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Therapeutic nanoparticle constructs of a JAK3 tyrosine kinase inhibitor against human B-lineage ALL cells.
Arzneimittelforschung. 2010;60(4):210-7
Authors: Uckun FM, Dibirdik I, Qazi S, Yiv S
WHI-P131 (CAS 202475-60-3) is a dual-function inhibitor of JAK3 tyrosine kinase that demonstrated potent in vivo anti-inflammatory and anti-leukemic activity in several preclinical animal models. This is the first report of the development of nanoparticle (NP) constructs ofWHI-P131. Fourty-eight distinct NP formulations were prepared and WHI-P131 encapsulation efficiencies > 95% and intraliposomal WHI-P131 concentrations >10 mg/mL were achieved in lead NP formulations. The anti-cancer activity of WHI-P131-NP, a PEGylated lead formulation was tested in vitro and in vivo. Notably, WHI-P131-NP was capable of causing apoptotic death in primary leukemia cells from chemotherapy-resistant acute lymphoblastic leukemia (ALL) as well as chronic lymphocytic leukemia (CLL) patients. WHI-P131-NP was also active in the RS4;11 SCID mouse xenograft model of chemotherapy-resistant B-lineage ALL. The life table analysis showed that WHI-P131-NP was more effective than WHI-P131 (P = 0.01), vincristine (P < 0.0001), or vehicle (P < 0.0001). These experimental results demonstrate that the nanotechnology-enabled delivery of WHI-P131 shows therapeutic potential against leukemias with constitutive activation of the JAK3-STAT3/STAT5 molecular target.
PMID: 20486472 [PubMed - indexed for MEDLINE]
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Development and modeling of arsenic-trioxide-loaded thermosensitive liposomes for anticancer drug delivery.
J Liposome Res. 2010 May 21;
Authors: Winter ND, Murphy RK, O'Halloran TV, Schatz GC
In this article, a novel delivery system for the anticancer drug, arsenic trioxide (ATO), is characterized. The release of ATO from DPPC liposomes with MPPC lysolipid incorporated into the bilayer was measured. Upon heating the liposomes to 37 degrees C, there was a 15-25% release over 24 hours. The ATO release from the DPPC and DPPC:MPPC (5%) systems leveled off after 10 hours at 37 degrees C, whereas the DPPC:MPPC (10%) liposomes continue to release ATO over the 24-hour time span. Upon heating the liposomes rapidly to 42 degrees C, the release rate was substantially increased. The systems containing lysolipids exhibited a very rapid release of a significant amount of arsenic in the first hour. In the first hour, the DPPC:MPPC (5%) liposomes released 40% of the arsenic and the DPPC:MPPC (10%) liposomes released 55% of the arsenic. Arsenic release from pure DPPC liposomes was comparable at 37 and 42 degrees C, indicating that the presence of a lysolipid is necessary for a significant enhancement of the release rate. A coarse-grained molecular dynamics (CGMD) model was used to investigate the enhanced permeability of lysolipid-incorporated liposomes and lipid bilayers. The CG liposomes did not form a gel phase when cooled due to the high curvature; however, permeability was still significantly lower below the liquid-to-gel phase-transition temperature. Simulations of flat DPPC:MPPC bilayers revealed that a peak in the permeability did coincide with the phase transition from the gel to LC state when the lysolipid, MPPC, was present. No pores were observed in the simulations, so it is unlikely this was the permeability-enhancing mechanism.
PMID: 20486887 [PubMed - as supplied by publisher]
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Canine spontaneous glioma: A translational model system for convection-enhanced delivery.
