Stimuli-Responsive Polymeric Nanocarriers Accelerate On-Demand Drug Release to Combat Glioblastoma.

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with a poor prognosis and limited treatment options. Drug delivery by stimuli-responsive nanocarriers holds great promise for improving the treatment modalities of GBM. At the beginning of the review, we highlighted the stimuli-active polymeric nanocarriers carrying therapies that potentially boost anti-GBM responses by employing endogenous (pH, redox, hypoxia, enzyme) or exogenous stimuli (light, ultrasonic, magnetic, temperature, radiation) as triggers for controlled drug release mainly via hydrophobic/hydrophilic transition, degradability, ionizability, etc. Modifying these nanocarriers with target ligands further enhanced their capacity to traverse the blood-brain barrier (BBB) and preferentially accumulate in glioma cells. These unique features potentially lead to more effective brain cancer treatment with minimal adverse reactions and superior therapeutic outcomes. Finally, the review summarizes the existing difficulties and future prospects in stimuli-responsive nanocarriers for treating GBM. Overall, this review offers theoretical guidelines for developing intelligent and versatile stimuli-responsive nanocarriers to facilitate precise drug delivery and treatment of GBM in clinical settings.

High Drug Loading, Reversible Disulfide Core-Cross-Linked Multifunctional Micelles for Triggered Release of Camptothecin.

Nanomedicines in polymeric therapeutics present a potential treatment for cancers. However, their clinical effectiveness still has room to be improved. Herein, reduction-responsive reversibly core-cross-linked micelles based on the poly(ethylene glycol)-dihydrolipoic acid (MeO-PEG2k-DHLA) conjugate were developed for triggered intracellular release of camptothecin (CPT). Coupling two molecules of dihydrolipoic acid (DHLA) to methyl-terminated PEG (Mw 2000) through a labile ester bond was performed by solution-phase condensation reaction. Due to the amphiphilic property, the MeO-PEG2k-DHLA conjugate formed micelles that were readily cross-linked with disulfide formation dispersed in water. These sole cross-linked micelles were 74.9 nm in hydrodiameter, as analyzed by dynamic light scattering (DLS). The nanostructures demonstrated excellent stability against extensive dilution, while rapidly dissociating under 10 mM glutathione (GSH), highlighting their potential for drug delivery. Interestingly, CPT was modified with a disulfide linkage and subsequently conjugated to the MeO-PEG2k-DHLA polymer scaffold. Core-cross-linking of the micelles achieved high drug loading of CPT (31.81%, wt %) and demonstrated that CPT release at pH 7.4 was significantly declined by cross-linking (i.e., less than 15% release in 24 h), whereas more than 90% of CPT was released under 10 mM GSH condition. In vitro cellular uptake and MTT assays showed that CPT-conjugated MeO-PEG2k-DHLA micelles were effectively internalized into tumor cells to induce the cytotoxic effects against HepG-2 and MCF-7 cells. Importantly, in vivo pharmacokinetics analysis demonstrated the nanoscale feature of micelles makes CPT to present longer retention time, resulting in a higher accumulation at tumor sites. Taken together, the disulfide core-cross-linked MeO-PEG2k-DHLA multifunctional micelles with high drug loading and excellent stability are potential candidates for tumor-targeting drug delivery.

Dual 7-ethyl-10-hydroxycamptothecin conjugated phospholipid prodrug assembled liposomes with in vitro anticancer effects.

