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Biomaterials (v.33, #19)

Editorial board (pp. ifc).

Common features of optimal collagen scaffolds that disrupt wound contraction and enhance regeneration both in peripheral nerves and in skin by Eric C. Soller; Dimitrios S. Tzeranis; Kathy Miu; Peter T.C. So; Ioannis V. Yannas (pp. 4783-4791).
The adult mammal responds to severe injury of most organs spontaneously by wound contraction and scar formation, rather than by regeneration. In severe skin wounds, the ability of porous collagen scaffolds to induce regeneration was found to correlate strongly with a reduction in wound contraction rate. Here, we present quantitative evidence of a similar positive relationship between the extent of disruption of tissue contraction and quality of peripheral nerve regeneration in transected rat peripheral nerves. Our observations suggest that porous collagen scaffolds enhance regeneration both in injured adult skin and peripheral nerves by disrupting the formation of a contractile cell capsule at the edges of the wound. Preliminary observations made with other injured organs support the hypothesis that capsules or clusters of contractile cells impose a universal mechanical barrier during wound healing which, if disrupted appropriately, enhances the quality of induced regeneration in a wider range of organs.

Keywords: Collagen scaffolds; Nerve regeneration; Wound contraction; Myofibroblasts

Sustained delivery of SDF-1α from heparin-based hydrogels to attract circulating pro-angiogenic cells by Silvana Prokoph; Emmanouil Chavakis; Kandice R. Levental; Andrea Zieris; Uwe Freudenberg; Stefanie Dimmeler; Carsten Werner (pp. 4792-4800).
Enrichment of progenitor cells in ischemic tissue has become a promising therapeutic strategy in the treatment of myocardial infarction. Towards this aim, we report a biology-inspired concept using sulfated glycosaminoglycans to sustainably generate chemokine gradients for the localized accumulation of early endothelial progenitor cells (eEPCs). StarPEG-heparin hydrogels, which have been previously demonstrated to support angiogenesis, were functionalized with SDF-1α, a potent chemoattractant known to act on EPCs. The gels were quantitatively shown to release the chemokine in amounts that are adjustable by the choice of loading concentrations and by matrix metalloprotease (MMP) mediated hydrogel cleavage. Transwell assays confirmed significantly enhanced migration of early EPCs towards concentration gradients of hydrogel-delivered SDF-1α in vitro. Subcutaneous implantation of SDF-1α-releasing gels in mice resulted in massive infiltration of early EPCs and subsequently improved vascularization. In conclusion, sustained delivery of SDF-1α from pro-angiogenic starPEG-heparin hydrogels can effectively attract early EPCs, offering a powerful means to trigger endogenous mechanisms of cardiac regeneration.

Keywords: Cardiac tissue engineering; Chemotaxis; Stromal cell-derived factor-1α; Endothelial progenitor cell; Biohybrid hydrogel

Injectable and thermo-sensitive PEG-PCL-PEG copolymer/collagen/n-HA hydrogel composite for guided bone regeneration by ShaoZhi Fu; PeiYan Ni; BeiYu Wang; BingYang Chu; Lan Zheng; Feng Luo; JingCong Luo; ZhiYong Qian (pp. 4801-4809).
A novel three-component biomimetic hydrogel composite was successfully prepared in this study, which was composed of triblock PEG-PCL-PEG copolymer (PECE), collagen and nano-hydroxyapatite (n-HA). The microstructure and thermo-responsibility of the obtained PECE/Collagen/n-HA hydrogel composite were characterized. Scanning electronic microscopy (SEM) showed that the composite exhibited an interconnected porous structure. The rheological analysis revealed that the composite existed good thermo-sensitivity. In vivo biocompatibility and biodegradability was investigated by implanting the hydrogel composite in muscle pouches of rats for 3, 7, and 14 days. Moreover, the osteogenic capacity was evaluated by means of implanting the composite material in cranial defects of New Zealand White rabbits for 4, 12 and 20 weeks. In vivo performances confirmed that the biodegradable PECE/Collagen/n-HA hydrogel composite had good biocompatibility and better performance in guided bone regeneration than the self-healing process. Thus the thermal-response PECE/Collagen/n-HA hydrogel composite had the great potential in bone tissue engineering.