Neuro Oncol. 2010 May 20;
Authors: Dickinson PJ, Lecouteur RA, Higgins RJ, Bringas JR, Larson RF, Yamashita Y, Krauze MT, Forsayeth J, Noble CO, Drummond DC, Kirpotin DB, Park JW, Berger MS, Bankiewicz KS
Canine spontaneous intracranial tumors bear striking similarities to their human tumor counterparts and have the potential to provide a large animal model system for more realistic validation of novel therapies typically developed in small rodent models. We used spontaneously occurring canine gliomas to investigate the use of convection-enhanced delivery (CED) of liposomal nanoparticles, containing topoisomerase inhibitor CPT-11. To facilitate visualization of intratumoral infusions by real-time magnetic resonance imaging (MRI), we included identically formulated liposomes loaded with Gadoteridol. Real-time MRI defined distribution of infusate within both tumor and normal brain tissues. The most important limiting factor for volume of distribution within tumor tissue was the leakage of infusate into ventricular or subarachnoid spaces. Decreased tumor volume, tumor necrosis, and modulation of tumor phenotype correlated with volume of distribution of infusate (Vd), infusion location, and leakage as determined by real-time MRI and histopathology. This study demonstrates the potential for canine spontaneous gliomas as a model system for the validation and development of novel therapeutic strategies for human brain tumors. Data obtained from infusions monitored in real time in a large, spontaneous tumor may provide information, allowing more accurate prediction and optimization of infusion parameters. Variability in Vd between tumors strongly suggests that real-time imaging should be an essential component of CED therapeutic trials to allow minimization of inappropriate infusions and accurate assessment of clinical outcomes.
PMID: 20488958 [PubMed - as supplied by publisher]
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Self-assembly of Janus dendrimers into uniform dendrimersomes and other complex architectures.
Science. 2010 May 21;328(5981):1009-14
Authors: Percec V, Wilson DA, Leowanawat P, Wilson CJ, Hughes AD, Kaucher MS, Hammer DA, Levine DH, Kim AJ, Bates FS, Davis KP, Lodge TP, Klein ML, DeVane RH, Aqad E, Rosen BM, Argintaru AO, Sienkowska MJ, Rissanen K, Nummelin S, Ropponen J
Self-assembled nanostructures obtained from natural and synthetic amphiphiles serve as mimics of biological membranes and enable the delivery of drugs, proteins, genes, and imaging agents. Yet the precise molecular arrangements demanded by these functions are difficult to achieve. Libraries of amphiphilic Janus dendrimers, prepared by facile coupling of tailored hydrophilic and hydrophobic branched segments, have been screened by cryogenic transmission electron microscopy, revealing a rich palette of morphologies in water, including vesicles, denoted dendrimersomes, cubosomes, disks, tubular vesicles, and helical ribbons. Dendrimersomes marry the stability and mechanical strength obtainable from polymersomes with the biological function of stabilized phospholipid liposomes, plus superior uniformity of size, ease of formation, and chemical functionalization. This modular synthesis strategy provides access to systematic tuning of molecular structure and of self-assembled architecture.
PMID: 20489021 [PubMed - indexed for MEDLINE]
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Preparation, safety, pharmacokinetics, and pharmacodynamics of liposomes containing Brucea javanica oil.
AAPS PharmSciTech. 2010 Jun;11(2):878-84
Authors: Cui Y, Wu Z, Liu X, Ni R, Zhu X, Ma L, Liu J
Brucea javanica oil-loaded liposomes (BJOL) were prepared through thin film hydration method and characterized by transmission electron microscope, dynamic light scattering, and differential scanning calorimetry. Acute toxicity of B. javanica oil (BJO) in liposomes was assessed by determining the number of deaths of Kunming mice over intravenous treatment for 2 weeks. The pharmacokinetic behavior of the main active component (oleic acid) was studied in SD rats. The pharmacodynamics of BJOL was investigated using MMC-7721 cell lines and mice with Lewis lung cancer. The commercial emulsion of BJO (BJOE) was used as a reference. The data showed that BJOL had an average diameter of 108.2 nm with a zeta potential of -57.0 mV, drug loading of 3.60%, and entrapment efficiency of 92.40%. The area under curve of BJO in liposomes and emulsions were 2.31 and 1.15 mg min/ml, respectively. Compared with BJOE, mean residence time and elimination half-time (t(1/2)) increased 2.8- and 4.0-fold, respectively, and the clearance (CL) decreased 0.5-fold. In the acute toxicity test, the median lethal dose (LD(50)) of BJOE was 7.35 g/kg. In contrast, all mice treated with liposomes survived even at the highest dosage (12.70 g/kg). The IC(50) value of BJOL group was one third of that of BJOE group (p < 0.01), and a less weight loss was observed in the BJOL-treated animals (p < 0.05). In conclusion, the present study suggests that BJOL significantly decreased toxicity of BJO and enhance the antitumor activity. Therefore, liposomes may be a potential effective delivery vehicle for this lipophilic antitumor drug.