7-Ethyl-10-hydroxycamptothecin (SN38), as a highly active topoisomerase I inhibitor, is 200-2000-fold more cytotoxic than irinotecan (CPT-11) commercially available as Camptosar®. However, poor solubility and low stability extensively restricted its clinical utility. In this report, dual SN38 phospholipid conjugate (Di-SN38-PC) prodrug based liposomes were developed in order to compact these drawbacks. Di-SN38-PC prodrug was first synthesized by inhomogeneous conjugation of two SN38-20-O-succinic acid molecules with L-α-glycerophosphorylcholine (GPC). The assembly of the prodrug was carried out without any excipient by using thin film method. Dynamic light scattering (DLS), transmission electron microscope (TEM) and cryogenic transmission electron microscopy (cyro-TEM) characterization indicated that Di-SN38-PC can form spherical liposomes with narrow particle size (<200nm) and negatively charged surface (-21.6±3.5mV). The loading efficiency of SN38 is 65.2 wt.% after a simple calculation. In vitro release test was further performed in detail. The results demonstrated that Di-SN38-PC liposomes were stable in neutral environment but degraded in a weakly acidic condition thereby released parent drug SN38 effectively. Cellular uptake studies reflected that the liposomes could be internalized into cells more significantly than SN38. In vitro antitumor activities were finally evaluated by MTT assay, colony formation assay, flow cytometry, RT-PCR analysis and Western Blot. The results showed that Di-SN38-PC liposomes had a comparable cytotoxicity with SN38 against MCF-7 and HBL-100, and a selective promotion of apoptosis of tumor cells. Furthermore, a pharmacokinetics test showed that Di-SN38-PC liposomes had a longer circulating time in blood compared with the parent drug. All the results indicate that Di-SN38-PC liposomes are an effective delivery system of SN38.

Association of the use of bacterial cell wall synthesis Inhibitor drugs in early childhood with the Developmental Defects of Enamel.

OBJECTIVE: Our objective of the study was to determine the association between frequent use of Penicillins and Cephalosporins with developmental defects of enamel in pediatric age group. METHODS: This is a cross sectional study, conducted at Ziauddin University. A total of 367 children, having the history of either Penicillin or Cephalosporin exposure were included. The parents of children were asked to complete a questionnaire related to disease and drug history. Dental examination was carried out to assess the hypomineralization in tooth enamel based on modified Developmental Defects of Enamel (DDE) index. RESULTS: Out of 367 children, 124 (34%) were males and females were 243(66%). In the study group 22.6% (n= 83) of children were found to be hypomineralized. The maximum type of teeth defects were diffused opacities that was 12.0% (n=44). The statistically significant association (p-value < 0.05) was found between frequency of antibiotic use and hypomineralization for most teeth. Children who were exposed to either Penicillins or Cephalosporin in early childhood showed significant (p-value < 0.002) hypomineralized enamel. CONCLUSION: This study concludes that frequent use of antibiotics such as penicillins and cephalosporins has positive association with enamel hypomineralization in developing tooth structure.

PEG length effect of peptide-functional liposome for blood brain barrier (BBB) penetration and brain targeting.

Nanoparticles, in particular PEGylated, show great potential for in vivo brain targeted drug delivery. Nevertheless, how polyethylene glycol (PEG) length of nanoparticles affects their blood brain barrier (BBB) penetration or brain targeting is still unclear. In this study, we investigated the power of PEG chain-lengths (2, 3.4, 5, 10 kDa) in BBB penetration and brain targeting using Angiopep-2 peptide decorated liposomes. We found that PEG chain-length is critical, where the shorter PEG enabled the Angiopep-2 decorated liposomes to display more potent in vitro cell uptake via endocytosis. In contrast, their in vitro BBB penetration via transcytosis was much weaker relative to the liposomes with longer PEG chains, which result from their ineffective BBB exocytosis. Interestingly, the in vivo brain targeting aligns with the in vitro BBB penetration, as the long chain PEG-modified liposomes exerted superior brain accumulation both in normal or orthotropic glioblastoma (GBM) bearing mice, which could be ascribed to the combinational effect of prolonged circulation and enhanced BBB penetration of long chain PEG attached liposomes. These results demonstrate the crucial role of PEG length of nanoparticles for BBB penetration and brain targeting, providing guidance for PEG length selection in the design of nanocarrier for brain diseases treatment.

Porous NiTi Dental Implant Fabricated by a Metal Injection Molding: An in Vivo Biocompatibility Evaluation in an Animal Model.

