angiogenesis can be an effective approach for cancer therapy. We focused on silencing the angiogenic gene PLXDC1 as an important factor for anti-angiogenesis tumor therapy. Herein, we developed PLXDC1 small interfering siRNA (siRNA)-incorporated chitosan nanoparticle (CH-NP/siRNA) coated with hyaluronic acid (HA) to target the CD44 receptor on tumor endothelial cells. This study aimed to improve targeted delivery and enhance therapeutic efficacy for tumor anti-angiogenesis. The HA-CH-NP/siRNA was 200 ± 10 nm in size with a zeta potential of 26.4 mV. The loading efficiency of siRNA to the HA-CH-NP/siRNA was up to 60%. The selective binding of HA-CH-NP/siRNA to CD44-positive tumor endothelial cells increased by 2.1-fold compared with that of the CD44 nontargeted CH-NP/siRNA. PLXDC1 silencing by the HA-CH-NP/siRNA significantly inhibited tumor growth in A2780 tumor-bearing mice compared with that in the control group (p < .01), and mRNA expression of PLXDC1 was significantly reduced in the HA-CH-NP/siRNA-treated group. Furthermore, treatment with HA-CH-NP/siRNA resulted in significant inhibition of cell proliferation (p < .001), reduced microvessel density (p < .001), and increased cell apoptosis (p < .001). This study demonstrates that HA-CH-NP/siRNA is a highly selective delivery platform for siRNA, and has broad potential to be used in anti-angiogenesis tumor therapy.


Subject(s)
Angiogenesis Inhibitors/administration & dosage , Chitosan/chemistry , Endothelial Cells/drug effects , Hyaluronan Receptors/genetics , Nanoparticles/chemistry , Neoplasm Proteins/genetics , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , RNA, Small Interfering/administration & dosage , Receptors, Cell Surface/genetics , Animals , Antineoplastic Agents/administration & dosage , Apoptosis/drug effects , Carcinoma, Ovarian Epithelial , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Delivery Systems/methods , Female , Gene Silencing/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Hyaluronic Acid/chemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Nanoparticles/administration & dosage , Particle Size , RNA, Messenger/genetics , Xenograft Model Antitumor Assays/methods
6.
RSC Adv ; 8(9): 4494-4502, 2018 Jan 24.
Article in English | MEDLINE | ID: mdl-35539534

ABSTRACT

Tumor spheroids are multicellular, three-dimensional (3D) cell culture models closely mimicking the microenvironments of human tumors in vivo, thereby providing enhanced predictability, clinical relevancy of drug efficacy and the mechanism of action. Conventional confocal microscopic imaging remains inappropriate for immunohistological analysis due to current technical limits in immunostaining using antibodies and imaging cells grown in 3D multicellular contexts. Preparation of microsections of these spheroids represents a best alternative, yet their sub-millimeter size and fragility make it less practical for high-throughput screening. To address these problems, we developed a pitch-tunable 5 × 5 mini-pillar array chip for culturing and sectioning tumor spheroids in a high throughput manner. Tumor spheroids were 3D cultured in an alginate matrix using a twenty-five mini-pillar array which aligns to a 96-well. At least a few tens of spheroids per pillar were cultured and as many as 25 different treatment conditions per chip were evaluated, which indicated the high throughput manner of the 5 × 5 pillar array chip. The twenty-five mini-pillars were then rearranged to a transferring pitch so that spheroid-containing gel caps from all pillars can be embedded into a specimen block. Tissue array sections were then prepared and stained for immunohistological examination. The utility of this pitch-tunable pillar array was demonstrated by evaluating drug distribution and expression levels of several proteins following drug treatment in 3D tumor spheroids. Overall, our mini-pillar array provides a novel platform that can be useful for culturing tumor spheroids as well as for immunohistological analysis in a multiplexed and high throughput manner.