Keywords: Injectable; PECE/Collagen/n-HA hydrogel composite; Thermo-sensitivity; Biocompatibility; Cranial defect; Bone regeneration

Chitosan-based scaffolds for the support of smooth muscle constructs in intestinal tissue engineering by Elie Zakhem; Shreya Raghavan; Robert R. Gilmont; Khalil N. Bitar (pp. 4810-4817).
Intestinal tissue engineering is an emerging field due to a growing demand for intestinal lengthening and replacement procedures secondary to massive resections of the bowel. Here, we demonstrate the potential use of a chitosan/collagen scaffold as a 3D matrix to support the bioengineered circular muscle constructs maintain their physiological functionality. We investigated the biocompatibility of chitosan by growing rabbit colonic circular smooth muscle cells (RCSMCs) on chitosan-coated plates. The cells maintained their spindle-like morphology and preserved their smooth muscle phenotypic markers. We manufactured tubular scaffolds with central openings composed of chitosan and collagen in a 1:1 ratio. Concentrically aligned 3D circular muscle constructs were bioengineered using fibrin-based hydrogel seeded with RCSMCs. The constructs were placed around the scaffold for 2 weeks, after which they were taken off and tested for their physiological functionality. The muscle constructs contracted in response to acetylcholine (Ach) and potassium chloride (KCl) and they relaxed in response to vasoactive intestinal peptide (VIP). These results demonstrate that chitosan is a biomaterial possibly suitable for intestinal tissue engineering applications.

Keywords: Rabbit circular smooth muscle (RCSM) constructs; Chitosan; Force generation; Scaffold; Concentric

The use of carbon nanotubes to induce osteogenic differentiation of human adipose-derived MSCs in vitro and ectopic bone formation in vivo by Xiaoming Li; Haifeng Liu; Xufeng Niu; Bo Yu; Yubo Fan; Qingling Feng; Fu-zhai Cui; Fumio Watari (pp. 4818-4827).
Carbon nanotubes (CNTs), one of the most concerned nanomaterials, with unique electrical, mechanical and surface properties, have been shown suitable for biomedical application. In this study, we evaluated attachment, proliferation, osteogenic gene expression, ALP/DNA, protein/DNA and mineralization of human adipose-derived stem cells cultured in vitro on multi-walled carbon nanotubes (MWNTs) and graphite (GP) compacts with the same dimension. Moreover, we assessed the effect of these two kinds of compacts on ectopic bone formation in vivo. First of all, higher ability of the MWNTs compacts to adsorb proteins, comparing with the GP compacts, was shown. During the conventional culture, it was shown that MWNTs could induce the expression of ALP, cbfa1 and COLIA1 genes while GP could not. Furthermore, alkaline phosphatase (ALP)/DNA and protein/DNA of the cell on the MWNTs compacts, was significantly higher than those of the cells on the GP compacts. With the adsorption of the proteins in culture medium with 50% fetal bovine serum (FBS) in advance, the increments of the ALP/DNA and protein/DNA for the MWNTs compacts were found respectively significantly more than the increments of those for the GP compacts, suggesting that the larger amount of protein adsorbed on the MWNTs was crucial. More results showed that ALP/DNA and protein/DNA of the cells on the two kinds of compacts pre-soaked in culture medium having additional rhBMP-2 were both higher than those of the cells on the samples re-soaked in culture medium with 50% FBS, and that those values for the MWNTs compacts increased much more. Larger mineral content was found on the MWNTs compacts than on the GP compacts at day 7. In vivo experiment showed that the MWNTs could induce ectopic bone formation in the dorsal musculature of ddy mice while GP could not. The results indicated that MWNTs might stimulate inducible cells in soft tissues to form inductive bone by concentrating more proteins, including bone-inducing proteins.