This study assessed the corrosion resistance, intracutaneous reactivity, acute systemic toxicity, and in situ tissue effect of the implantation of porous NiTi fabricated by metal injection molding in animal models. For the intracutaneous reactivity study, five intracutaneous injections were administered per site with and without the tested extract in polar and nonpolar solutions. The extract was also delivered via intravenous and intraperitoneal routes for acute systemic toxicity. TiAl6 V4 (control) and porous NiTi were implanted in rabbit femora for a period of 13 weeks to evaluate the in situ tissue response. Corrosion was evaluated through open and cyclic polarization in PBS, while biocompatibility was investigated by assessing the general conditions, skin irritation score (edema and erythema), and histopathology. No active dissolution or hysteresis loop was observed in the corrosion study. None of the animals exhibited death, moribundity, impending death, severe pain, self-mutilation, or overgrooming. No edema was observed at injection sites. Only the positive control showed an erythematous reaction at 24, 48, and 72 h observations (p < 0.001). Porous NiTi showed a low in situ biological response for inflammation, neovascularization, and fibrosis in comparison to the control implant (p = 0.247, 0.005, and 0.011, respectively). Porous NiTi also demonstrated high pitting corrosion resistance while causing no acute hypersensitivity or acute systemic toxicity. The study concludes that porous NiTi implants were unlikely to cause local sensitization, acute systemic toxicity, or chronic inflammatory reactions in an animal model. Porous NiTi also exhibited osseointegration equivalent to Ti6AI4 V of known biocompatibility.

Targeted liposomes for combined delivery of artesunate and temozolomide to resistant glioblastoma.

The effective treatment of glioblastoma (GBM) is a great challenge because of the blood-brain barrier (BBB) and the growing resistance to single-agent therapeutics. Targeted combined co-delivery of drugs could circumvent these challenges; however, the absence of more effective combination drug delivery strategies presents a potent barrier. Here, a unique combination ApoE-functionalized liposomal nanoplatform based on artesunate-phosphatidylcholine (ARTPC) encapsulated with temozolomide (ApoE-ARTPC@TMZ) was presented that can successfully co-deliver dual therapeutic agents to TMZ-resistant U251-TR GBM in vivo. Examination in vitro showed ART-mediated inhibition of DNA repair through the Wnt/ß-catenin signaling cascade, which also improved GBM sensitivity to TMZ, resulting in enhanced synergistic DNA damage and induction of apoptosis. In assessing BBB permeation, the targeted liposomes were able to effectively traverse the BBB through low-density lipoprotein family receptors (LDLRs)-mediated transcytosis and achieved deep intracranial tumor penetration. More importantly, the targeted combination liposomes resulted in a significant decrease of U251-TR glioma burden in vivo that, in concert, substantially improved the survival of mice. Additionally, by lowering the effective dosage of TMZ, the combination liposomes reduced systemic TMZ-induced toxicity, highlighting the preclinical potential of this novel integrative strategy to deliver combination therapies to brain tumors.

ROS-mediated liposomal dexamethasone: a new FA-targeted nanoformulation to combat rheumatoid arthritis via inhibiting iRhom2/TNF-α/BAFF pathways.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder that has seriously affected human health worldwide and its current management requires more successful therapeutic approaches. The combination of nanomedicines and pathophysiology into one system may provide an alternative strategy for precise RA treatment. In this work, a practical ROS-mediated liposome, abbreviated as Dex@FA-ROS-Lips that comprised synthetic dimeric thioether lipids (di-S-PC) and a surface functionalized with folic acid (FA), was proposed for dexamethasone (Dex) delivery. Incorporation with thioether lipids and a FA segment significantly improved the triggered release and improved the triggered release of cytotoxic Dex as well as the active targeting of RA, altering its overall pharmacokinetics and safety profiles in vivo. As proof, the designed Dex@FA-ROS-Lips demonstrated effective internalization by LPS-activated Raw264.7 macrophages with FA receptor overexpression and released Dex at the inflammatory site due to the ROS-triggered disassembly. Intravenous injection of this Dex@FA-ROS-Lips into adjuvant-induced arthritis (AIA) mice led to its incremental accumulation in inflamed joint tissues and significantly alleviated the cartilage destruction and joint swelling via suppression of proinflammatory cytokines (iRhom2, TNF-α and BAFF), as compared to the effect of commercial free Dex. Importantly, the Dex@FA-ROS-Lips nanoformulation showed better hemocompatibility with less adverse effects on the body weight and immune organ index of AIA mice. The anti-inflammatory mechanism of Dex@FA-ROS-Lips was further studied and it was found that it is possibly associated with the down-regulation of iRhom2 and the activation of the TNF-α/BAFF signaling pathway. Therefore, the integration of nanomedicines and the RA microenvironment using multifunctional Dex@FA-ROS-Lips shall be a novel RA treatment modality with full clinical potential, and based on the enhanced therapeutic effect, the signaling pathway of iRhom2/TNF-α/BAFF reasonably explained the mechanism of Dex@FA-ROS-Lips in anti-RA, which suggested a molecular target for RA therapy and other inflammatory diseases.

