Development and characteristics of temperature-sensitive liposomes for vinorelbine bitartrate

A novel liposome with temperature-sensitivity for vinorelbine bitartrate (VB) was designed to enhance VB targeted delivery and antitumor effect. Liposomes without drugs were prepared by thin film hydration, and then VB was entrapped into liposomes by pH gradient loading method. The mean particle size of the liposomes was about 100 nm, and the drug entrapment efficiency was more than 90%. Stability data indicated that the liposome was physically and chemically stable for at least 6 months at 4 °C. In vitro drug release study showed that drugs hardly released at 37 °C; while at 42 °C, drugs released quickly. For in vivo experiments, the lung tumor model was established by subcutaneous inoculation of cell suspension on mice, liposomes and free VB were injected i.v. in mice, followed by exposure the tumors to hyperthermia (HT) for 30 min after administration. The ratio of inhibition tumor of temperature-sensitive liposomes group was significantly higher than the normal injection group. Combining temperature-sensitive liposomes with HT enhanced the delivery of VB and, consequently, its antitumor effects. This liposome could potentially produce viable clinical strategies for improved targeting and delivery of VB for treatment of cancer.     

Self-delivering prodrug-nanoassemblies fabricated by disulfide bond bridged oleate prodrug of docetaxel for breast cancer therapy

Breast cancer leads to high mortality of women in the world. Docetaxel (DTX) has been widely applied as one of the first-line chemotherapeutic drugs for breast cancer therapy. However, the clinical outcome of DTX is far from satisfaction due to its poor drug delivery efficiency. Herein, a novel disulfide bond bridged oleate prodrug of DTX was designed and synthesized to construct self-delivering prodrug-based nanosystem for improved anticancer efficacy of DTX. The uniquely engineered prodrug-nanoassemblies showed redox-responsive drug release, increased cellular uptake and comparable cytotoxicity against 4T1 breast cancer cells when compared with free DTX. In vivo, oleate prodrug-based nanoparticles (NPs) demonstrated significantly prolonged systemic circulation and increased accumulation in tumor site. As a result, prodrug NPs produced a notable antitumor activity in 4T1 breast cancer xenograft in BALB/c mice. This prodrug-based self-assembly and self-delivery strategy could be utilized to improve the delivery efficiency of DTX for breast cancer treatment.     

Thermo-Sensitive Liposome co-Loaded of Vincristine and Doxorubicin Based on Their Similar Physicochemical Properties had Synergism on Tumor Treatment

Purpose

To develop vincristine (VCR) and doxorubicin (DOX) co-encapsulated thermo-sensitive liposomes (VD-TSL) against drug resistance, with increased tumor inhibition rate and decreased system toxicity, improving drug targeting efficiency upon mild hyperthermia (HT) in solid tumor.

Methods

Based on similar physicochemical properties, VCR and DOX were co-loaded in TSL with pH gradient active loading method and characterized. The time-dependent drug release profiles at 37 and 42°C were assessed by HPLC. Then we analysed the phospholipids in filtrate after ultrafiltration and studied VD-TSL stability in mimic in vivo conditions and long-time storage conditions (4°C and ?20°C). Cytotoxic effect was studied on PANC and sw-620 using MTT. Intracellular drug delivery was studied by confocal microscopy on HT-1080. In vivo imaging of TSL pharmacokinetic and biodistribution was performed on MCF-7 tumor-bearing nude mice. And therapeutic efficacy on these xenograft models were followed under HT.

Results

VD-TSL had excellent particle distribution (about 90 nm), high entrapment efficiency (>95%), obvious thermo-sensitive property, and good stability. MTT proved VD-TSL had strongest cell lethality compared with other formulations. Confocal microscopy demonstrated specific accumulation of drugs in tumor cells. In vivo imaging proved the targeting efficiency of TSL under hyperthermia. Then therapeutic efficacy revealed synergism of VCR and DOX co-loaded in TSL, together with HT.