7.
Cancer Sci ; 108(12): 2470-2477, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28940685

ABSTRACT

We investigated the combinatorial effects of pentoxifylline (PTX) on the efficacy of gemcitabine (GEM) in a human pancreatic tumor xenograft model. PTX significantly improved the efficacy of GEM, as shown by a 50% reduction in tumor growth rate at 4 weeks of treatment compared with that in animals given GEM alone. The fluorescent drug doxorubicin (DOX) was used to test whether drug delivery was improved by PTX, contributing to the improved efficacy of GEM. PTX given for 2 weeks prior to giving DOX improved drug distribution by 1.8- to 2.2-fold with no changes in vessel density, suggesting that improvement in drug delivery was not related to the vascular mechanism. Instead, collagen I content in tumor stroma was significantly reduced, as was the expression of alpha-smooth muscle actin of cancer-associated fibroblasts and connective tissue growth factor (CTGF) by PTX pretreatment. Overall, our data demonstrated that increased efficacy of GEM by PTX was associated with improved drug delivery to tumor tissue, which may be attributed to decreased expression of CTGF and subsequent reduction in the stromal collagen matrix in the pancreatic ductal adenocarcinoma tumor. These results support the usefulness of PTX in combination with chemotherapy for targeting drug delivery barriers associated with the stromal matrix, which should be further evaluated for clinical development.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Deoxycytidine/analogs & derivatives , Pancreatic Neoplasms/pathology , Pentoxifylline/pharmacology , Animals , Deoxycytidine/pharmacology , Drug Synergism , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Phosphodiesterase Inhibitors/pharmacology , Tissue Distribution , Xenograft Model Antitumor Assays , Gemcitabine
8.
Sci Rep ; 6: 38348, 2016 12 02.
Article in English | MEDLINE | ID: mdl-27910914

ABSTRACT

Dentritic cell (DC)-based cancer immunotherapy faces challenges in both efficacy and practicality. However, DC-based vaccination requires multiple injections and elaborates ex vivo manipulation, which substantially limits their use. Therefore, we sought to develop a chitosan nanoparticle (CH-NP)-based platform for the next generation of vaccines to bypass the ex vivo manipulation and induce immune responses via active delivery of polyinosinic-polycytidylic acid sodium salt (poly I:C) to target Toll-like receptor 3 (TLR3) in endosomes. We developed CH-NPs encapsulating ovalbumin (OVA) as a model antigen and poly I:C as the adjuvant in an ionic complex. These CH-NPs showed increased in vivo intracellular delivery to the DCs in comparison with controls after injection into tumor-bearing mice, and promoted DC maturation, leading to emergence of antigen-specific cytotoxic CD8+ T cells. Finally, the CH-NPs showed significantly greater antitumor efficacy in EG.7 and TC-1 tumor-bearing mice compared to the control (p < 0.01). Taken together, these data show that the CH-NP platform can be used as an immune response modulatory vaccine for active cancer immunotherapy without ex vivo manipulation, thus resulting in increased anticancer efficacy.


Subject(s)
Antigens/immunology , Immunotherapy/methods , Lung Neoplasms/therapy , Lymphoma/therapy , Ovalbumin/immunology , Poly I-C/administration & dosage , Adjuvants, Immunologic/administration & dosage , Animals , Antigen Presentation/drug effects , Antigens/administration & dosage , Antigens/chemistry , Cancer Vaccines/administration & dosage , Cancer Vaccines/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Chitosan/chemistry , Chitosan/metabolism , Dendritic Cells/cytology , Dendritic Cells/drug effects , Dendritic Cells/immunology , Female , Gene Expression , Immunomodulation/drug effects , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Lymphoma/immunology , Lymphoma/pathology , Mice , Mice, Inbred C57BL , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Nanotechnology/methods , Ovalbumin/administration & dosage , Ovalbumin/chemistry , T-Lymphocytes, Cytotoxic/cytology , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/immunology , Transfection
9.
Int J Nanomedicine ; 11: 5729-5742, 2016.
Article in English | MEDLINE | ID: mdl-27843314