PMID: 20490956 [PubMed - in process]
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Mesenchymal stem cells: A promising targeted-delivery vehicle in cancer gene therapy.
J Control Release. 2010 May 19;
Authors: Hu YL, Fu YH, Tabata Y, Gao JQ
The targeting drug delivery systems (TDDS) have attracted extensive attention of researchers in recent years. More and more drug/gene targeted delivery carriers, such as liposome, magnetic nanoparticles, ligand-conjugated nanoparticles, microbubbles, etc., have been developed and under investigation for their application. However, the currently investigated drug/gene carriers have several disadvantages, which limit their future use in clinical practice. Therefore, design and development of novel drug/gene delivery vehicles has been a hot area of research. Recent studies have shown the ability of mesenchymal stem cells (MSCs) to migrate towards and engraft into the tumor sites, which make them a great hope for efficient targeted-delivery vehicles in cancer gene therapy. In this review article, we examine the promising of using mesenchymal stem cells as a targeted-delivery vehicle for cancer gene therapy, and summarize various challenges and concerns regarding these therapies.
PMID: 20493219 [PubMed - as supplied by publisher]
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DNA-METAFECTENE PRO complexation: a physical chemistry study.
Phys Chem Chem Phys. 2010 Jul 21;12(27):7464-72
Authors: Alatorre-Meda M, González-Pérez A, RodrÃguez JR
Complexes formed between cationic liposomes and DNA (also known as lipoplexes or genosomes) have proven, for years now, to be a suitable option for gene delivery to cells, transfection, however, some aspects regarding the liposome-DNA interaction mechanism and complex stability remain still unclear. This work aims to improve the understanding of the poorly defined mechanisms and structural conformation associated with the interaction of METAFECTENE PRO (MEP), a commercial liposomal transfection reagent, with poly-anion DNA at mass ratios around the mass ratio recommended for transfection (L/D congruent with 700). A physical chemistry characterization was conducted at a pH of 6.5 and at a temperature of 25 degrees C by means of dynamic light scattering (DLS), electrophoretic mobility (zeta-potential), transmission electron microscopy (TEM), and atomic force microscopy (AFM). Five parameters important for transfection were determined for the lipoplexes: (i) the hydrodynamic radius, R(H), (ii) the stability with time, (iii) the mass ratio of at which both moieties start to interact, (L/D)(i), (iv) the overall charge, and (v) the morphology. Results in ensemble point to a "beads on a string" conformation, with the lipoplex formation occurring well below isoneutrality from (L/D)(i) congruent with 600. The lipoplexes were found to be stable within at least seven days presenting an average R(H) of 135 nm.
PMID: 20495721 [PubMed - in process]
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Strategy for effective brain drug delivery.
Eur J Pharm Sci. 2010 Aug 11;40(5):385-403
Authors: Alam MI, Beg S, Samad A, Baboota S, Kohli K, Ali J, Ahuja A, Akbar M
Blood-brain barrier (BBB) together with enzymes restricts the entry of substances for maintaining the internal milieu of the brain. Because of the presence of multiple endogenous transporters, BBB allows a selective entry of nutrients and minerals across it and limits the entry of foreign substances like drugs as well as neuropharmaceutical agents. This makes the CNS treatment ineffective. The conventional drug delivery systems which release drug into general circulation fail to deliver drugs effectively to brain and is therefore not very useful in treating certain diseases that affect CNS including Alzheimer's disease, dementia, Parkinson's disease, mood disorder, AIDS, viral and bacterial meningitis. Therefore there is a need to develop and design approaches which specifically target to brain in a better and effective way. The present review enlightens about several novel approaches including nanotechnology based approach like nanoparticles, liposomes, antibody mediated delivery approach and application of genomics in brain drug targeting that would give an insight to the researchers, academia and industrialists.
PMID: 20497904 [PubMed - in process]
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Tissue distribution, pharmacokinetics and stability studies of zidovudine delivered by niosomes and proniosomes.