Conclusion

VD-TSL could increase drug efficacy and decrease system toxicity, by making good use of synergism of VCR and DOX, as well as high targeting efficiency of TSL.

     

Docetaxel-loaded exosomes for targeting non-small cell lung cancer: preparation and evaluation in vitro and in vivo

Non-small cell lung cancer (NSCLC) is a highly lethal disease and the majority of NSCLC patients are desperate for therapies that can effectively target their cancer and ultimately improve their overall survival. Docetaxel (DTX) represents the first-line of the antitumor agent that is used to treat NSCLC; however, it has poor solubility in water and unsatisfactory encapsulation efficiency. In our study, exosomes were isolated from A549 cancer cells by ultracentrifugation and then characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot (WB). The particle size changes of EXO and EXO-DTX were measured daily for seven days to test the stability. DTX was selected payload by electroporation (EXO-DTX). For the in vitro evaluation, cell proliferation, cell cycle, cell apoptosis, reactive oxygen species (ROS) assay and cellular uptake were evaluated in the A549 cells. Also, this study evaluated the target and therapeutic effect of DTX as an antitumor agent in vivo. As a result, EXO-DTX with a particle size of 149.5 nm were successfully prepared and the cytotoxicity of the EXO-DTX was much greater than that of DTX monomers. Exosomes significantly increased the cellular uptake in vitro evaluation and showed better targeting to tumor tissue compared to the free DTX in the mice. We also explored the potential of tumor cell-derived exosomes as a drug delivery agent to target the parent cancer. Hence, we conclude that exosomes might be used as a potential antitumor drug delivery system (DDS).     

RGD-based strategies for improving antitumor activity of paclitaxel-loaded liposomes in nude mice xenografted with human ovarian cancer

Tumor-targeting drug delivery systems are being the ideal carrier for systemic administration of antiproliferative drugs. RGD peptide (arginine–glycine–aspartic acid) modified liposomes containing paclitaxel (RGD-SSL-PTX). The arginine-glycine-aspartic acid tripeptide (RGD) modified sterically stabilized liposomes (SSL) containing paclitaxel (PTX) (RGD-SSL-PTX), which could increase targeting to tumor by binding with the integrin receptors overexpressed on tumor cells. The encapsulation efficiency was more than 90% and the mean particle size was of 120 nm with a narrow size distribution. It was indicated that significant cytotoxicity (3.5 times lower IC₅₀) was found in the SKOV-3 human ovarian cancer cells treated with RGD-SSL-PTX preparation, as well as the intracellular uptake of liposomes (a 6.21-fold increase in fluorescence intensity), when compared to those of non-targeted liposomes (SSL). For in vivo antitumor activity, it was shown in the present study that RGD-SSL-PTX preparation had the strongest tumor growth inhibition among the test formulations (P < 0.05) in BALB/c nude mice xenografted with SKOV-3 solid tumor. Meanwhile, there was no significant change in the body weight of the animals treated with RGD-SSL-PTX for intravenous injection at a dose of 12.5 mg/kg. It was suggested that the RGD-SSL-PTX preparation might have a great advantage over present-day chemotherapy with Taxol^® in curing those tumors overexpressing integrin receptors.     

Development of a bone targeted thermosensitive liposomal doxorubicin formulation based on a bisphosphonate modified non-ionic surfactant

Bone is among the most common sites of metastasis in cancer patients, so it is an urgent need to develop drug delivery systems targeting tumor bone metastasis with the feature of controlled release. This study aimed to delivery of thermosensitive liposomal doxorubicin to bone for tumor metastasis treatment. First, Brij78 (polyoxyethylene stearyl ether) was conjugated with Pamidronate (Pa). By incorporating Pa-Brij78 to DPPC/Chol liposomes, we developed Pa surface functionalized liposomes. The Pa-Brij78/DPPC/Chol liposomes (PB-liposomes) exhibited a stronger binding affinity to hydroxyapatite (HA), a major component of bone, than Brij78/DPPC/Chol liposomes (B-liposomes). Doxorubicin (Dox) was then encapsulated in PB-liposomes and the results demonstrated complete release of Dox from PB-liposomes or the complex of HA/PB-liposomes within 10?min at 42?°C. Next, human lung cancer A549 cells were treated with the thermosensitive complex of HA/PB-liposomes/Dox to mimic tumor bone metastasis treatment through bone targeted delivery of therapeutic agents. Pre-incubation of HA/PB-liposomes/Dox with mild heat at 42?°C induced subsequent higher cytotoxicity to A549 cells than incubation of the same complex at 37?°C, suggesting more active drug release triggered by heat. In conclusion, we synthesized a novel surfactant Pa-Brij78 and it has the potential to be used for development of a bone targeted thermosensitive liposome formulation for treatment of tumor bone metastasis.     