ABSTRACT

Dendritic cells (DCs) are potent professional antigen-presenting cells that are capable of initiating a primary immune response and activating T cells, and they play a pivotal role in the immune responses of the host to cancer. Prior to antigen presentation, efficient antigen and adjuvant uptake by DCs is necessary to induce their maturation and cytokine generation. Nanoparticles (NPs) are capable of intracellular delivery of both antigen and adjuvant to DCs. Here, we developed an advanced poly(d,l-lactide-co-glycolide) (PLGA)-NP encapsulating both ovalbumin (OVA) as a model antigen and polyinosinic-polycytidylic acid sodium salt (Toll-like receptor 3 ligand) as an adjuvant to increase intracellular delivery and promote DC maturation. The PLGA-NPs were taken up by DCs, and their uptake greatly facilitated major histocompatibility class I antigen presentation in vitro. Moreover, vaccination with PLGA-NP-treated DCs led to the generation of ovalbumin-specific CD8+ T cells, and the resulting antitumor efficacy was significantly increased in EG.7 and TC-1 tumor-bearing mice compared to control mice (P<0.01). Taken together, these findings demonstrated that the PLGA-NP platform may be an effective method for delivering tumor-specific antigens or adjuvants to DCs.


Subject(s)
Dendritic Cells/immunology , Immunotherapy , Lactic Acid/chemistry , Nanoparticles/chemistry , Neoplasms, Experimental/therapy , Polyglycolic Acid/chemistry , Thymoma/therapy , Toll-Like Receptor 3/immunology , Adjuvants, Immunologic , Animals , Antigen Presentation/immunology , Antigens, Neoplasm/immunology , Female , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/immunology , Neoplasms, Experimental/pathology , Ovalbumin/immunology , Polylactic Acid-Polyglycolic Acid Copolymer , T-Lymphocytes/immunology , T-Lymphocytes, Cytotoxic/immunology , Thymoma/immunology , Thymoma/pathology , Thymus Neoplasms/immunology , Thymus Neoplasms/pathology , Thymus Neoplasms/therapy , Toll-Like Receptor 3/metabolism
10.
Mol Cancer Ther ; 15(4): 618-27, 2016 04.
Article in English | MEDLINE | ID: mdl-26861249

ABSTRACT

Although cytotoxic chemotherapy is widely used against epithelial ovarian cancer (EOC), adverse side effects and emergence of resistance can limit its utility. Therefore, new drugs with systemic delivery platforms are urgently needed for this disease. In this study, we developed linalool-incorporated nanoparticles (LIN-NP) as a novel anticancer agent. We prepared LIN-NPs by the self-assembly water-in-oil-in-water (w/o/w) emulsion method. LIN-NP-mediated cytotoxicity and apoptosis was assessed in EOC cells, and the role of reactive oxygen species (ROS) generation as the mechanism of action was evaluated. In addition, therapeutic efficacy of LIN-NP was assessed in cell lines and patient-derived xenograft (PDX) models for EOC. LIN-NPs had significant cytotoxicity and apoptotic activity against EOC cells, including A2780, HeyA8, and SKOV3ip1. LIN-NP treatment increased apoptosis in EOC cells through ROS generation and a subsequent decrease in mitochondrial membrane potential and increase in caspase-3 levels. In addition, 100 mg/kg LIN-NPs significantly decreased tumor weight in the HeyA8 (P < 0.001) and SKOV3ip1 (P = 0.006) in vivo models. Although treatment with 50 mg/kg LIN-NP did not decrease tumor weight compared with the control group, combination treatment with paclitaxel significantly decreased tumor weight compared with paclitaxel alone in SKOV3ip1 xenografts (P = 0.004) and the patient-derived xenograft model (P = 0.020). We have developed LIN-NPs that induce ROS generation as a novel anticancer agent for EOC. These findings have broad applications for cancer therapy. Mol Cancer Ther; 15(4); 618-27. ©2016 AACR.