Synthetic dimeric-drug phospholipid: a versatile liposomal platform for cancer therapy.

An amphiphilic dimeric-podophyllotoxin (PODO) phospholipid was synthesized to assemble into liposomes as a combination of prodrug and nanocarrier. The results have demonstrated that the cell membrane-like delivery system possessed an improved cellular uptake and favorable antitumor efficacy with reduced side-effects. This strategy provides a new effective platform in drug delivery for cancer chemotherapy.

Green biolubricant infused slippery surfaces to combat marine biofouling.

HYPOTHESIS: Marine biofouling is a global, longstanding problem for maritime industries and coastal areas arising from the attachment of fouling organisms onto solid immersed surfaces. Slippery Liquid Infused Porous Surfaces (SLIPS) have recently shown promising capacity to combat marine biofouling. In most SLIPS coatings, the lubricant is a silicone/fluorinated-based synthetic component that may not be fully compatible with the marine life. We hypothesized that eco-friendly biolubricants could be used to replace synthetic lubricants in SLIPS for marine anti-fouling. EXPERIMENTS: We developed SLIPS coatings using oleic acid (OA) and methyl oleate (MO) as infusing phases. The infusion efficiency was verified with confocal microscopy, surface spectroscopy, wetting efficiency, and nanocontact mechanics. Using green mussels as a model organism, we tested the anti-fouling performance of the biolubricant infused SLIPS and verified its non-cytotoxicity against fish gill cells. FINDINGS: We find that UV-treated PDMS infused with MO gives the most uniform infused film, in agreement with the lowest interfacial energy among all surface/biolubricants produced. These surfaces exhibit efficient anti-fouling properties, as defined by the lowest number of mussel adhesive threads attached to the surface as well as by the smallest surface/thread adhesion strength. We find a direct correlation between anti-fouling performance and the substrate/biolubricant interfacial energy.

Evaluation of the acute toxicity of profenofos and its effects on the behavioral pattern of fingerling common carp (Cyprinus carpio L., 1758).

Profenofos, an organophosphate insecticide is acetylcholinesterase inhibitor that has the potential to contaminate the ground water. The 96 h LC(50) value of profenofos was determined in 3-month-old fingerling common carp (Cyprinus carpio) with a body weight 1.04 +/- 0.25 g and a body length 4.25 +/- 0.75 cm at 26 +/- 1 degrees C temperature. Trimmed Spearman-Karber (TSK) software was used for the statistical analysis, which calculated the LC(50) value as 62.4 microg/L for three replicates of the assay. The behavioral responses of fish exposed to profenofos included loss of balance, moving in spiral fashion with sudden jerky movements, lying on their sides and rapid flapping of the operculum with the mouth open.

Lipoic acid-derived cross-linked liposomes for reduction-responsive delivery of anticancer drug.

Liposomes have emerged as a fascinating nanocarriers for the delivery of cancer therapeutics. However, their efficacy for cancer therapy is reduced partially because of the serum-instability and incomplete drug release. In this study, a novel disulfide cross-linked liposomes (CLs) assembled from dimeric lipoic acid-derived glycerophosphorylcholine (di-LA-PC) conjugate was developed. The conjugate was synthesized by a facial esterification of lipoic acid (LA) and glycerophosphorylcholine (GPC) and characterized by MS, 1H NMR and 13C NMR. Featuring the enhanced serum-stability and intracellular drug release determined by in vitro stability and GSH-responsive behavior, CLs prepared with dried thin film technique following 10 % dithiothreitol (DTT) cross-linking can attain effective delivery of anticancer candidates. Notably, CLs stably encapsulated doxorubicin (Dox) in their vesicular structures and showed a remarkable thiol-sensitive release of payload upon cellular uptake by cancer cells, compared to that of uncross-linked liposomes (uCLs) or Doxil-like liposome (DLLs). The cell viability and apoptosis of Dox-loaded CLs worked the pronounced cytotoxic effects to MCF-7 cells with an IC50 value of 10.8 µg Dox equiv./mL comparable to free Dox and 2.8-fold higher than DLLs. More importantly, it is demonstrated that the nanoscale characteristics of Dox-loaded CLs could prevent the proliferation of adriamycin-resistant MCF-7/ADR cell line, highlighting their potential in reversal of drug resistance. Furthermore, the preliminary in vivo test (n = 3) showed that disulfide cross-linked liposomal formulation of Dox (Dox-CLs) improved the therapeutic efficacy compared to free Dox and DLLs in a human breast carcinoma xenograft mouse model. Therefore, the current thiol-responsive cross-linked liposome may provide a robust drug delivery platform for cancer therapy.