Multifunctional Tumor-Targeting Nanocarriers Based on Hyaluronic Acid-Mediated and pH-Sensitive Properties for Efficient Delivery of Docetaxel

Purpose

The objective of this work was to develop a multifunctional tumor-targeting nanocarrier based on the mechanism of CD44-mediated endocytosis and pH-induced drug release to improve the therapeutic efficacy of docetaxel (DTX).

Methods

Hyaluronic acid-coated docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) were prepared. The physiochemical properties and pH-dependent drug release of HA-CHEMS vesicles were evaluated. The HA-CHEMS vesicles were investigated for CD44-mediated internalization and in vitro cell viability using MCF-7,A549 and L929 cells.In addition,tissue distribution as well as antitumor efficacy was also evaluated in MCF-7 tumor-bearing mouse model.

Results

The particle size and zeta potential of HA-CHEMS vesicles were 131.4?±?6.2 nm and ?13.3?±?0.04 mV,respectively. The in vitro drug release results demonstrated a pH-responsive drug release under different pH conditions. In vitro cell viability tests suggested that the encapsulation of DTX in HA-CHEMS vesicles led to more than 51.6-fold and 46.3-fold improved growth inhibition in MCF-7 and A549 cell lines,respectively compared to Taxotere®. From the cell uptake studies,the coumarin 6-loaded HA-CHEMS vesicles enhanced intracellular fluorescent intensity in the CD44-overexpressing cell line (MCF-7). Biodistribution studies revealed selective accumulation of HA-CHEMS vesicles in the MCF-7 bearing BalB/c nude mice as a result of passive accumulation and active targeting (CD44-mediated endocytosis). Compared to Taxotere®,HA-CHEMS vesicles exhibited higher antitumor activity by reducing tumor volume (P?<?0.05) and drug toxicity,demonstrating the success of the multifunctional targeting delivery.

Conclusions

This work corresponds to the preparation of a multifunctional tumor-targeted delivery system. Our investigation shows that hyaluronan-bearing docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) is a highly promising therapeutic system,leading to tumor regression after intravenous administration without visible toxicity.     

A thermo-sensitive PLGA-PEG-PLGA hydrogel for sustained release of docetaxel

The aim of this study was to investigate the suitability of poly-(d,l-lactic acid-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-PLGA triblock copolymer as a matrix material for a sustained-release system for docetaxel (DTX). The copolymers were synthesized by ring-opening polymerization reaction and characterized by ¹H-NMR and gel permeation chromatography. The DTX-loaded formulations were prepared, characterized. And the antitumor efficacy and the pharmacokinetics of DTX-loaded copolymer on A-549 lung tumor-bearing BALB/cA mice were investigated. The results showed that DTX-loaded copolymer highly increased the solubility of DTX by more than 3000-fold. And copolymer concentration as well as drug loading level exerted appreciable influence on the drug release behavior. Further, the pharmacokinetic test showed that DTX-loaded copolymer could be with the sustained-release nature for over 3 weeks, which correlated well with the in vitro release. Additionally, one intratumoral injection of the thermo-sensitive hydrogel containing DTX was comparable to three intravenous injections of DTX injection in inhibiting the tumor growth in A-549 lung tumor-bearing BALB/cA mice with a less toxic manner. PLGA-PEG-PLGA could thus provide a promising alternate locally delivered vehicle for DTX to achieve prolonged exposure having greater efficacy in inhibiting tumor growth with lower toxicity.     