Subject(s)
Antineoplastic Agents/administration & dosage , Monoterpenes/administration & dosage , Nanoparticles , Acyclic Monoterpenes , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Carcinoma, Ovarian Epithelial , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease Models, Animal , Drug Therapy, Combination , Female , Humans , Membrane Potential, Mitochondrial/drug effects , Mice , Monoterpenes/chemistry , Nanoparticles/chemistry , Neoplasms, Glandular and Epithelial/drug therapy , Neoplasms, Glandular and Epithelial/metabolism , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Paclitaxel/pharmacology , Reactive Oxygen Species/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
11.
Mater Sci Eng C Mater Biol Appl ; 60: 511-517, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26706558

ABSTRACT

Fluoroquinolone antibiotics with concentration-dependent killing effects and a well-established broad spectrum of activity are used commonly to treat infectious diseases caused by bacteria. However, frequent and excessive administration of these antibiotics is a serious problem, and leads to increased number of drug-resistant bacteria. Thus, there is an urgent need for novel fluoroquinolone antibiotic formulations that minimize the risk of resistance while maximizing their efficacy. In this study, we developed intramuscularly injectable polymeric microparticles (MPs) that encapsulated with marbofloxacin (MAR) and were composed of poly(D,L-lactide-co-glycolic acid) (PLGA) and poloxamer (POL). MAR-encapsulated MP (MAR-MP) had a spherical shape with particle size ranging from 80 µm to 120 µm. Drug loading efficiency varied from 55 to 85% (w/w) at increasing amount of hydrophilic agent, POL. Drug release from MAR-MP demonstrated a significant and sustained increase at increased ratios of POL to PLGA. These results indicate that MAR-MP is an improved drug delivery carrier for fluoroquinolone antibiotics, which can reduce the number of doses needed and sustain a high release rate of MAR for 2-3 days. As a novel and highly effective drug delivery platform, MAR-MP has great potential for use in a broad range of applications for the treatment of various veterinary diseases.


Subject(s)
Fluoroquinolones/chemistry , Polymers/chemistry , Veterinary Drugs/chemistry , Delayed-Action Preparations , Drug Liberation
12.
J Control Release ; 216: 132-9, 2015 Oct 28.
Article in English | MEDLINE | ID: mdl-26247553

ABSTRACT

Stimulus-triggered drug release based on the liposomal drug delivery platform has been studied vigorously to increase drug release at the target site. Although the delivery system has been developed, an effective carrier system is needed to achieve effective therapeutic efficacy. Therefore, we focused on the development of gold cluster bound thermosensitive liposomes (G-TSL), which are capable of triggered drug release when stimulated by external near-infrared (NIR) irradiation in the tumor microenvironment. The size of doxorubicin (DOX)-loaded G-TSL (DOX/G-TSL) was 171.5 ± 8.3 nm, and the efficiency of DOX encapsulation was up to 90%. The release of DOX from DOX/G-TSL was increased 70% by NIR irradiation (1.50 W/cm(2) for 0.5 min) compared to non-gold-coated TSL. Consequentially, the gold cluster on the TSL enabled the light-controlled DOX release through the photothermal conversion of the energy of NIR-absorbed light, leading to membrane destabilization. Cell cytotoxicity of DOX/G-TSL was also increased by their NIR irradiation-triggered DOX release compared to non-NIR-irradiated DOX/G-TSL. In addition, we demonstrated the therapeutic efficacy of DOX/G-TSL against the MDA-MB-231 tumor model. The NIR-irradiated DOX/G-TSL treatment showed greater therapeutic efficacy than that of the non-NIR-irradiated DOX/G-TSL and control (p<0.05). Taken together, DOX/G-TSL has the potential for remote-triggered drug release upon stimulation with NIR irradiation in the tumor microenvironment, and may be applied to a broad range of photothermal-based disease therapies.


Subject(s)
Gold/pharmacology , Liposomes/chemistry , Neoplasms/metabolism , Tumor Microenvironment/drug effects , Animals , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Doxorubicin/administration & dosage , Doxorubicin/pharmacology , Drug Compounding , Drug Delivery Systems , Female , Gold/chemistry , Hot Temperature , Humans , Infrared Rays , Light , Mice , Mice, Nude , Particle Size
13.
Acta Biomater ; 24: 279-285, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26102337