J Biomed Nanotechnol. 2010 Feb;6(1):43-51
Authors: Ruckmani K, Sankar V, Sivakumar M
Niosomes containing zidovudine (ZDV), an anti-HIV drug for intravenous administration were formulated by a thin-film hydration technique. Proniosomes were prepared in the form of a slurry using beta-cyclodextrin as carrier. The effect of the surfactants Tween and Span and the negative charge-inducing agent dicetylphosphate (DCP) on tissue distribution of niosomes and proniosomes was studied. The distribution of ZDV in lungs, kidney, heart, liver and spleen of mice after intravenous bolus injection was higher in Tween 80 niosomes without DCP than either niosomes with DCP or Tween 80 proniosomes. The amount of ZDV in plasma was low in Tween 80 niosomes without DCP. The results of a pharmacokinetic study in rabbits confirmed that Tween 80 formulations with DCP were cleared from the circulation within five hours. An increased half-life of 202 minutes and mean residence time of 212.1 minutes was observed in Tween 80 formulation. A stability study showed that after 90 days of storage, the drug leakage from Tween 80 formulations stored at room temperature was significant (p < 0.001) compared to niosomes stored at 4 degrees C. Encapsulation ZDV in proniosomes reduced drug leakage from vesicles stored at room temperature. These results demonstrate that niosomes are a promising vehicle for targeted delivery of ZDV to macrophages in spleen and liver.
PMID: 20499831 [PubMed - indexed for MEDLINE]
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Targeted delivery of oligomannose-coated liposome to the omental micrometastasis by peritoneal macrophages from patients with gastric cancer.
Cancer Sci. 2010 Jul;101(7):1670-7
Authors: Matsui M, Shimizu Y, Kodera Y, Kondo E, Ikehara Y, Nakanishi H
We recently developed a novel drug delivery system (DDS) using oligomannose-coated liposomes (OMLs), which are effectively taken up by mouse peritoneal macrophages to carry anticancer drugs to omental milky spots known as initial metastatic sites in the peritoneal cavity in mice. However, the feasibility of the clinical application of this DDS to gastric cancer patients remains essentially unknown. In the present study, we investigated whether human peripheral blood monocytes (PBMs) and human peritoneal macrophages (PEMs) could successfully uptake OMLs and deliver them to the micrometastatic foci in the mouse omentum and resected omentum from cancer patients ex vivo. When OMLs were incubated with the PBMs from four healthy volunteers in vitro, an average 88% of CD14-positive PBMs, most of which also express CD206, took up OMLs, and this uptake was significantly inhibited by alpha-methylmannoside. In the experiment using PEMs obtained from peritoneal washes of five gastric cancer patients, the average uptake rate (63%) of OML by CD14-positive PEMs was somewhat lower than that of PBMs, but in three advanced gastric cancer patients the uptake rate of OMLs was 76% which was comparable to that of mouse PEMs. Oligomannose-coated liposome (OML)-incorporated PBMs and PEMs were successfully accumulated at the micrometastatic foci at the omentum formed after intraperitoneal injection of GFP-tagged gastric cancer cells into mice. Furthermore, OML-incorporated PBMs substantially accumulated to tumor foci in the surgically resected human omentum ex vivo. These results suggest that OMLs using human monocytes/macrophages as a cellular vehicle have the potential to target peritoneal micrometastasis in the omentum of gastric cancer patients.
PMID: 20507320 [PubMed - in process]
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Mitochondria-targeted penetrating cations as carriers of hydrophobic anions through lipid membranes.
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Mitochondria-targeted penetrating cations as carriers of hydrophobic anions through lipid membranes.
Biochim Biophys Acta. 2010 Sep;1798(9):1698-1706
Authors: Rokitskaya TI, Sumbatyan NV, Tashlitsky VN, Korshunova GA, Antonenko YN, Skulachev VP
High negative electric potential inside mitochondria provides a driving force for mitochondria-targeted delivery of cargo molecules linked to hydrophobic penetrating cations. This principle is utilized in construction of mitochondria-targeted antioxidants (MTA) carrying quinone moieties which produce a number of health benefitting effects by protecting cells and organisms from oxidative stress. Here, a series of penetrating cations including MTA were shown to induce the release of the liposome-entrapped carboxyfluorescein anion (CF), but not of glucose or ATP. The ability to induce the leakage of CF from liposomes strongly depended on the number of carbon atoms in alkyl chain (n) of alkyltriphenylphosphonium and alkylrhodamine derivatives. In particular, the leakage of CF was maximal at n about 10-12 and substantially decreased at n=16. Organic anions (palmitate, oleate, laurylsulfate) competed with CF for the penetrating cation-induced efflux. The reduced activity of alkylrhodamines with n=16 or n=18 as compared to that with n=12 was ascribed to a lower rate of partitioning of the former into liposomal membranes, because electrical current relaxation studies on planar bilayer lipid membranes showed rather close translocation rate constants for alkylrhodamines with n=18 and n=12. Changes in the alkylrhodamine absorption spectra upon anion addition confirmed direct interaction between alkylrhodamines and the anion. Thus, mitochondria-targeted penetrating cations can serve as carriers of hydrophobic anions across bilayer lipid membranes.