Localized delivery to CT-26 tumors in mice using thermosensitive liposomes

A heat-sensitive liposomal drug delivery system was tested using Colon-26 (CT-26) cultured cells and tumors in mice. Lucifer yellow iodoacetamide (LY) was used as a fluorescence marker. The heat-sensitive liposomes exploit the temperature-dependence of critical micellar concentrations of the poloxamer, F127. LY release from unilamellar liposomes at different temperatures was measured. Onset of LY release occurred near 33 degrees C, and reached plateau above 42 degrees C when 90% of the LY was released. Temperature-treated liposomes were mixed with CT-26 cells to measure the binding of the released LY to cell surface. Temperature-dependency of cell-bound LY corresponds to the release curve. CT-26 tumors were grown subcutaneously in both hind legs of Balb/c mice. Mice received heat-sensitive or plain liposomes via tail vein injections, or no liposomes. For each mouse, one tumor was kept at 31.5 degrees C, while the counterlateral tumor was heated to 42 degrees C during injection and for 30min after. LY released in tumors was determined from fluorescence intensity. Tumors receiving heat-sensitive liposomes plus heat treatment showed 2.5-fold greater fluorescence than all other tumors, which were at the background level. This study demonstrates the possible use of poloxamer-containing liposomes as a heat-sensitive drug delivery system in vivo.     

Trastuzumab-conjugated vitamin E TPGS liposomes for sustained and targeted delivery of docetaxel

Objectives: In this study, the authors developed d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or simply TPGS) liposomes and further conjugated them to trastuzumab for controlled and targeted delivery of docetaxel (DTX) as a model hydrophobic drug.

Methods: DTX- or coumarin-6-loaded liposomes were prepared by solvent injection method and characterized for size and size distribution, surface charge, surface chemistry and drug encapsulation efficiency and drug release profile. SK-BR-3 cells were employed as an in vitro model for HER2-positive breast cancer and assessed for their cellular uptake and cytotoxicity of the two liposomal formulations. In vivo pharmacokinetics (PK) was investigated in Sprague–Dawley rats.

Results: The IC₅₀ value was found to be 20.23 ± 1.95, 3.74 ± 0.98, 0.08 ± 0.4 μg/ml for the marketed preparation of DTX, TPGS liposomes and trastuzumab-conjugated TPGS liposomes, respectively after 24 h incubation with SK-BR-3 cells. In vivo PK experiments showed that i.v. administration of trastuzumab-conjugated liposomes achieved 1.9 and 10 times longer half-life, respectively than PEG-coated liposomes and DTX. The area under the curve (AUC) was increased by 3.47- and 1.728-fold, respectively.

Conclusion: The trastuzumab-conjugated vitamin E TPGS-coated liposomes showed greater potential for sustained and targeted chemotherapy in the treatment of HER2 overexpressing breast cancer.     

Plasma membrane targeting by short chain sphingolipids inserted in liposomes improves anti-tumor activity of mitoxantrone in an orthotopic breast carcinoma xenograft model