ABSTRACT

Drug delivery using thermosensitive liposomes (TSL) has significant potential for tumor drug targeting and can be combined with local hyperthermia to trigger drug release. Although TSL-mediated drug delivery can be effective by itself, we developed doxorubicin (DOX)-containing CO2 bubble-generating TSL (TSL-C) that were found to enhance the antitumor effects of DOX owing to the synergism between burst release of drug and hyperthermia-induced CO2 generation. An ultrasound imaging system was used to monitor hyperthermia-induced CO2 generation in TSL-C and the results revealed that hyperthermia-induced CO2 generation in TSL-C led to increased DOX release compared to that observed for non-CO2-generating TSL. Moreover, TSL-C significantly inhibited the tumor growth in MDA-MB-231 tumor-bearing mice compared to TSL (p<0.004). Taken together, we demonstrated that the TSL-C platform increased the therapeutic efficacy of cancer chemotherapy and showed the applicability of this approach to increase drug release within the tumor microenvironment. As a novel and highly effective drug delivery platform, TSL-C has great potential for use in a broad range of applications for the treatment of various human diseases. STATEMENT OF SIGNIFICANCE: We have developed a novel method for drug release from liposomes by gas (CO2) generation in tumor microenvironment. In addition, we demonstrate therapeutic efficacy in breast carcinoma. CO2-generated liposomal doxorubicin is a novel and highly attractive delivery system for anticancer drug with the potential for broad applications in human disease.


Subject(s)
Breast Neoplasms/drug therapy , Carbon Dioxide/chemistry , Doxorubicin/chemistry , Doxorubicin/pharmacology , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Humans , Liposomes , Mice , Mice, Nude , Xenograft Model Antitumor Assays
14.
BMC Immunol ; 15: 48, 2014 Oct 18.
Article in English | MEDLINE | ID: mdl-25323934

ABSTRACT

BACKGROUND: The application of vaccine adjuvants has been vigorously studied for a diverse range of diseases in order to improve immune responses and reduce toxicity. However, most adjuvants have limited uses in clinical practice due to their toxicity. METHODS: Therefore, to reduce health risks associated with the use of such adjuvants, we developed an advanced non-toxic adjuvant utilizing biodegradable chitosan hydrogel (CH-HG) containing ovalbumin (OVA) and granulocyte-macrophage colony-stimulating factor (GM-CSF) as a local antigen delivery system. RESULTS: After subcutaneous injection into mice, OVA/GM-CSF-loaded CH-HG demonstrated improved safety and enhanced OVA-specific antibody production compared to oil-based adjuvants such as Complete Freund's adjuvant (CFA) or Incomplete Freund's adjuvant (IFA). Moreover, CH-HG system-mediated immune responses was characterized by increased number of OVA-specific CD4(+) and CD8(+) INF-γ(+) T cells, leading to enhanced humoral and cellular immunity. CONCLUSIONS: In this study, the improved safety and enhanced immune response characteristics of our novel adjuvant system suggest the possibility of the extended use of adjuvants in clinical practice with reduced apprehension about toxic side effects.


Subject(s)
Adjuvants, Immunologic/toxicity , Chitosan/toxicity , Epitopes/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Hydrogel, Polyethylene Glycol Dimethacrylate/toxicity , Immunity/drug effects , Animals , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Female , Freund's Adjuvant , Immunization , Immunoglobulin G/immunology , Injections, Subcutaneous , Lipids , Mice, Inbred C57BL , Ovalbumin/immunology
15.
Nanoscale Res Lett ; 9(1): 209, 2014.
Article in English | MEDLINE | ID: mdl-24855464

ABSTRACT

Liposome-based drug delivery systems hold great potential for cancer therapy. However, to enhance the localization of payloads, an efficient method of systemic delivery of liposomes to tumor tissues is required. In this study, we developed cationic liposomes composed of polyethylenimine (PEI)-conjugated distearoylglycerophosphoethanolamine (DSPE) as an enhanced local drug delivery system. The particle size of DSPE-PEI liposomes was 130 ± 10 nm and the zeta potential of liposomes was increased from -25 to 30 mV by the incorporation of cationic PEI onto the liposomal membrane. Intracellular uptake of DSPE-PEI liposomes by tumor cells was 14-fold higher than that of DSPE liposomes. After intratumoral injection of liposomes into tumor-bearing mice, DSPE-PEI liposomes showed higher and sustained localization in tumor tissue compared to DSPE liposomes. Taken together, our findings suggest that DSPE-PEI liposomes have the potential to be used as effective drug carriers for enhanced intracellular uptake and localization of anticancer drugs in tumor tissue through intratumoral injection.