Keywords: Carbon nanotubes; Osteogenic differentiation; Protein adsorption; Osteoinduction

Tissue engineered regeneration of completely transected spinal cord using human mesenchymal stem cells by Kkot Nim Kang; Da Yeon Kim; So Mi Yoon; Ju Young Lee; Bit Na Lee; Jin Seon Kwon; Hyo Won Seo; Il Woo Lee; Ha Cheol Shin; Young Man Kim; Hyun Soo Kim; Jae Ho Kim; Byoung Hyun Min; Hai Bang Lee; Moon Suk Kim (pp. 4828-4835).
The present study employed a combinatorial strategy using poly(d,l-lactide-co-glycolide) (PLGA) scaffolds seeded with human mesenchymal stem cells (hMSCs) to promote cell survival, differentiation, and neurological function in a completely transected spinal cord injury (SCI) model. The SCI model was prepared by complete removal of a 2-mm length of spinal cord in the eighth-to-ninth spinal vertebra, a procedure that resulted in bilateral hindlimb paralysis. PLGA scaffolds 2 mm in length without hMSCs (control) or with different numbers of hMSCs (1 × 105, 2 × 104, and 4 × 103) were fitted into the completely transected spinal cord. Rats implanted with hMSCs received Basso-Beattie-Bresnahan scores for hindlimb locomotion of about 5, compared with ∼2 for animals in the control group. The amplitude of motor-evoked potentials (MEPs) averaged 200–300 μV in all hMSC-implanted SCR model rats. In contrast, the amplitude of MEPs in control group animals averaged 135 μV at 4 weeks and then declined to 100 μV at 8 weeks. These results demonstrate functional recovery in a completely transected SCI model under conditions that exclude self-recovery. hMSCs were detected at the implanted site 4 and 8 weeks after transplantation, indicating in vivo survival of implanted hMSCs. Immunohistochemical staining revealed differentiation of implanted hMSCs into nerve cells, and immunostained images showed clear evidence for axonal regeneration only in hMSC-seeded PLGA scaffolds. Collectively, our results indicate that hMSC-seeded PLGA scaffolds induced nerve regeneration in a completely transected SCI model, a finding that should have significant implications for the feasibility of therapeutic and clinical hMSC-delivery using three-dimensional scaffolds, especially in the context of complete spinal cord transection.

Keywords: Spinal cord injury; Human mesenchymal stem cells; Scaffold; Nerve; Regeneration

MRI-monitored long-term therapeutic hydrogel system for brain tumors without surgical resection by Jang Il Kim; Bora Kim; ChangJu Chun; Seung Hoon Lee; Soo-Chang Song (pp. 4836-4842).
To overcome the unresolved issues of conventional therapeutic approaches such as radiation therapy, chemotherapy, combinational chemotherapy, and surgical treatment, we designed an injectable ‘MRI-monitored long-term therapeutic hydrogel (MLTH)’ system as an alternative/adjuvant approach for brain tumors. The MLTH system consists of a thermosensitive/magnetic poly(organophosphazene) hydrogel (the magnetic hydrogel) as a biodegradable imaging platform and an anticancer drug as a therapeutic agent via a simple physical mixing. The MLTH system has adequate properties for the MRI-monitored long-term therapy as follows: injectability, localizability due to fast gelation at body temperature, biocompatibility, biodegradability, sustained drug release, and MR imaging function. Since the MLTH system only requires a very small-sized pin hole injected into the area of brain tumors stereotactically, we suggest that the MLTH system can be an alternative/adjuvant approach to treat the malignant brain tumors without any surgical resection. Furthermore, we expect that the MLTH system can minimize the side effects from either an intravenous injection or surgical operation because one of the aims of MLTH is to focus on the sustained local delivery of anticancer drugs via a one- or two-time intratumoral injections. Thus, we assessed successfully the MRI-monitored long-term therapeutic potentialities of the MLTH system for brain tumors and estimated the inhibition efficacy of tumor growth via an MRI-monitored long-term therapy in this study.

Keywords: MRI-monitored long-term therapeutic hydrogel; Imaging agents; Phosphazenes; Irinotecan; Brain tumors