Mitoxantrone (MTO) is clinically used for treatment of various types of cancers providing an alternative for similarly active, but more toxic chemotherapeutic drugs such as anthracyclines. To further decrease its toxicity MTO was encapsulated into liposomes. Although liposomal drugs can accumulate in target tumor tissue, they still face the plasma membrane barrier for effective intracellular delivery. Aiming to improve MTO tumor cell availability, we used short chain lipids to target and modulate the tumor cell membrane, promoting MTO plasma membrane traversal. MTO was encapsulated in liposomes containing the short chain sphingolipid (SCS), C₈-Glucosylceramide (C₈-GluCer) or C₈-Galactosylceramide (C₈-GalCer) in their bilayer. These new SCS-liposomes containing MTO (SCS-MTOL) were tested in vivo for tolerability, pharmacokinetics, biodistribution, tumor drug delivery by intravital microscopy and efficacy, and compared to standard MTO liposomes (MTOL) and free MTO.Liposomal encapsulation decreased MTO toxicity and allowed administration of higher drug doses. SCS-MTOL displayed increased clearance and lower skin accumulation compared to standard MTOL. Intratumoral liposomal drug delivery was heterogeneous and rather limited in hypoxic tumor areas, yet SCS-MTOL improved intracellular drug uptake in comparison with MTOL. The increased MTO availability correlated well with the improved antitumor activity of SCS-MTOL in a MDAMB-231 breast carcinoma model. Multiple dosing of liposomal MTO strongly delayed tumor growth compared to free MTO and prolonged mouse survival, whereas among the liposomal MTO treatments, C8-GluCer-MTOL was most effective. Targeting plasma membranes with SCS improved MTO tumor availability and thereby therapeutic activity and represents a promising approach to improve MTO-based chemotherapy.     

Chitooligosaccharides Modified Reduction-Sensitive Liposomes: Enhanced Cytoplasmic Drug Delivery and Osteosarcomas-Tumor Inhibition in Animal Models

Purpose

To investigate the potential of a reduction-sensitive and fusogenic liposomes, enabled by surface-coating with chotooligosaccharides (COS) via a disulfide linker, for tumor-targeted cytoplasmic drug delivery.

Methods

COS (MW2000-5000) were chemically tethered onto the liposomes through a disulfide linker (-SS-) to cholesterol (Chol). Doxorubicin (DOX) was actively loaded in the liposomes. Their reduction-sensitivities, cellular uptake, cytotoxicity, pharmacokinetics and antitumor efficacy were investigated.

Results

The Chol-SS-COS/DOX liposomes (100 nm) had zeta potential of 33.9 mV and high drug loading (13% w/w). The liposomes were stable with minimal drug leakage under physiological conditions but destabilized in the presence of reducing agents, dithiothreitol (DTT) or glutathione (GSH) at 10 mM, the cytosolic level. MTT assay revealed that the cationic Chol-SS-COS/DOX liposomes had higher cytotoxicity to MG63-osteosarcoma cells than non-reduction sensitive liposome (Chol-COS/DOX). Flow cytometry and confocal microscopy revealed that Chol-SS-COS/DOX internalized more efficiently than Chol-COS/DOX with more content to cytoplasm whereas Chol-COS/DOX located around the cell membrane. Chol-SS-COS/DOX preferentially internalized into MG63 cancer cell over LO2 normal liver cells. In rats both liposomes produced a prolonged half-life of DOX by 4 - 5.5 fold (p < 0.001) compared with the DOX solution. Chol-SS-COS/DOX exhibited strong inhibitory effect on tumor growth in MG63 cell-bearing nude mice (n = 6), and extended animal survival rate.

Conclusions

Reduction-responsive Chol-SS-COS liposomes may be an excellent platform for cytoplasmic delivery of anticancer drugs. Conjugation of liposomes with COS enhanced tumor cell uptake, antitumor effect and survival rate in animal models.

     

Effect of surface ligand density on cytotoxicity and pharmacokinetic profile of docetaxel loaded liposomes

Various biotin-modified liposomes incorporated with docetaxel (DTX) were prepared to study the effect of surface biotin density on the pharmacokinetic profile of the liposome. Four types of liposomes such as PEG modified liposome (PDL), 0.5% (mol) biotin modified liposome (0.5BDL), 1% (mol) biotin modified liposome (1BDL) and 2% (mol) biotin modified liposome (2BDL) were prepared using thin film dispersion method. The prepared liposomes were characterized by measuring encapsulation efficiency (EE), particle size, Zeta-potential, physical stability and drug release profiles in vitro. MTT assay was performed to elevate the cytotoxicity of liposomes on MCF-7 cells. In vivo evaluation was further performed to investigate the effect of biotin surface density on the pharmacokinetic profiles. All the prepared liposomes exhibited high encapsulation efficiency, small particle size, narrow particle distribution and sustained release profiles in vitro. In MTT assay, 0.5BDL showed largest tumor cell toxicity, compared with DTX solution. All liposomes containing DTX showed prolonged blood circulation in vivo, and 0.5BDL showed the longest circulation time among the biotin modified liposome. Surface modification of liposome had a negative impact on the circulation of liposomes in the blood, which needs to be considered when designing the ligand mediated targeting delivery systems. A proper amount of biotin liposome with 0.5% molar ratio is expected to produce the best anti-tumor effect.     