16.
Nanoscale Res Lett ; 9(1): 38, 2014 Jan 18.
Article in English | MEDLINE | ID: mdl-24438671

ABSTRACT

The purpose of this study was to synthesize biocompatible poly(2-hydroxyethyl aspartamide)-C16-iron oxide (PHEA-C16-iron oxide) nanoparticles and to evaluate their efficacy as a contrast agent for magnetic resonance imaging of lymph nodes. The PHEA-C16-iron oxide nanoparticles were synthesized by coprecipitation method. The core size of the PHEA-C16-iron oxide nanoparticles was about 5 to 7 nm, and the overall size of the nanoparticles was around 20, 60, and 150 nm in aqueous solution. The size of the nanoparticles was controlled by the amount of C16. The 3.0-T MRI signal intensity of a rabbit lymph node was effectively reduced after intravenous administration of PHEA-C16-iron oxide with the size of 20 nm. The in vitro and in vivo toxicity tests revealed the high biocompatibility of PHEA-C16-iron oxide nanoparticles. Therefore, PHEA-C16-iron oxide nanoparticles with 20-nm size can be potentially useful as T2-weighted MR imaging contrast agents for the detection of lymph nodes.

17.
Nanoscale Res Lett ; 7(1): 462, 2012 Aug 17.
Article in English | MEDLINE | ID: mdl-22901317

ABSTRACT

Ultrasound-sensitive (sonosensitive) liposomes for tumor targeting have been studied in order to increase the antitumor efficacy of drugs and decrease the associated severe side effects. Liposomal contrast agents having Gd(III) are known as a nano-contrast agent system for the efficient and selective delivery of contrast agents into pathological sites. The objective of this study was to prepare Gd(III)-DOTA-modified sonosensitive liposomes (GdSL), which could deliver a model drug, doxorubicin (DOX), to a specific site and, at the same time, be capable of magnetic resonance (MR) imaging. The GdSL was prepared using synthesized Gd(III)-DOTA-1,2-distearoyl-sn-glycero-3-phosphoethanolamine lipid. Sonosensitivity of GdSL to 20-kHz ultrasound induced 33% to 40% of DOX release. The relaxivities (r1) of GdSL were 6.6 to 7.8 mM-1 s-1, which were higher than that of MR-bester®. Intracellular uptake properties of GdSL were evaluated according to the intensity of ultrasound. Intracellular uptake of DOX for ultrasound-triggered GdSL was higher than that for non-ultrasound-triggered GdSL. The results of our study suggest that the paramagnetic and sonosensitive liposomes, GdSL, may provide a versatile platform for molecular imaging and targeted drug delivery.

18.
Colloids Surf B Biointerfaces ; 91: 130-6, 2012 Mar 01.
Article in English | MEDLINE | ID: mdl-22104404

ABSTRACT

Polyethylene glycol-modified (PEGylated) liposomes have been widely used because of their long circulation time, but they have a major drawback of limited cellular uptake. In this study, liposomes modified with a thermosensitive biopolymer, elastin-like polypeptide (ELP), were prepared to enhance cellular uptake in tumor cells. Synthesized ELP exhibited an inverse transition temperature (T(t)) of 40°C in serum with hyperthermia treatment and contained a lysine residue for conjugation with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[poly(ethylene-glycol)]-hydroxy succinamide, PEG MW 2000 (DSPE-PEG2000-NHS). ELP was covalently conjugated with liposomes encapsulating a high concentration of doxorubicin (Dox). Size and drug release properties of liposomes were investigated over a range of temperatures. ELP-modified liposomes tended to aggregate but did not show temperature-triggered release by phase transition of ELP molecules. Cellular uptake efficiency of liposomes was evaluated under normothermic and hyperthermic condition. Dox accumulation from liposomes was determined by flow cytometry and confocal microscopy. Higher internalization occurred in the ELP-modified liposomes than in ELP-unmodified liposomes. The results suggest that dehydration of ELP molecules on the liposomal surface can induce efficient cellular uptake, which can improve existing chemotherapeutic efficacy.