An125I-labeled octavalent peptide fluorescent nanoprobe for tumor-homing imaging in vivo by Haiming Luo; Jiyun Shi; Honglin Jin; Di Fan; Lisen Lu; Fan Wang; Zhihong Zhang (pp. 4843-4850).
Targeting radiopeptides are promising agents for radio-theranostics. However, in vivo evaluation of their targeting specificity is often obscured by their short biologic half-lives and low binding affinities. Here, we report an approach to efficiently examine targeting radiopeptides with a new class of octavalent peptide fluorescent nanoprobe (Octa-FNP) platform, which is composed of candidate targeting peptides and a tetrameric far-red fluorescent protein (tfRFP) scaffold. To shed light on this process,125I-Octa-FNP,125I-tfRFP and125I-peptide were synthesized, and their targeting functionalities were compared. Both fluorescence imaging and radioactive quantification results confirmed that125I-Octa-FNP had a significantly higher cellular binding capability than125I-tfRFP. In vivo biodistribution studies show that at 6 h post-injection,125I-Octa-FNP had 2-fold and 30-fold higher tumor uptake than that of125I-tfRFP and125I-peptide, respectively. Moreover, γ-imaging at 24 h post-injection revealed a remarkable accumulation of125I-Octa-FNP in the tumor while maintaining an extremely low background contrast, which was further confirmed by immunofluorescence analysis. These data suggested that, as an engineered and multivalent platform, Octa-FNP could enhance the tumor targeting of a designed peptide and provide excellent contrast radioimaging, making it a valuable tool for the evaluation of the targeting ability of specifically designed radiopeptides for cancer theranostics.

Keywords: Far-red fluorescent protein; Targeting peptide; Tetrameric; Protein scaffold; γ-Imaging

Photosensitizer encapsulated organically modified silica nanoparticles for direct two-photon photodynamic therapy and In Vivo functional imaging by Jun Qian; Dan Wang; Fuhong Cai; Qiuqiang Zhan; Yalun Wang; Sailing He (pp. 4851-4860).
Nanoparticle-assisted two-photon imaging and near infrared (NIR) imaging are two important technologies in biophotonics research. In the present paper, organically modified silica (ORMOSIL) nanoparticles encapsulated with either PpIX (protoporphyrin IX) photosensitizers or IR-820 NIR fluorophores were synthesized and optically characterized. Using the former ORMOSIL nanoparticles, we showed: (i) direct excitation of the fluorescence of PpIX through its efficient two-photon absorption in the intracellular environment of tumor cells, and (ii) cytotoxicity towards tumor cells by PpIX under two-photon irradiation. The latter ORMOSIL nanoparticles can be used as efficient NIR fluorescent contrast agents for various types in vivo animal imaging. We applied IR-820 doped ORMOSIL nanoparticles in in vivo brain imaging of mice. We also demonstrated the applications of them to sentinel lymph node (SLN) mapping of mice. Finally, we showed that the nanoprobes could target the subcutaneously xenografted tumor of a mouse for long time observations. ORMOSIL nanoparticles have great potentials for disease diagnosis and clinical therapies.

Keywords: ORMOSIL nanoparticles; Two-photon; Photodynamic therapy; NIR; Fluorescence; In vivo; imaging

Heparin-coated superparamagnetic iron oxide for in vivo MR imaging of human MSCs by Ji-hye Lee; Min Jin Jung; Yong Hwa Hwang; Young Jun Lee; Seungsoo Lee; Dong Yun Lee; Heungsoo Shin (pp. 4861-4871).
Human mesenchymal stem cells (hMSCs) offer significant therapeutic potential in the field of regenerative medicine and high-resolution magnetic resonance imaging (MRI) is useful modality to visualize in vivo kinetics of transplanted stem cells. For successful MR imaging, there is a great need for effective contrast agents for stem cell labeling with high uptake yield and low toxicity. Here, we present superparamagnetic iron oxide (SPIO) nanoparticles coated with unfractionated heparin (UFH-SPIO) as a new negative contrast agent for in vivo MR imaging of hMSCs. The uptake of UFH-SPIO by hMSCs was effective without the aid of transfection agents, which was dependent on the concentration and exposure time. The uptake efficiency of UFH-SPIO was greater than that of DEX-SPIO (SPIO coated with dextran) by approximately 3 folds when treated for 1 h. TEM and Prussian blue staining confirmed that UFH-SPIO nanoparticles were internalized into the cytosol of hMSCs which existed during in vitro subculture for 28 days. Low temperature endocytosis inhibition assay demonstrated that the incorporation of UFH-SPIO into hMSCs was likely to be mediated by endocytosis. When the phantom of UFH-SPIO-labeled hMSCs was visualized with 3-TT 2-weighted MRI, the hypointensity signals of UFH-SPIO-labeled hMSCs were linearly correlated with the concentration of the nanoparticles. The cellular labeling using UFH-SPIO did not reduce the viability, proliferation or differentiation potential to osteogenic and adipogenic lineages of hMSCs. When the UFH-SPIO-labeled hMSCs were transplanted into the left renal subcapsular membranes of nude mice, they were successfully visualized and detected byT 2 and T2-weighted MRI for a month. Collectively, these results suggest that UFH-SPIO nanoparticles are promising as a new MRI contrast agent for in vivo long-term tracking of hMSCs.