Dual Role of Photosensitizer and Carrier Material of Fullerene in Micelles for Chemo–Photodynamic Therapy of Cancer

Derivatives of fullerene (C60) as photosensitizers have rarely been studied as delivery carrier materials. The focus of this study was to explore the potential advantages of diadduct malonic acid‐fullerene (DMA‐C60) as delivery carrier materials and combination of chemo–phototherapy of some tumors. In this study, DMA‐C60 and docetaxel (DTX) were coentrapped in micelles (MCs) (DMA‐C60/DTX‐MC). The addition of DMA‐C60 could obviously improve static stability and decrease critical MC concentration of DTX‐MC without hemolysis. The sustained release of DTX and DMA‐C60 could be achieved, following Higuichi and first‐order model, respectively. DMA‐C60 could still produce reactive oxygen species efficiently in HeLa cells after encapsulation in MC. The addition of DMA‐C60 under irradiation caused DTX‐MC more stronger cytotoxicity, cell cycle changes, and more early apoptotic cells in vitro. More importantly, after intravenous injection, the addition of DMA‐C60 in DTX‐MC could result in 2.25‐fold and 4.57‐fold longer mean residence time compared with DTX‐MC and Duopafei®, increase drug intratumoral distribution and decrease drug distribution in heart and kidney, and enhance antitumor effect under irradiation without body weight loss. These results suggested tremendous promise of DMA‐C60 as carrier materials of MC and significant advantages in combination of chemo–phototherapy of some tumors.     

白细胞介素2脂质体的制备及其抗肿瘤作用的研究

采用逆相蒸发法制备稳定的白细胞介素2（IL－2）大单层脂质体，对其包封率、稳定性及活性进行了测定。建立C57BL／6小鼠荷瘤动物模型，通过给荷瘤小鼠腹腔注射空白脂质体、单纯IL-2及IL-2脂质体来比较其在肿瘤生长中的抑制作用，结果3组抑癌率分别为4．26％、34．04％和54.60％。空白脂质体组与单纯对照组相比尤显著性差异（P＞0．05），脂质体-IL-2组与单纯IL-2组之间存在显著性差异（P＜0．05），抑瘤率提高了20.6％。     

PHSCNK-Modified and doxorubicin-loaded liposomes as a dual targeting system to integrin-overexpressing tumor neovasculature and tumor cells

The aim of this study was to prepare a liposome system targeting to both tumor angiogenesis and tumor cells, and to achieve the proof-of-principle. ATN-161 (N-acetyl-proline-histidine-serine-cysteine-asparagine-amide, PHSCN) is a ligand of integrin α5β1 which is the receptor overexpressed on tumor neovasculature and some tumor cells. In this study, doxorubicin (DOX) was used as the model drug, and a derivative of PHSCN, N-acetyl-proline-histidine-serine-cysteine-asparagine-lysine (amide)-COOH (PHSCNK), was firstly coupled to the surface of PEGylated DOX liposomes (PL-DOX) by a novel approach to obtain the PHSCNK-modified and DOX-loaded PEGylated liposomes (PHSCNK-PL-DOX). These two vehicles were less than 100?nm in average, negatively charged and rather stable at 4°C or 25°C, while they exhibited similar release kinetics in vitro. Cell-specific uptake and cytotoxicity were investigated on human umbilical vein endothelial cells and breast cancer cells by confocal microscopy and sulforhodamine B (SRB) assay. It was found that PHSCNK-PL-DOX significantly enhanced the cell uptake and cytotoxicity of DOX on both cell lines, due to the integrin-mediated endocytosis. It was concluded that, PHSCNK-PL-DOX, which can actively delivery the drug into both tumor neovasculature and tumor cells, may be a promising targeted delivery system for anticancer drug.     