PMID: 20510172 [PubMed - as supplied by publisher]
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Lipophilic photosensitizer administration via the prostate arteries for photodynamic therapy of the canine prostate.
Photodiagnosis Photodyn Ther. 2010 Jun;7(2):106-14
Authors: Xiao Z, Owen RJ, Liu W, Tulip J, Brown K, Woo T, Moore RB
BACKGROUND: Current limitations of interstitial photodynamic therapy (PDT) for treatment of prostate cancer include low drug selectivity after intravenous (i.v.) administration and incomplete ablation of glandular tissue. To overcome these limitations, intra-arterial (i.a.) injection of a photosensitizer was tested in a canine model. METHODS: A lipophilic photosensitizer, SL052 formulated in liposomes or dissolved in dimethyl sulphoxide (DMSO), was injected into male dogs as an intravenous injection or intra-arterially via the prostate arteries. Optical fibers were inserted into the prostate 3h after i.v. or immediately following i.a. drug delivery. Laser light was delivered through the fibers in cycles controlled by a computer-driven switch. Drug concentration (fluorescence) and light transmission in prostate tissue were monitored during the course of PDT. Side effect profile and completeness of prostate gland ablation were the primary parameters compared among treatment groups. Control animals received drug-only or light-only treatment. RESULTS AND CONCLUSION: Thirteen dogs were treated by PDT mediated by i.a. injection of SL052 dissolved in DMSO and attained either complete ablation of prostatic glandular tissue or significant reduction of prostate volume compared with that of pre-PDT (p<0.0001). When compared to i.v. administration the i.a. route resulted in more complete photo-ablation. Associated side effect included acute urinary retention which resolved overtime. No incontinence was observed. With careful tailoring of PDT drug and light doses, interstitial PDT with i.a. injection of SL052-DMSO has the potential to provide effective treatment for prostate disease.
PMID: 20510305 [PubMed - in process]
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Tumor-suppressive mir-663 gene induces mitotic catastrophe growth arrest in human gastric cancer cells.
Oncol Rep. 2010 Jul;24(1):105-12
Authors: Pan J, Hu H, Zhou Z, Sun L, Peng L, Yu L, Sun L, Liu J, Yang Z, Ran Y
Increasing evidence suggests that microRNAs are involved in human carcinogenesis as tumor suppressors or oncogenes. A growing number of reports has shown that an interest has been sparked in aberrant microRNA expression and how they can be used to treat human diseases, including cancer. However, their precise biological role remains largely unknown. In the present study, we aimed to identify micro-RNA species involved in the regulation of tumor growth. By performing quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis, we demonstrated that mir-663 was downregulated in human gastric cancer cell lines unlike in normal cells. A transient introduction of mir-663 into the human gastric cancer cell lines BGC823 and SNU5 induced morphology changes and suppression of proliferation of these cells. In addition, mir-663 alters the DNA content and induces phenotypes of mitotic catastrophe in tumor cells. Moreover, the liposome-mediated delivery of mir-663 suppressed the in vivo growth of the BGC823 and SNU5 cells. Western blot analyses performed after the introduction of mir-663 revealed upregulation of cyclin B following transfection with mir-663. Our results provide evidence that downregulation of mir-663 in tumor cells may contribute to aberrant cell hyperplasia, leading to the development of gastric cancer. Therefore, mir-663 might function as a potent suppressor of tumor growth.
PMID: 20514450 [PubMed - in process]
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Sustained release of hydroxycamptothecin after subcutaneous administration using a novel phospholipid complex-DepoFoam technology.