Subject(s)
Elastin/metabolism , Liposomes , Neoplasms/metabolism , HeLa Cells , Humans
19.
Pharmazie ; 66(6): 430-5, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21699082

ABSTRACT

Topical vitamin B12 was shown to be effective for atopic dermatitis. However, vitamin B12 itself is light sensitive and has low skin permeability, thus reducing its therapeutic effectiveness. In the present study, we prepared a liposomal hydrogel of adenosylcobalamin (AdCbl), a vitamin B12 derivative, and investigated possible beneficial effects of AdCbl on atopic dermatitis using an NC/Nga murine atopic dermatitis model. AdCbl was loaded into liposomes prepared by a thin film hydration method using a pH gradient method that employed citric acid buffer solution. This resulted in AdCbl-loaded liposomes that were 106.4 +/- 2.2 nm in size. The loading efficiency was 40% (of the initial AdCbl amount). Lipo-AdCbl had enhanced skin permeability, being about 17-fold compared with AdCbl-gel. Topical administration of Lipo-AdCbl-gel to 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis-like skin lesions in NC/Nga mice ameliorated lesion intensity scores, dorsal skin thickness, and total serum IgE in a concentration-dependent manner. Other preparations, including AdCbl solution, AdCbl cream, liposomes alone, and a mixture of AdCbl solution and liposomes had little effect. Taken together, our findings indicate that Lipo-AdCbl-gel has protective effects against atopic dermatitis symptoms, and suggest that it may be of benefit in the treatment of human inflammatory skin diseases.


Subject(s)
Dermatitis, Atopic/drug therapy , Vitamin B 12/administration & dosage , Vitamin B 12/therapeutic use , Administration, Topical , Animals , Buffers , Dermatitis, Atopic/pathology , Diffusion Chambers, Culture , Dinitrochlorobenzene , Drug Carriers , Female , Hydrogel, Polyethylene Glycol Dimethacrylate , Hydrogels , Hydrogen-Ion Concentration , Immunoglobulin E/blood , In Vitro Techniques , Irritants , Liposomes , Mice , Mice, Inbred BALB C , Particle Size , Permeability , Skin/pathology , Skin Absorption
20.
Colloids Surf B Biointerfaces ; 84(1): 82-7, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21251801

ABSTRACT

Gadolinium (Gd)-based cancer therapeutic liposomes can be used for chemotherapeutics and diagnostics. In this study, dual functional liposomes co-encapsulating doxorubicin (Dox) and Gd were prepared by Dox-transition metal complexation. Preparation conditions were optimized to obtain liposomes containing high concentrations of Dox and Gd. The optimized liposomes Gd250 co-encapsulated 3.6 mM of Dox and 1.9 mM of Gd. The magnetic resonance (MR) properties of Gd250 liposomes were determined using a 4.7 T MR system. Cellular uptake of Dox was determined using a flow cytometer and a confocal microscopy and that of Gd was measured using an inductively coupled plasma-atomic emission spectrometer. Although encapsulated Gd exhibited lower relaxivity than MRbester®, which is widely used for clinical diagnosis, because of limited diffusion across the liposome membrane, Gd250 liposomes showed much higher cellular uptake than that of MRbester®. In Gd250 liposomes, Gd was highly accumulated in B16F10 cells, which could provide improved contrast sensitivity for molecular imaging. Additionally, in Gd250 liposomes, Dox was highly internalized, which could enhance its cancer therapeutic effects. Consequently, we suggest that dual functional liposomes can be used as therapeutic and diagnostic carriers.


Subject(s)
Antineoplastic Agents/chemistry , Doxorubicin/chemistry , Drug Carriers , Gadolinium/chemistry , Liposomes , Animals , Cell Line, Tumor , Liposomes/therapeutic use , Magnetic Resonance Imaging , Mice , Microscopy, Confocal
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