Heat-Treated Emulsions with Cross-Linking Bovine Serum Albumin Interfacial Films and Different Dextran Surfaces: Effect of Paclitaxel Delivery

In this study, a type of biocompatible and biodegradable oil-in-water emulsion for hydrophobic drug delivery was evaluated in vitro and in vivo. Bovine serum albumin (BSA)-dextran conjugates with different dextran molecular weights and different conjugation degrees were used as the emulsifier and stabilizer. Paclitaxel (PTX), a hydrophobic antitumor drug, was effectively loaded inside the oil droplets via high-pressure homogenization. The emulsions were heated at 90° C for 1 h to eliminate the anaphylaxis of BSA. By virtue of the cross-linked BSA films at the oil–water interfaces produced by the heat treatment and the hydrophilic dextran surfaces, the emulsions are stable in blood serum, as well as stable against long-term storage. In vitro cytotoxicity study verifies that the unloaded emulsions are biocompatible and the PTX-loaded emulsions have similar antitumor activity as PTX solution. In vivo investigation of murine ascites hepatoma H22-tumor-bearing mice demonstrates that the PTX-loaded emulsion with shorter and denser dextran surface has better tumor inhibition and survivability efficacy than the commercial PTX injection.     

Ceramide lipid-based nanosuspension for enhanced delivery of docetaxel with synergistic antitumor efficiency

Ceramide (CE), a bioactive lipid with tumor suppression, has been widely used as a drug carrier and enhancer for cancer therapy. CE-based combination therapy was prone to be attractive in cancer therapy. In our previous study, the combination of CE and docetaxel (DTX) was proved to be an effective strategy for cancer therapy. To further improve the antitumor efficiency of DTX, the CE lipid-based nanosuspensions (LNS) was prepared for the delivery of DTX to exhibit synergistic therapeutic effect. The enhanced delivery and synergistic therapeutic effect of DTX-loaded CE-LNS (CE?+?DTX-LNS) were evaluated. CE?+?DTX-LNS exhibited spherical or ellipsoidal shape, uniform particle size distribution (108.1?±?3.8?nm), sustained release characteristics and good stability in vitro. Notably, CE?+?DTX-LNS could effectively co-localize CE and DTX into same tumor cell and subsequently play synergistic cell damage effect compared with CE-LNS?+?DTX-LNS (p?in vivo fluorescence imaging results showed that CE?+?DTX-LNS could effectively prolong the in vivo circulation time and enhance the accumulation in tumor sites. Moreover, the antitumor efficacy of CE?+?DTX-LNS observed in B16 murine melanoma model was 93.94?±?2.77%, significantly higher than that of CE-LNS, DTX-LNS, Duopafei® (p?p?相似文献   

A two-component drug delivery system using Her-2-targeting thermosensitive liposomes

We report on a new method for enhancing the specificity of drug delivery for tumor cells, using thermosensitive immunoliposomes. The liposomes are conjugated to the antibody trastuzumab (Herceptin^®), which targets the human epidermal growth factor receptor 2 (Her-2), a cell membrane receptor overexpressed in many human cancers. Being thermosensitive, the liposomes only release their contents when heated slightly above body temperature, allowing for the possibility of tissue targeting through localized hyperthermia. Using self-quenching calcein, we demonstrate the release of liposome contents into cell endosomes after brief heating to 42°C. To further increase targeting specificity, we incorporate the concept of a two-component delivery system that requires the interaction of two different liposomes within the same endosome for cytoplasmic delivery. Experimental evaluation of the technique using fluorescently labeled liposomes shows that a two-component delivery system, combined with intracellular disruption of liposomes by hyperthermia, significantly increases specificity for Her-2-overexpressing tumor cells.