Drug Dev Ind Pharm. 2010 Jul;36(7):823-31
Authors: Zhao Y, Liu J, Sun X, Zhang ZR, Gong T
OBJECTIVE: In order to prolong the duration of drug in the circulation, multivesicular liposome (MVL, namely DepoFoam) was utilized as a sustained-release delivery system for hydroxycamptothecin (HCPT). METHODS: HCPT is insoluble in both water and physiological acceptable organic solvents; therefore, HCPT-phospholipid complex (HCPT-PCC) was prepared by solvent evaporation method to improve its liposolubility. In this study, preparation, characterization, in vitro release, and in vivo pharmacokinetics of HCPT-phospholipid complex-loaded MVLs (HCPT-MVLs) were investigated. RESULTS: The results showed that the average particle size of HCPT-MVL was 9 mum and the encapsulation efficiency was 90%. In addition, HCPT-MVLs could improve both in vitro release and in vivo pharmacokinetic behaviors of the original drug, with a sustained release of drugs over 5-6 days. CONCLUSION: These data suggested that by combined use of DepoFoam and phospholipid complex formation technique HCPT could be successfully entrapped into the MVLs, which might provide a paradigm for sustained release of insoluble drugs.
PMID: 20515403 [PubMed - in process]
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Polymer- and liposome-based nanoparticles in targeted drug delivery.
Front Biosci (Schol Ed). 2010;2:801-14
Authors: S Venkatraman S, Ma LL, Natarajan JV, Chattopadhyay S
This review focuses on polymer- and liposome-based nanoparticles used in targeted delivery of bioactive molecules, from drugs to siRNA to pDNA. The perspective centers around commercial and clinical successes, and a rationalization of these successes. Microparticulate systems are not covered, and only those applications that truly utilize the advantages of nano size are covered. "Stealth" systems dominate in this review, as most of the clinical successes are for passive targeting rather than for active targeting of tissue. The relevance of nano size to gene delivery is also discussed with relevant examples.
PMID: 20515826 [PubMed - in process]
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Effect of pazopanib on tumor microenvironment and liposome delivery.
Mol Cancer Ther. 2010 Jun;9(6):1798-808
Authors: Tailor TD, Hanna G, Yarmolenko PS, Dreher MR, Betof AS, Nixon AB, Spasojevic I, Dewhirst MW
Pathologic angiogenesis creates an abnormal microenvironment in solid tumors, characterized by elevated interstitial fluid pressure (IFP) and hypoxia. Emerging theories suggest that judicious downregulation of proangiogenic signaling pathways may transiently "normalize" the vascular bed, making it more suitable for drug delivery and radiotherapy. In this work, we investigate the role of pazopanib, a small-molecule inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, on tumor IFP, angiogenesis, hypoxia, and liposomal drug delivery. Nude mice bearing A549 human non-small cell lung cancer xenografts were treated with 100 mg/kg pazopanib (n = 20) or vehicle (n = 20) through oral gavage for 8 days, followed by a one-time intravenous dose of 10 mg/kg Doxil (liposomal doxorubicin). Pazopanib treatment resulted in significant reduction of tumor IFP and decreased vessel density, assessed by CD31 staining. Despite these trends toward normalization, high-performance liquid chromatography revealed no differences in doxorubicin concentration between pazopanib-treated and control tumors, with Doxil penetration from microvessels being significantly reduced in the pazopanib group. Additionally, tumor hypoxia, evaluated by CA-IX immunostaining and confirmed in a second study by EF5 expression (n = 4, 100 mg/kg pazopanib; n = 4, vehicle), was increased in pazopanib-treated tumors. Our results suggest that the classic definition of tumor "normalization" may undermine the crucial role of vessel permeability and oncotic pressure gradients in liposomal drug delivery, and that functional measures of normalization, such as reduced IFP and hypoxia, may not occur in parallel temporal windows.
PMID: 20515941 [PubMed - in process]
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Paclitaxel-Loaded Polymeric Micelles Modified with MCF-7 Cell-Specific Phage Protein: Enhanced Binding to Target Cancer Cells and Increased Cytotoxicity.
