Hyaluronic acid/doxorubicin nanoassembly-releasing microspheres for the transarterial chemoembolization of a liver tumor

<p>Doxorubicin (DOX)-loaded, hyaluronic acid-ceramide (HACE) nanoassembly-releasing poly(lactic-co-glycolic acid) (PLGA) microspheres (MSs) were developed for transarterial chemoembolization (TACE) therapy of liver cancer. DOX/HACE MSs with a mean diameter of 27 μm and a spherical shape were prepared based on the modified emulsification method. Their <i>in vitro</i> biodegradability in artificial biological fluids was observed. A more sustained drug release pattern was observed from DOX/HACE MS than from DOX MS at pH 7.4. The cellular internalization efficiency of DOX of the DOX/HACE MS group was higher than that of the DOX MS group in liver cancer cells (HepG2 and McA-RH7777 cells), mainly due to CD44 receptor-mediated endocytosis of the released DOX/HACE nanoassembly. In both HepG2 and McA-RH7777 cells, the antiproliferation and apoptotic potentials of the DOX/HACE MS were significantly higher than those of the DOX MS (<i>p</i> < .05). Notably, in the McA-RH7777 tumor-implanted rat models, a better tumor growth suppression, a lower tumor viable portion, and a higher incidence of apoptosis were presented in the DOX/HACE MS group than in the DOX MS group after intra-arterial (IA) administration. DOX/HACE-based nanoassembly release from the DOX/HACE MS seems to elevate the cellular accumulation of DOX and its anticancer activities. The developed DOX/HACE MS can be used as a drug-loaded HA nanoassembly-releasing MS system for TACE therapy of liver cancer.</p

Hepatotoxicity measurement after intraarterial administration of formulations (A, B, and C).

<p>Each point indicates mean ± SD (n = 5). a) AST value profiles according to the time. b) ALT value profiles according to the time.</p

Mussel-Inspired Hyaluronic Acid Derivative Nanostructures for Improved Tumor Targeting and Penetration

An amphiphilic hyaluronic acid-ceramide-dopamine (HACE-d) conjugate was prepared, and HACE-d-based nanoparticles (NPs) including phloretin (as an inhibitor of glucose transporter (GLUT1)) were fabricated. Mussel-inspired property of d was introduced to HACE NPs, and it may improve tumor targetability and penetration in addition to passive (based on enhanced permeability and retention effect) and active (interaction between HA and CD44 receptor) tumor targeting effects. HACE-d/phloretin NPs with 279 nm mean diameter, ∼0.2 polydispersity index, and −18 mV zeta potential were successfully fabricated, and a sustained drug release pattern was observed. HACE-d/phloretin NPs exhibited enhanced cellular accumulation efficiency and antiproliferation property, compared with HACE/phloretin NPs, in MDA-MB-231 cells (GLUT1 and CD44 receptor-expressed human breast adenocarcinoma cells). In a MDA-MB-231 spheroid model, HACE-d NPs group showed better tumor penetration efficiency and spheroid growth inhibitory effect rather than HACE NPs group. According to the optical imaging test in MDA-MB-231 tumor-xenografted mouse, HACE-d NPs group exhibited more selective distribution in tumor region and deeper infiltration into the inner part of tumor compared with HACE NPs group. After intravenous injection, HACE-d/phloretin NPs group also exhibited improved antitumor efficacies rather than the other experimental groups in MDA-MB-231 tumor-xenografted mouse. All these findings suggested that HACE-d/phloretin NP may be a promising tumor targetable and penetrable nanosystem for the therapy and imaging of GLUT1 and CD44 receptor-expressed cancers

DOX release profiles from four types of emulsion systems and DEBs.

<p>Each point indicates mean ± standard deviation (SD) (n = 4).</p

Drug concentration (ng/g in tissues) in normal liver and tumor region after intraarterial injection in rabbits at a dose of 0.8 mg/kg.

+<p><i>p</i><0.05 compared to DEBs group (group C).</p><p>Rabbits were sacrificed 7 days postinjection and drug concentrations in the tissues were determined.</p><p>Data present as mean ± SD (<i>n</i>≥3).</p><p>Post hoc: LSD.</p><p>Drug concentration (ng/g in tissues) in normal liver and tumor region after intraarterial injection in rabbits at a dose of 0.8 mg/kg.</p

Asymmetric Syntheses of 1-Deoxy-6,8a-di-<i>epi</i>-castanospermine and 1-Deoxy-6-<i>epi</i>-castanospermine

Asymmetric syntheses of both 1-deoxy-6,8a-di-<i>epi</i>-castanospermine and 1-deoxy-6-<i>epi</i>-castanospermine, polyhydroxylated indolizidine alkaloids that act as selective glycosidase inhibitors, have been accomplished in seven steps. The key feature of our unique syntheses includes the stereoselective introduction of the C-3 and C-4 hydroxyl groups utilizing the aza-Claisen rearrangement-induced ring expansion of 1-acyl-2-alkoxyvinyl pyrrolidine and a substrate-controlled stereoselective transannulation of the resulting azoninone intermediate

Results of histologic examinations.

<p>Results of histologic examinations.</p

The procedural steps of <i>in vivo</i> experiment using VX2 rabbit liver tumor model.

<p>a) CT scan of portal venous phase showed a well-demarcated solitary tumor in the left hepatic lobe of the rabbit (arrowheads). b) Common hepatic angiography shows a hypervascular tumor staining (arrowhead). c) CT scan of portal venous phase 1 week after TACE using drug-eluting beads demonstrates no enhancement within the tumor (arrowheads). d) Photomicroscopic slide of the tumor specimen indicates focal viable tumor (arrowheads) (Hematoxylin-Eosin staining, X1). e) TUNEL staining indicates focal viable tumor (arrowheads).</p

DOX concentration in plasma after intraarterial administration of emulsions composed of Lipiodol and DOX in Pamiray (A and B) and DEBs 100–300 µm (C).

<p>Each point indicates mean ± SD (n≥3).</p

Photograph of four types of Lipiodol emulsions: (A) 10 mg of DOX in 0.5 ml of Pamiray mixed with 2 ml of Lipiodol, (B) 10 mg of DOX in 1.25 ml of Pamiray mixed with 1.25 ml of Lipiodol, (C) 10 mg of DOX in 0.5 ml of NS mixed with 2 ml of Lipiodol, (D) 10 mg of DOX in 1.25 ml of NS mixed with 1.25 ml of Lipiodol.

<p>Left images were obtained 1 minute after pumping and right images were obtained 10 minutes after pumping. Most stable w/o emulsion was prepared by 4∶1 volume ratio of Lipiodol and DOX solution in Pamiray (A).</p