Liposomes of dimeric artesunate phospholipid: A combination of dimerization and self-assembly to combat malaria.

Artemisinin and its derivatives are highly effective drugs in the treatment of P. falciparum malaria. However, their clinical applications face challenges because of short half-life, poor bioavailability and growing drug resistance. In this article, novel dimeric artesunate phospholipid (Di-ART-GPC) based liposomes were developed by combination of dimerization and self-assembly to address these shortcomings. Firstly, Di-ART-GPC conjugate was synthesized by a facile esterification of artesunate (ART) and glycerophosphorylcholine (GPC) and confirmed by MS, 1H NMR and 13C NMR. The conjugate was then assembled to form liposomes without excipient by thin film hydration method. The assembled Di-ART-GPC liposomes have typical multilamellar vesicle structure with bilayer morphology as determined by transmission electron microscopy (TEM) and cryogenic electron microscopy (cryo-EM). Moreover, the liposomes displayed an average hydrodynamic diameter of 190 nm and negative zeta potential at -20.35 mV as determined by Zetasizer. The loading capacity of ART was calculated approximately 77.6% by weight with this liposomal formulation after a simple calculation. In vitro drug release and degradation results showed that the Di-ART-GPC liposomes were stable in neutral physiological conditions but effectively degraded to release parent ART in simulated weakly acidic microenvironment. In vivo pharmacokinetics study revealed that Di-ART-GPC liposomes and conjugate have longer retention half-life in bloodstream. Importantly, Di-ART-GPC liposomes (IC50 0.39 nM) and the conjugate (IC50 1.90 nM) demonstrated excellent in vitro antiplasmodial activities without causing hemolysis of erythrocytes, which were superior to free ART (IC50 5.17 nM) and conventional ART-loaded liposomes (IC50 3.13 nM). Furthermore, the assembled liposomes resulted in enhanced parasites killing in P. berghei-infected mice in vivo with delayed recrudescence and improved survivability, compared to free ART administration. Based on these encouraging results, Di-ART-GPC liposomal formulation could be a replacement to parent ART in clinical malarial therapy after thorough investigation.

Liposomes assembled from dimeric retinoic acid phospholipid with improved pharmacokinetic properties.

All-trans-retinoic acid (ATRA) exhibits potent cytotoxicities against different cancer cells by binding to retinoic acid receptors (RARs), which is regarded as the first example of targeted therapy in acute promyelocytic leukemia (APL). However, its extensive clinical applications have been limited because of poor aqueous solubility, short half-life time and side effects. In this report, dimeric ATRA phosphorylcholine prodrug (Di-ATRA-PC) was designed and assembled into nanoliposomes to improve its pharmacokinetic properties. Di-ATRA-PC prodrug was synthesized by a facile esterification and characterized by mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR). The Di-ATRA-PC assembled liposomes were prepared by thin film hydration method with ATRA loading efficiency up to 73wt%. The liposomes have a uniform particle size (73.1±3.6nm) with negatively charged surface (-20.5±2.5mV) and typical lipid bilayer structure as measured by dynamic light scattering (DLS), transmission electron microscope (TEM) and cryogenic transmission electron microscope (cryo-TEM). In vitro drug release study confirmed that Di-ATRA-PC liposomes could sustainedly release free ATRA in a weakly acidic condition. Furthermore, cellular uptake, MTT and cell apoptosis analysis demonstrated that the liposomes could be successfully internalized into tumor cells to induce apoptosis of MCF-7 and HL-60 cells. More importantly, in vivo pharmacokinetic assay indicated that Di-ATRA-PC liposomes had much longer retention time in comparison with ATRA. In conclusion, Di-ATRA-PC liposomal formulation could be a potential drug delivery system of ATRA with enhanced pharmacokinetic properties.

