Development of Miriplatin-loaded Nanoparticles against Non-small Cell Lung Cancer

Lung cancer claims the highest mortality and the second-most new cases among all oncological diseases. NSCLC accounts for approximately 85% of all newly diagnosed lung cancers. Although platinum-based drugs are standard first-line chemotherapy for stage IIIB/IV NSCLC, accumulating reports have shown the failure of conventional platinum-based regimens due to drug resistance. Miriplatin is a lipophilic anti-cancer drug that has been approved in Japan for transcatheter arterial chemoembolization treatment of hepatocellular carcinoma. Lipid-based nanoparticles such as liposomes, micelles, and solid lipid nanoparticles (SLNs) can encapsulate anti-cancer drugs to improve their water solubility and bioavailability

Development of Lipid-based Nano Formulations of Miriplatin against Lung Cancer

Lung cancer claims the highest mortality and the second most new cases in the US. Cisplatin, the first platinum-based anticancer drug, has the highest potency against lung cancer but carries many severe adverse effects. Miriplatin was discovered with a higher lipophilicity and approved in Japan for the treatment of hepatocellular carcinoma (HCC). Nanocarriers provide a promising platform to overcome the physiochemical barrier of solid tumors and to reduce the toxicity of anticancer drugs

DEVELOPMENT OF MIRIPLATIN-LOADED NANOPARTICLES AGAINST NON-SMALL CELL LUNG CANCER

Lung cancer claims the highest mortality and the second-most estimated new cases among all oncological diseases [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all newly diagnosed lung cancers [2]. Approximately 40% of newly diagnosed lung cancer patients are stage IV. For stage IIIB/IV NSCLC, cytotoxic combination chemotherapy is standard first-line chemotherapy. A regimen of platinum (cisplatin or carboplatin) plus paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, or pemetrexed is the recommended clinical treatment [3]. Cisplatin is the first-generation platinum-based anti-cancer drug. Although cisplatin is much more effective than other platinum drugs at the same dosage [4], accumulating reports have shown the failure of conventional platinum-based chemotherapy due to various side effects and drug resistance [5]. Miriplatin, a member of platinum drug family, has been approved in Japan in 2009 for transcatheter arterial chemoembolization treatment of hepatocellular carcinoma (HCC) [6]. Miriplatin is a lipophilic platinum drug that contains myristates (14-carbon chains) as leaving groups and diamino cyclohexane as the non-leaving carrier ligand. The application of miriplatin in clinic is limited because it has very poor solubilities both in water and in common organic solvents [7]. The structure of solid tumors and tumor microenvironment (TME) in lung cancer constitute a barrier to the deep penetration of chemotherapy agents, which limits the effectiveness of chemotherapy [8]. Nanoparticles with appropriate properties provide a promising delivery system to overcome the biological and physiochemical barriers that hinder anti-cancer activity [9]. Lipid-based nanoparticles such as liposomes, micelles, and solid lipid nanoparticles (SLNs) can delivery anti-cancer drugs to improve their anti-cancer activities. In this study, we formulated miriplatin into various micelles, liposomes, and SLNs by film-hydration and evaluated their physicochemical properties and anti-cancer activity against NSCLC cells in culture. Miriplatin-loaded formulations with different compositions were successfully prepared by the film-hydration method. Most miriplatin-loaded micelles were more homogeneous and much smaller than miriplatin-loaded liposomes and SLNs. The majority of miriplatin-loaded micelles were about 15 nm in diameter, while SLNs were around 120 nm, and liposomes were about 180 nm. Formulations with a higher molar ratio of PE-PEG2000 had smaller sizes. SLNs loaded with a higher molar ratio of miriplatin in the compositions showed smaller sizes. Inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma optical emission spectrometry (ICP-OES) techniques were attempted to quantify the platinum element in the formulations. Formulations with a higher molar ratio of PE-PEG2000 had higher recovery of platinum element. Most miriplatin-loaded formulations had higher than 80% platinum recovery. The recovery of intact miriplatin was characterized by HPLC. Miriplatin-loaded micelles had much higher intact miriplatin recovery (about 100%) than SLNs (about 30%). By TEM imaging, the micelles showed the morphology of spherical dots of about 10 nm in diameter while SLNs showed both spherical and rodlike structures of about 120 nm in diameter. The TEM results were consistent with the size and PDI results by the Zetasizer. Three-dimensional multicellular spheroids (3D MCS) of A549 and A549-iRFP cell lines were successfully established as cell culture models to evaluate activity against non-small cell lung cancer. The viability of 3D MCS after 7-days treatment with miriplatin-loaded micelles was about 0%, which was similar to cisplatin. Miriplatin-loaded formulations with a higher molar ratio of PE-PEG2000 in the compositions had higher anti-cancer activity against 3D MCS. The anticancer activity of miriplatin-loaded formulations against 3D MCS was positively associated with the recovery of intact miriplatin from the formulations. The IC50 value of miriplatin-loaded micelles against A549-iRFP 3D MCS was around 25 µM, while that of cisplatin was 84.78 µM. In summary, the reported lipid-based nano-formulations represent a promising delivery system of miriplatin against NSCLC