Mol Pharm. 2010 Jun 10;
Authors: Wang T, Petrenko VA, Torchilin VP
Polymeric micelles are used as pharmaceutical carriers to increase solubility and bioavailability of poorly water-soluble drugs. Different ligands are used to prepare targeted polymeric micelles. Earlier, we developed the method for use of specific landscape phage fusion coat proteins as targeted delivery ligands and demonstrated the efficiency of this approach with doxorubicin-loaded PEGylated liposomes. Here, we describe a MCF-7 cell-specific micellar formulation self-assembled from the mixture of the micelle-forming amphiphilic polyethylene glycol-phosphatidylethanolamine (PEG-PE) conjugate, MCF-7-specific landscape phage fusion coat protein, and the hydrophobic drug paclitaxel. These micelles demonstrated a very low cmc value and specific binding to target cells. Using an in vitro coculture model, FACS analysis, and fluorescence microscopy we showed that MCF-7 targeted phage-micelles preferentially bound to target cells compared to nontarget cells. As a result, targeted paclitaxel-loaded phage-micelles demonstrated a significantly higher cytotoxicity toward target MCF-7 cells than free drug or nontargeted micelle formulations, but failed to show such a differential toxicity toward nontarget C166 cells. Overall, cancer cell-specific phage proteins identified from phage display peptide libraries can serve as targeting ligands ("substitute antibody") for polymeric micelle-based pharmaceutical preparations.
PMID: 20518562 [PubMed - as supplied by publisher]
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Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells.
Gene Ther. 2010 Jun 3;
Authors: Kato T, Natsume A, Toda H, Iwamizu H, Sugita T, Hachisu R, Watanabe R, Yuki K, Motomura K, Bankiewicz K, Wakabayashi T
Glioblastoma multiforme (GBM) is one of the most formidable brain tumors with a mean survival period of approximately 12 months. To date, a combination of radiotherapy and chemotherapy with an oral alkylating agent, temozolomide (TMZ), has been used as first-line therapy for glioma. However, the efficacy of chemotherapy for treating GBM is very limited; this is partly because of the high activity levels of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) in tumor cells, which creates a resistant phenotype by blunting the therapeutic effect of alkylating agents. Thus, MGMT may be an important determinant of treatment failure and should be considered as a suitable target for intervention, in an effort to improve the therapeutic efficacy of TMZ. In this study, we showed that small-interfering RNA (siRNA)-based downregulation of MGMT could enhance the chemosensitivity of malignant gliomas against TMZ. Notably, TMZ-resistant glioma-initiating cells with increased DNA repair and drug efflux capabilities could be efficiently transduced with MGMT-siRNA by using a novel liposome, LipoTrust. Accordingly, such transduced glioma-initiating cells could be sensitized to TMZ in both in vitro and in vivo tumor models. Taken together, this study provides an experimental basis for the clinical use of such therapeutic combinations.Gene Therapy advance online publication, 3 June 2010; doi:10.1038/gt.2010.88.
PMID: 20520650 [PubMed - as supplied by publisher]
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In vitro evaluation of inhalable isoniazid-loaded surfactant liposomes as an adjunct therapy in pulmonary tuberculosis.
J Biomed Mater Res B Appl Biomater. 2010 Jul;94(1):1-10
Authors: Chimote G, Banerjee R
In this study, exogenous pulmonary surfactant was evaluated as an inhalable drug carrier for antitubercular drug isoniazid (INH). Isoniazid-entrapped liposomes of dipalmitoylphosphatidylcholine (DPPC) (the most abundant lipid of lung surfactant and exogenous surfactant) were developed and evaluated for size, drug entrapment, release, in vitro alveolar deposition, biocompatibility, antimycobacterial activity, and pulmonary surfactant action. Isoniazid-entrapped DPPC liposomes were about 750 nm in diameter and had entrapment efficiency of 36.7% +/- 1.8%. Sustained release of INH from DPPC liposomes was observed over 24 h. In vitro alveolar deposition efficiency using the twin impinger exhibited approximately 25-27% INH deposition in the alveolar chamber upon one minute nebulization using a jet nebulizer. At 37 degrees C, the formulation had better pulmonary surfactant function with quicker reduction of surface tension on adsorption (36.7 +/- 0.4 mN/m) than DPPC liposomes (44.7 +/- 0.6 mN/m) and 87% airway patency was exhibited by the formulation in a capillary surfactometer. The formulation was biocompatible and had antimycobacterial activity. The isoniazid-entrapped DPPC liposomes could fulfill the dual purpose of pulmonary drug delivery and alveolar stabilization due to antiatelectatic effect of the surfactant action which can improve the reach of antitubercular drug INH to the alveoli.