Dimeric camptothecin derived phospholipid assembled liposomes with high drug loading for cancer therapy.

In this study, a newly liposomal formulation of camptothecin (CPT) based on the dimeric camptothecin glycerophosphorylcholine (di-CPT-GPC) prodrug was developed. The di-CPT-GPC prodrug was synthesized through the heterogeneous conjugation of camptothecin-20 succinate with glycerophosphorylcholine. It undergoes assembly to form liposomes without any excipient through the thin film hydration method, which, confirmed by dynamic light scattering (DLS), have an average diameter of approximately 165 ±â€¯5 nm. Observations on cryogenic transmission electron microscopy (cryo-TEM) demonstrated that the liposomes possess a typical multilamellar vesicle structure with a bilayer thickness of approximately 4 nm. The liposomes with a CPT loading up to 62 wt% maintained good stability in simulated physiological fluid. This can be attributed to the protection of the liposomes having CPT groups sequestered within the bilayer interior. Moreover, the in vitro release behavior of di-CPT-GPC liposomes was monitored using different media. The results showed that the liposomes could dissociate and sustainably release free active form CPT in a weak acidic environment. In vitro anticancer activity tests indicated that di-CPT-GPC liposomes had comparable cytotoxicity to the parent drug against MCF-7, HeLa and HepG-2 cells. Finally, a preliminary in vivo antitumor evaluation revealed that the liposomes inhibited tumor growth. Taken together, the di-CPT-GPC assembled liposomes with high drug loading could be a promising nanoformulation of CPT.

Novel dual VES phospholipid self-assembled liposomes with an extremely high drug loading efficiency.

Vitamin E succinate (VES), a unique selective anti-cancer drug, has attracted much attention for its ability to induce apoptosis in various cancer cells. Importantly, it has been reported that VES is largely non-toxic to normal cells. However, poor aqueous solubility and bioavailability extensively restricted its clinical utility. In this report, dual VES phospholipid conjugate (di-VES-GPC) prodrug based liposomes were prepared in order to develop an efficient delivery system for VES. Di-VES-GPC was first synthesized by conjugating VES with l-α-glycerophosphorylcholine (GPC) using N,N'-dicyclohexylcarbodiimide (DCC) as a coupling agent. The di-VES-GPC prodrug was able to self-assemble into liposomes by reverse-phase evaporation method. The structure of the liposomes was characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and cryo-TEM. The results showed that di-VES-GPC assembled liposomes were spherical with an average diameter approximately 183nm. Cryo-TEM data confirmed the formation of multilamellar liposomes with the bilayer thickness about 5nm by the assembly of the conjugate without any excipient. The VES drug loading highly reaches up to 82.8wt% in the liposomes after a simple calculation. Furthermore, the in vitro release behavior of di-VES-GPC liposomes was evaluated in different media. It was found that the liposomes could release free VES at a weakly acidic microenvironment but exhibited good stability under a simulated biological condition. The cellular uptake and intracellular drug release tests demonstrated that di-VES-GPC liposomes could be internalized effectively and converted into parent drug VES in cancer cells. Furthermore, in vitro antitumor activities of the di-VES-GPC liposomes were evaluated by MTT assay and flow cytometry. It was revealed that the liposomes presented comparable cytotoxicities to free VES. Taken together, the di-VES-GPC liposomes might provide an excellent formulation of VES which have potential in the treatment of cancers.

Assembled liposomes of dual podophyllotoxin phospholipid: preparation, characterization and in vivo anticancer activity.