Keywords: Stem cell; MRI (magnetic resonance imaging); Superparamagnetic iron oxide(SPIO); Heparin

Towards whole-body imaging at the single cell level using ultra-sensitive stem cell labeling with oligo-arginine modified upconversion nanoparticles by Chao Wang; Liang Cheng; Huan Xu; Zhuang Liu (pp. 4872-4881).
Mesenchymal stem cells (MSCs) have shown great potential in regenerative medicine. Sensitive and reliable methods for stem cell labeling and in vivo tracking are thus of great importance. Herein, we report the use of upconversion nanoparticles (UCNPs) as an exogenous contrast agent to track mouse MSCs (mMSCs) in vivo. To improve the labeling efficiency, oligo-arginine is conjugated to polyethylene glycol (PEG) coated UCNPs to enhance the nanoparticles uptake by mMSCs. Systematic in vitro tests reveal that the proliferation and differentiation of mMSCs are not notably affected by UCNP-labeling, suggesting that the labeled cells are able to maintain their stem cell potency. No apparent exocytosis is found in our in vitro labeling experiment by using a transwell culture system over a course of 10 days, indicating the potential capability of using our UCNP-labeling method for long-term stem cell tracking. To demonstrate the tracking sensitivity of our stem cell labeling approach, UCNP-labeled mMSCs are subcutaneously transplanted into mice and imaged using an in vivo upconversion luminescence (UCL) imaging system. As few as ∼10 cells labeled with UCNPs are detected in vivo, evidencing a remarkable improvement in detection sensitivity of our UCNP-labeled hMSCs compared with other stem cell labeling techniques using conventional exogenous agents. We further track UCNP-labeled mMSCs after intravenous injection, and observe the translocation of mMSCs from lung where they initially accumulate, to liver, a phenomenon consistent to previous reports. Our results highlight the promise of using UCNPs as a new type of ultra-sensitive probes for labeling and in vivo tracking of stem cells at nearly the single cell level.

Keywords: Upconversion nanoparticles; Oligo-arginine; Mesenchymal stem cells; In vivo imaging; Single-cell level tracking

The cytotoxic effects of polymer-coated quantum dots and restrictions for live cell applications by Stefaan J. Soenen; Jo Demeester; Stefaan C. De Smedt; Kevin Braeckmans (pp. 4882-4888).
The interest in the biomedical use of highly fluorescent and photostable nanoparticles such as quantum dots (QDots) is vastly increasing. One major hurdle that impedes QDot use in live cells and animals is their potential toxicity. Here, we employ a recently described multiparametric setup to determine the concentration at which common polymer-coated QDots become non-cytotoxic. We found that toxic effects are strongly related to the intracellular QDot amount that can be controlled by their specific surface coating. Using lysosomal buffer systems and proliferation-restricted cells, intracellular QDots were found to localize in endosomes, where they generate reactive oxygen species, interfere with cell cytoskeleton and leach free Cd2+ ions due to QDot dissolution, resulting in increased toxicity and impeded QDot fluorescence. Furthermore, we find that asymmetric partitioning of QDots upon recurrent cell division results in the sacrifice of heavily-loaded cells and a rapid loss of particles in live cells, limiting the use of currently available QDots for long-term imaging and defining the non-cytotoxic concentration as 10-fold lower than commonly used concentrations.