PMID: 20524179 [PubMed - in process]
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A Novel Octreotide Modified Lipid Vesicle Improved the Anticancer Efficacy of Doxorubicin in Somatostatin Receptor 2 Positive Tumor Models.
Mol Pharm. 2010 Jun 14;
Authors: Zhang J, Jin W, Wang X, Wang J, Zhang X, Zhang Q
Octreotide (Oct) is a potential ligand due to its high affinity to somatostatin receptors (SSTRs), especially subtype 2 (SSTR2), as many tumor cells specifically overexpress SSTR2. In this study, we conjugated Oct to the PEG end of DSPE-PEG and prepared a novel doxorubicin (DOX)-loaded and Oct-modified sterically stabilized liposomes (Oct-SSL-DOX), in order to facilitate intracellular delivery of chemotherapeutic agent to the related tumor cells through active targeting and finally improve its antitumor activity. Three cells were proved to be different in expression level of SSTR2 and were used as model or control. It was demonstrated by fluorescence spectrophotometry, confocal laser scanning microscopy and flow cytometry that active sterically stabilized liposomes (SSL) increased intracellular delivery of DOX in SSTR2-positive cells, through a mechanism of receptor-mediated endocytosis. Compared to SSL, Oct modification on SSL exhibited little effect on the physicochemical properties of SSL. However, it reduced the circulation time of loaded-DOX to some extent in rats, increased cytotoxicity in SSTR2-positive tumor cells, enhanced drug accumulation in tumor tissue and improved anticancer efficacy in SSTR2-overexpressing tumor model. The correlation was found among intracellular uptake, cytotoxicity, drug distribution in tumor and pharmacodynamics of Oct-SSL-DOX, but not the pharmacokinetics based on plasma drug concentration. In summary, octreotide-modified SSL might be a promising system for the treatment of SSTR2-overexpressing cancers.
PMID: 20524673 [PubMed - as supplied by publisher]
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Gene therapy for psoriasis in the K14-VEGF transgenic mouse model by topical transdermal delivery of interleukin-4 using ultradeformable cationic liposome.
J Gene Med. 2010 Jun;12(6):481-90
Authors: Li J, Li X, Zhang Y, Zhou XK, Yang HS, Chen XC, Wang YS, Wei YQ, Chen LJ, Hu HZ, Liu CY
BACKGROUND: Topical transdermal gene delivery to the skin shows great potential for painless, non-invasive administration of vaccines and therapeutic agents. Interleukin (IL)-4 strategies have shown a good antipsoriatic effect in clinic trials. To date, no information has been acquired on the effectiveness of gene therapy for psoriasis in the K14-VEGF transgenic mouse model by topical transdermal penetration of murine IL-4 (mIL-4) using ultradeformable cationic liposome (UCL). METHODS: In the present study, we synthesized an UCL and determined a suitable formula for transdermally delivering plasmid DNA to mouse skin. We then tested the antipsoriatic efficacy in the K14-VEGF transgenic mouse model by transdermal delivery of mIL-4 using UCL. RESULTS: We found that plasmid DNA was transdermally delivered to vicinal sites of epidermis and hair follicles using this optimized formula. Plasmid DNA expression was detected in ear skin. Twenty-four hours after topical application, plasmid DNA was not detected in blood serum and liver, which may decrease the risk of insertion of promoter from plasmid to genomic DNA. Mice treated with UCL/mIL-4 displayed a mild psoriasis phenotype. Histological analysis of pathological score using the Baker scoring system revealed an antipsoriatic effect. Immunohistochemical analysis revealed that hyperplastic and inflamed vessels were suppressed. CONCLUSIONS: These observations provide evidence of antipsoriatic efficacy by topical transdermal delivery of mIL-4. Therefore, topical transdermal gene transfer is attractive and offers future potential for application in human patients with other dermatogic diseases.
PMID: 20527041 [PubMed - in process]
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