AIM: A novel amphiphilic prodrug dual podophyllotoxin (PPT) succinate glycerophosphorylcholine (Di-PPT-GPC) assembled liposomes was developed to improve efficiency of PPT. MATERIALS & METHODS: Di-PPT-GPC liposomes were prepared by thin film technique and characterized by dynamic light scattering and cryo-electron microscopy. RESULTS: In vitro release studies showed that Di-PPT-GPC liposomes could significantly release PPT in weakly acidic environment but had good stability under biological conditions. Methyl tetrazolium assay data revealed that the liposomes have comparable cytotoxicities to free PPT against MCF-7, HeLa and U87 cells. More importantly, in vivo antitumor evaluation indicated that Di-PPT-GPC liposomes exhibited favorable tumor growth inhibition without side effects. CONCLUSION: Di-PPT-GPC liposomes might have potential to promote the therapeutic effect of PPT for cancer therapy.

Self-assembled liposomes of dual paclitaxel-phospholipid prodrug for anticancer therapy.

In this report, a newly liposomal formulation of paclitaxel (PTX) based on dual paclitaxel succinate glycerophosphorylcholine (Di-PTX-GPC) prodrug was developed. The Di-PTX-GPC prodrug was synthesized by conjugating PTX with GPC through esterification under N,N'-carbonyldiimidazole (CDI) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) catalytic system. Di-PTX-GPC liposomes were prepared by thin film method and characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). The results indicated that the liposomes have an average diameter of 157.9nm with well-defined spherical morphology. In vitro drug release studies confirmed that the Di-PTX-GPC liposomes have controlled release profile of PTX at a weakly acidic environment, which formulates them suitable for sustained drug delivery. Additionally, in vitro cellular uptake analysis and cytotoxicity evaluation showed that Di-PTX-GPC liposomes were internalized successfully into tumor cells to induce the apoptosis against MCF-7, HeLa and HepG-2 cells. In vivo pharmacokinetics study revealed that such liposomal formulation of Di-PTX-GPC has longer retention half-life in bloodstream, which subsequently leads to slight accumulate in tumor sites due to enhanced permeability and retention (EPR) effect. More importantly, Di-PTX-GPC liposomes demonstrated good in vivo anticancer activities compared to Taxol with reduced adverse effects. Conclusively, these results suggest that Di-PTX-GPC liposomes could be an effective PTX delivery vehicles in clinical cancer chemotherapy.

Silicone hydrogels grafted with natural amino acids for ophthalmological application.

In this report, protein repelling silicone hydrogels with improved hydrophilicity were prepared by photo-polymerization of silicone-containing monomer and glycidyl methacrylate followed by grafting zwitterionic amino acids. The grafted silicone hydrogels possessed excellent hydrophilic surfaces due to the enrichment of amino acids, which was confirmed by attenuated total reflectance Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, contact angle, and equilibrium water content measurements. Remarkable resistance to bovine serum albumin and lysozyme fouling was observed for the silicone hydrogels immobilized with neutrally charged amino acids because of the formation of zwitterionic surfaces with pairs of protonated secondary ammonium cations and deprotonated carboxyl anions. Meanwhile, the silicone hydrogels grafted with positively or negatively charged amino acids were able to repulse same charged protein with reduced deposition and attract oppositely charged protein with increased adsorption. Preliminary cytotoxicity test indicated that the zwitterionic silicone hydrogels were non-cytotoxic. Similarly, three types of natural amino acids, including serine, aspartic acid and histidine, modified silicone hydrogel contact lenses exhibited excellent hydrophilicity and non-damage to the rabbit's eyes, but only serine modified zwitterionic contact lens showed superior protein fouling resistance compared with the current commercial hydrogel contact lens, which may have great potential application in ophthalmology.

Formation of microporous NiTi by transient liquid phase sintering of elemental powders.

Porous metallic structures are attractive for biomedical implant applications as their open porosity simultaneously improves the degree of fixation and decreases the mismatch in stiffness between bone and implant, improving bonding and reducing stress-shielding effects respectively. NiTi alloys exhibit both the shape memory effect and pseudoelasticity, and are of particular interest, though they pose substantial problems in their processing. This is because the shape memory and pseudoelastic behaviours are exceptionally sensitive to the presence of oxygen, and other minor changes in alloy chemistry. Thus in processing careful control of composition and contamination is vital. In this communication, we investigate these issues in a novel technique for producing porous NiTi parts via transient liquid phase sintering following metal injection moulding (MIM) of elemental Ni and Ti powders, and report a new mechanism for pore formation in the powder processing of metallic materials from elemental powders.