Keywords: Nanoparticle; Cytotoxicity; Cell morphology; Cell signaling; Cell labeling; Quantum dot

Vitamin E TPGS as a molecular biomaterial for drug delivery by Zhiping Zhang; Songwei Tan; Si-Shen Feng (pp. 4889-4906).
d-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or simply TPGS) is a water-soluble derivative of natural Vitamin E, which is formed by esterification of Vitamin E succinate with polyethylene glycol (PEG). As such, it has advantages of PEG and Vitamin E in application of various nanocarriers for drug delivery,  including extending the half-life of the drug in plasma and enhancing the cellular uptake of the drug. TPGS has an amphiphilic structure of lipophilic alkyl tail and hydrophilic polar head with a hydrophile/lipophile balance (HLB) value of 13.2 and a relatively low critical micelle concentration (CMC) of 0.02% w/w, which make it to be an ideal molecular biomaterial in developing various drug delivery systems, including prodrugs, micelles, liposomes and nanoparticles, which would be able to realize sustained, controlled and targeted drug delivery as well as to overcome multidrug resistance (MDR) and to promote oral drug delivery as an inhibitor of P-glycoprotein (P-gp). In this review, we briefly discuss its physicochemical and pharmaceutical properties and its wide applications in composition of the various nanocarriers for drug delivery, which we call TPGS-based drug delivery systems.

Keywords: Cancer nanotechnology; Biodegradable polymers; Liposomes; Micelles; Nanoparticles; Prodrugs

Gene and doxorubicin co-delivery system for targeting therapy of glioma by Shuhuan Liu; Yubo Guo; Rongqin Huang; Jianfeng Li; Shixian Huang; Yuyang Kuang; Liang Han; Chen Jiang (pp. 4907-4916).
The combination of gene therapy and chemotherapy is a promising treatment strategy for brain gliomas. In this paper, we designed a co-delivery system (DGDPT/pORF-hTRAIL) loading chemotherapeutic drug doxorubicin and gene agent pORF-hTRAIL, and with functions of pH-trigger and cancer targeting. Peptide HAIYPRH (T7), a transferrin receptor-specific peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. T7-modified co-delivery system showed higher efficiency in cellular uptake and gene expression than unmodified co-delivery system in U87 MG cells, and accumulated in tumor more efficiently in vivo. DOX was covalently conjugated to carrier though pH-trigged hydrazone bond. In vitro incubation of the conjugates in buffers led to a fast DOX release at pH 5.0 (intracellular environment) while at pH 7.4 (blood) the conjugates are relatively stable. The combination treatment resulted in a synergistic growth inhibition (combination index, CI < 1) in U87 MG cells. The synergism effect of DGDPT/pORF-hTRAIL was verified in vitro and in vivo. In vivo anti-glioma efficacy study confirmed that DGDPT/pORF-hTRAIL displayed anti-glioma activity but was less toxic.

Keywords: Combination therapy; Doxorubicin; pH-sensitive; Cancer targeting; T7 peptide

Arginine functionalized peptide dendrimers as potential gene delivery vehicles by Kui Luo; Caixia Li; Li Li; Wenchuan She; Gang Wang; Zhongwei Gu (pp. 4917-4927).
The quest for highly efficient and safe gene delivery systems has become the key factor for successful application of gene therapy. Peptide dendrimers are currently investigated as excellent candidates for non-viral gene delivery vectors. In this study, we report the synthesis and characterization of arginine functionalized peptide dendrimer-based vectors ranging from 5th generation (G5A) to 6th generation (G6A) via click chemistry, and their use for gene transfection in vitro and in vivo. The dendrimers can condense plasmid DNA (pDNA) and protect pDNAs from nuclease digestion. Both atomic force microscopy (AFM) and dynamic light scattering (DLS) revealed that the sizes of dendrimer/DNA particles were within 180–250 nm range. In vitro studies showed that the functionalized peptide dendrimers provided serum independent and high transfection efficiency on all studied cells, as over 2 fold higher than that of branched polyetherimide (PEI) in the presence of serum. DendrimerG5A with molecular weight of 17 kDa demonstrated 6-fold transfection activity than PEI in breast tumor models, as well as good biosafety proved by in vitro and in vivo toxicity evaluation. However,G6A with molecular weight of 46 kDa showed much higher cytotoxicity. The functionalized dendrimerG5A with optimal generation may be therefore a potential candidate for gene delivery vehicle.