DEVELOPMENT OF MIRIPLATIN-LOADED NANOPARTICLES AGAINST NON-SMALL CELL LUNG CANCER

Lung cancer claims the highest mortality and the second-most estimated new cases among all oncological diseases [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all newly diagnosed lung cancers [2]. Approximately 40% of newly diagnosed lung cancer patients are stage IV. For stage IIIB/IV NSCLC, cytotoxic combination chemotherapy is standard first-line chemotherapy. A regimen of platinum (cisplatin or carboplatin) plus paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, or pemetrexed is the recommended clinical treatment [3]. Cisplatin is the first-generation platinum-based anti-cancer drug. Although cisplatin is much more effective than other platinum drugs at the same dosage [4], accumulating reports have shown the failure of conventional platinum-based chemotherapy due to various side effects and drug resistance [5]. Miriplatin, a member of platinum drug family, has been approved in Japan in 2009 for transcatheter arterial chemoembolization treatment of hepatocellular carcinoma (HCC) [6]. Miriplatin is a lipophilic platinum drug that contains myristates (14-carbon chains) as leaving groups and diamino cyclohexane as the non-leaving carrier ligand. The application of miriplatin in clinic is limited because it has very poor solubilities both in water and in common organic solvents [7]. The structure of solid tumors and tumor microenvironment (TME) in lung cancer constitute a barrier to the deep penetration of chemotherapy agents, which limits the effectiveness of chemotherapy [8]. Nanoparticles with appropriate properties provide a promising delivery system to overcome the biological and physiochemical barriers that hinder anti-cancer activity [9]. Lipid-based nanoparticles such as liposomes, micelles, and solid lipid nanoparticles (SLNs) can delivery anti-cancer drugs to improve their anti-cancer activities. In this study, we formulated miriplatin into various micelles, liposomes, and SLNs by film-hydration and evaluated their physicochemical properties and anti-cancer activity against NSCLC cells in culture. Miriplatin-loaded formulations with different compositions were successfully prepared by the film-hydration method. Most miriplatin-loaded micelles were more homogeneous and much smaller than miriplatin-loaded liposomes and SLNs. The majority of miriplatin-loaded micelles were about 15 nm in diameter, while SLNs were around 120 nm, and liposomes were about 180 nm. Formulations with a higher molar ratio of PE-PEG2000 had smaller sizes. SLNs loaded with a higher molar ratio of miriplatin in the compositions showed smaller sizes. Inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma optical emission spectrometry (ICP-OES) techniques were attempted to quantify the platinum element in the formulations. Formulations with a higher molar ratio of PE-PEG2000 had higher recovery of platinum element. Most miriplatin-loaded formulations had higher than 80% platinum recovery. The recovery of intact miriplatin was characterized by HPLC. Miriplatin-loaded micelles had much higher intact miriplatin recovery (about 100%) than SLNs (about 30%). By TEM imaging, the micelles showed the morphology of spherical dots of about 10 nm in diameter while SLNs showed both spherical and rodlike structures of about 120 nm in diameter. The TEM results were consistent with the size and PDI results by the Zetasizer. Three-dimensional multicellular spheroids (3D MCS) of A549 and A549-iRFP cell lines were successfully established as cell culture models to evaluate activity against non-small cell lung cancer. The viability of 3D MCS after 7-days treatment with miriplatin-loaded micelles was about 0%, which was similar to cisplatin. Miriplatin-loaded formulations with a higher molar ratio of PE-PEG2000 in the compositions had higher anti-cancer activity against 3D MCS. The anticancer activity of miriplatin-loaded formulations against 3D MCS was positively associated with the recovery of intact miriplatin from the formulations. The IC50 value of miriplatin-loaded micelles against A549-iRFP 3D MCS was around 25 µM, while that of cisplatin was 84.78 µM. In summary, the reported lipid-based nano-formulations represent a promising delivery system of miriplatin against NSCLC