Keywords: Dendrimer; Click chemistry; Gene delivery; Transfection efficiency; Cytotoxicity; Biocompatibility

Endosomal escape and transfection efficiency of PEGylated cationic liposome–DNA complexes prepared with an acid-labile PEG-lipid by Chia-Ling Chan; Ramsey N. Majzoub; Rahau S. Shirazi; Kai K. Ewert; Yen-Ju Chen; Keng S. Liang; Cyrus R. Safinya (pp. 4928-4935).
Cationic liposome–DNA (CL–DNA) complexes are being pursued as nonviral gene delivery systems for use in applications that include clinic trials. However, to compete with viral vectors for systemic delivery in vivo, their efficiencies and pharmacokinetics need to be improved. The addition of poly (ethylene glycol)-lipids (PEGylation) prolongs circulation lifetimes of liposomes, but inhibits cellular uptake and endosomal escape of CL–DNA complexes. We show that this limits their transfection efficiency (TE) in a manner dependent on the amount of PEG-lipid, the lipid/DNA charge ratio, and the lipid membrane charge density. To improve endosomal escape of PEGylated CL–DNA complexes, we prepared an acid-labile PEG-lipid (HPEG2K-lipid, PEG MW 2000) which is designed to lose its PEG chains at the pH of late endosomes. The HPEG2K-lipid and a similar but acid-stable PEG-lipid were used to prepare PEGylated CL–DNA complexes. TLC and dynamic light scattering showed that HPEG2K-CL–DNA complexes are stable at pH 7.4 for more than 24 h, but the PEG chains are cleaved at pH 5 within 1 h, leading to complex aggregation. The acid-labile HPEG2K-CL–DNA complexes showed enhanced TE over complexes stabilized with the acid-stable PEG-lipid. Live-cell imaging showed that both types of complexes were internalized to quantitatively similar particle distributions within the first 2 h of incubation with cells. Thus, we attribute the increased TE of the HPEG2K-CL–DNA complexes to efficient endosomal escape, enabled by the acid-labile HPEG2K-lipid which sheds its PEG chains in the low pH environment of late endosomes, effectively switching on the electrostatic interactions that promote fusion of the membranes of complex and endosome.

Keywords: Cationic lipid; Gene therapy; Acid-labile; Poly(ethylene glycol); Nonviral; PEGylation

The prolongation of the lifespan of rats by repeated oral administration of [60]fullerene by Tarek Baati; Fanchon Bourasset; Najla Gharbi; Leila Njim; Manef Abderrabba; Abdelhamid Kerkeni; Henri Szwarc; Fathi Moussa (pp. 4936-4946).
Countless studies showed that [60]fullerene (C60) and derivatives could have many potential biomedical applications. However, while several independent research groups showed that C60 has no acute or sub-acute toxicity in various experimental models, more than 25 years after its discovery the in vivo fate and the chronic effects of this fullerene remain unknown. If the potential of C60 and derivatives in the biomedical field have to be fulfilled these issues must be addressed. Here we show that oral administration of C60 dissolved in olive oil (0.8 mg/ml) at reiterated doses (1.7 mg/kg of body weight) to rats not only does not entail chronic toxicity but it almost doubles their lifespan. The effects of C60-olive oil solutions in an experimental model of CCl4 intoxication in rat strongly suggest that the effect on lifespan is mainly due to the attenuation of age-associated increases in oxidative stress. Pharmacokinetic studies show that dissolved C60 is absorbed by the gastro-intestinal tract and eliminated in a few tens of hours. These results of importance in the fields of medicine and toxicology should open the way for the many possible -and waited for- biomedical applications of C60 including cancer therapy, neurodegenerative disorders, and ageing.