Development of Lipid-based Nano Formulations of Miriplatin against Lung Cancer

Lung cancer claims the highest mortality and the second most new cases in the US. Cisplatin, the first platinum-based anticancer drug, has the highest potency against lung cancer but carries many severe adverse effects. Miriplatin was discovered with a higher lipophilicity and approved in Japan for the treatment of hepatocellular carcinoma (HCC). Nanocarriers provide a promising platform to overcome the physiochemical barrier of solid tumors and to reduce the toxicity of anticancer drugs

Effect of Al-Sr-Y intermediate alloy on microstructure and mechanical properties of A356 alloy

In this experiment, an intermediate alloy (Al-3Sr-8Y) that can refine and modify A356 alloy simultaneously was developed, and the synergistic effect of Sr and Y on the microstructure and mechanical properties of A356 alloy was investigated. The results show that when the content of Al-3Sr-8Y intermediate alloy reaches 0.3 wt%, the morphology of α -Al dendrites is significantly refined and the secondary dendrite arm spacing (SDAS) was significantly reduced. Moreover, the morphology of eutectic Si transforms from acicular to small fibrous, and the average area and aspect ratio of eutectic Si decrease to 0.81 μ m ^2 , and 2.01. This change is caused by the twin plane re-entrant edge (TPRE) poisoning mechanism, where the addition of Al-3Sr-8Y can poison the intrinsic growth position of the Si phase, reduce the growth rate of the Si phase, promote isotropic growth, and achieve a highly branched morphology of the Si phase to form a fibrous structure. Due to the excellent synergistic effect of Sr and Y, the tensile strength and elongation of the alloy reached the maximum values of 303.5 MPa and 9.5% when 0.3 wt% Al-3Sr-8Y was added after heat treatment, which is an increase of 18.2% and 86.3% compared with the untreated A356 alloy, respectively

Simultaneous refinement of α-Al and modification of Si in Al–Si alloy achieved via the addition of Y and Zr

Due to the Si/Zr-poisoning effect, conventional refiners often yield unsatisfactory results in refining α-Al grains for Al–Si alloys. In this work, the refinement of α-Al grains and the modification of eutectic Si are simultaneously achieved through the combined addition of Y and Zr to A356 alloy. The results indicate that the individual addition of Zr aids in refinement due to the formation of heterogeneous nuclei Al3Zr, while Y alone can refine α-Al grains and modify eutectic Si to a certain extent. When Y and Zr are added together, not only is the size of α-Al grains further refined to 22.1 μm, but the morphology of eutectic Si is also completely transformed into a fibrous structure. The interaction between Zr and Y decreases their solubility in the matrix, enhances heterogeneous nucleation, and induces the formation of a Al8FeMg3Si6YxZry phase enriched at grain boundaries, suppressing the growth of eutectic Si flakes. Compared to the use of Al–Ti–B refiners and Sr modifiers, the alloy with 0.25Zr and 0.3Y additions exhibits more significant grain refinement and Si modification. Furthermore, it facilitates the precipitation of fine Al3(Y, Zr) particles during the T6 heat treatment process, resulting in an optimal ultimate tensile strength (UST) of 289 MPa and an elongation of 9.75%