Keywords: Fullerenes; Toxicity; Pharmacokinetics; Ageing; Oxidative stress

The biocompatibility and antibacterial properties of collagen-stabilized, photochemically prepared silver nanoparticles by Emilio I. Alarcon; Klas Udekwu; Mårten Skog; Natalia L. Pacioni; Kevin G. Stamplecoskie; María González-Béjar; Naresh Polisetti; Abeni Wickham; Agneta Richter-Dahlfors; May Griffith; Juan C. Scaiano (pp. 4947-4956).
Spherical 3.5 nm diameter silver nanoparticles (AgNP) stabilized in type I collagen (AgNP@collagen) were prepared in minutes (5–15 min) at room temperature by a photochemical method initiated by UVA irradiation of a water-soluble non-toxic benzoin. This biocomposite was examined to evaluate its biocompatibility and its anti-bacterial properties and showed remarkable properties. Thus, while keratinocytes and fibroblasts were not affected byAgNP@collagen, it was bactericidal against Bacillus megaterium and E. coli but only bacteriostatic against S. epidermidis. In particular, the bactericidal properties displayed byAgNP@collagen were proven to be due to AgNP inAgNP@collagen, rather than to released silver ions, since equimolar concentrations of Ag are about four times less active thanAgNP@collagen based on total Ag content. This new biocomposite was stable over a remarkable range of NaCl, phosphate, and 2-(N-morpholino)ethanesulfonic acid concentrations and for over one month at 4 °C. Circular dichroism studies show that the conformation of collagen inAgNP@collagen remains intact. Finally, we have compared the properties ofAgNP@collagen with a similar biocomposite prepared using α-poly-l-Lysine and also with citrate stabilized AgNP; neither of these materials showed comparable biocompatibility, stability, or anti-bacterial activity.

Keywords: Silver nano particles; Type-I collagen; Poly-L-Lysine; Cell toxicity; Antimicrobial activity

Role of sustained antigen release from nanoparticle vaccines in shaping the T cell memory phenotype by Stacey L. Demento; Weiguo Cui; Jason M. Criscione; Eric Stern; Jacob Tulipan; Susan M. Kaech; Tarek M. Fahmy (pp. 4957-4964).
Particulate vaccines are emerging promising technologies for the creation of tunable prophylactics against a wide variety of conditions. Vesicular and solid biodegradable polymer platforms, exemplified by liposomes and polyesters, respectively, are two of the most ubiquitous platforms in vaccine delivery studies. Here we directly compared the efficacy of each in a long-term immunization study and in protection against a model bacterial antigen. Immunization with poly(lactide-co-glycolide) (PLGA) nanoparticles elicited prolonged antibody titers compared to liposomes and alum. The magnitude of the cellular immune response was also highest in mice vaccinated with PLGA, which also showed a higher frequency of effector-like memory T cell phenotype, leading to an effective clearance of intracellular bacteria. The difference in performance of these two common particulate platforms is shown not to be due to material differences but appears to be connected to the kinetics of antigen delivery. Thus, this study highlights the importance of sustained antigen release mediated by particulate platforms and its role in the long-term appearance of effector memory cellular response.

Keywords: Liposome; PLGA; Nanoparticle; Persistence; Vaccine; Memory T cellsAbbreviations; PLGA; poly (lactic co-glycolic acid); TLR; Toll-like receptor; OVA; Ovalbumin; LM-OVA; Listeria monocytogenes-OVA construct

Molecular modeling of the relationship between nanoparticle shape anisotropy and endocytosis kinetics by Ye Li; Tongtao Yue; Kai Yang; Xianren Zhang (pp. 4965-4973).
In this work, an N-varied dissipative particle dynamics (DPD) simulation technique is applied to investigate detailed endocytosis kinetics for ligand-coated nanoparticles with different shapes, including sphere-, rod- and disk-shaped nanoparticles. Our results indicate that the rotation of nanoparticles, which is one of the most important mechanisms for endocytosis of shaped nanoparticle, regulates the competition between ligand–receptor binding and membrane deformation. Shape anisotropy of nanoparticles divides the whole internalization process into two stages: membrane invagination and nanoparticle wrapping. Due to the strong ligand–receptor binding energy, the membrane invagination stage is featured by the rotation of nanoparticles to maximize their contact area with the membrane. While the kinetics of the wrapping stage is mainly dominated by the part of nanoparticles with the largest local mean curvature, at which the membrane is most strongly bent. Therefore, nanoparticles with various shapes display different favorable orientations for the two stages, and one or two orientation rearrangement may be required during the endocytosis process. Our simulation results also demonstrate that the shape anisotropy of nanoparticles generates a heterogeneous membrane curvature distribution and might break the symmetry of the internalization pathway, and hence induce an asymmetric endocytosis.

Keywords: Nanoparticles; Membrane; Molecular modeling; Endocytosis; Shape anisotropy; Rotation

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