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Biomaterials (v.33, #4)

Editorial board (pp. ifc).

Microfluidic 3D bone tissue model for high-throughput evaluation of wound-healing and infection-preventing biomaterials by Joung-Hyun Lee; Yexin Gu; Hongjun Wang; Woo Y. Lee (pp. 999-1006).
We report the use of a microfluidic 3D bone tissue model, as a high-throughput means of evaluating the efficacy of biomaterials aimed at accelerating orthopaedic implant-related wound-healing while preventing bacterial infection. As an example of such biomaterials, inkjet-printed micropatterns were prepared to contain antibiotic and biphasic calcium phosphate (BCP) nanoparticles dispersed in a poly(d,l-lactic-co-glycolic) acid matrix. The micropatterns were integrated with a microfluidic device consisting of eight culture chambers. The micropatterns immediately and completely killed Staphylococcus epidermidis upon inoculation, and enhanced the calcified extracellular matrix production of osteoblasts. Without antibiotic elution, bacteria rapidly proliferated to result in an acidic microenvironment which was detrimental to osteoblasts. These results were used to demonstrate the tissue model’s potential in: (i) significantly reducing the number of biomaterial samples and culture experiments required to assess in vitro efficacy for wound-healing and infection prevention and (ii) in situ monitoring of dynamic interactions of biomaterials with bacteria as wells as with tissue cells simultaneously.

Keywords: Micropatterning; Antibacterial; Calcium phosphate; Bone tissue engineering; Osteoblast


Glycosaminoglycan (GAG) binding surfaces for characterizing GAG-protein interactions by David E. Robinson; David J. Buttle; Robert D. Short; Sally L. McArthur; David A. Steele; Jason D. Whittle (pp. 1007-1016).
Glycosaminoglycans play an important role in tissue organisation through interactions with a diverse range of proteins, growth factors and other chemokines. In this report, we demonstrate the GAG-binding ‘fingerprint’ of two important GAG-binding proteins – osteoprotogerin and TIMP-3. The technique uses a straightforward method for attaching GAGs to assay surfaces in a non-covalent manner using plasma polymerization that leaves the adsorbed GAG able to participate in subsequent ligand binding. We show that OPG and TIMP-3 bind preferentially to different GAGs in a simple ELISA and that this binding does not correlate directly with simple GAG properties such as degree of sulfation. The methods outlined in this report can be easily applied to tissue engineering scaffolds in order to exploit the potential of surface-bound GAGs in influencing the structure of engineered tissues.

Keywords: Glycosaminoglycan; Osteoprotegerin; Tissue inhibitor of metalloproteinase-3; Tumor necrosis factor-stimulated gene-6; ELISA; Plasma polymerisation


Impact of processing parameters on the haemocompatibility of Bombyx mori silk films by F. Philipp Seib; Manfred F. Maitz; Xiao Hu; Carsten Werner; David L. Kaplan (pp. 1017-1023).
Silk has traditionally been used for surgical sutures due to its lasting strength and durability; however, the use of purified silk proteins as a scaffold material for vascular tissue engineering goes beyond traditional use and requires application-orientated biocompatibility testing. For this study, a library of Bombyx mori silk films was generated and exposed to various solvents and treatment conditions to reflect current silk processing techniques. The films, along with clinically relevant reference materials, were exposed to human whole blood to determine silk blood compatibility. All substrates showed an initial inflammatory response comparable to polylactide- co-glycolide (PLGA), and a low to moderate haemostasis response similar to polytetrafluoroethylene (PTFE) substrates. In particular, samples that were water annealed at 25 °C for 6 h demonstrated the best blood compatibility based on haemostasis parameters (e.g. platelet decay, thrombin-antithrombin complex, platelet factor 4, granulocytes-platelet conjugates) and inflammatory parameters (e.g. C3b, C5a, CD11b, surface-associated leukocytes). Multiple factors such as treatment temperature and solvent influenced the biological response, though no single physical parameter such as β-sheet content, isoelectric point or contact angle accurately predicted blood compatibility. These findings, when combined with prior in vivo data on silk, support a viable future for silk-based vascular grafts.

Keywords: Silk; Blood compatibility; PLGA; Bombyx mori


Three-dimensional paper-based electrochemiluminescence immunodevice for multiplexed measurement of biomarkers and point-of-care testing by Lei Ge; Jixian Yan; Xianrang Song; Mei Yan; Shenguang Ge; Jinghua Yu (pp. 1024-1031).
In this work, electrochemiluminescence (ECL) immunoassay was introduced into the recently proposed microfluidic paper-based analytical device (μPADs) based on directly screen-printed electrodes on paper for the very first time. The screen-printed paper-electrodes will be more important for further development of this paper-based ECL device in simple, low-cost and disposable application than commercialized ones. To further perform high-performance, high-throughput, simple and inexpensive ECL immunoassay on μPAD for point-of-care testing, a wax-patterned three-dimensional (3D) paper-based ECL device was demonstrated for the very first time. In this 3D paper-based ECL device, eight carbon working electrodes including their conductive pads were screen-printed on a piece of square paper and shared the same Ag/AgCl reference and carbon counter electrodes on another piece of square paper after stacking. Using typical tris-(bipyridine)-ruthenium (Ⅱ) - tri- n-propylamine ECL system, the application test of this 3D paper-based ECL device was performed through the diagnosis of four tumor markers in real clinical serum samples. With the aid of a facile device-holder and a section-switch assembled on the analyzer, eight working electrodes were sequentially placed into the circuit to trigger the ECL reaction in the sweeping range from 0.5 to 1.1 V at room temperature. In addition, this 3D paper-based ECL device can be easily integrated and combined with the recently emerging paper electronics to further develop simple, sensitive, low-cost, disposable and portable μPAD for point-of-care testing, public health and environmental monitoring in remote regions, developing or developed countries.

Keywords: Electrochemiluminescence immunoassay; Lab on paper; Screen-printed electrode; Biomarker; Point-of-care testing


Modulation of the migration and differentiation potential of adult bone marrow stromal stem cells by nitric oxide by John W. Fuseler; Mani T. Valarmathi (pp. 1032-1043).
Nitric oxide (NO) is a diffusible free radical, which serves as a pluripotent intracellular messenger in numerous cell systems. NO has been demonstrated to regulate actin dependent cellular functions and functions as a putative inductive agent in directing stem cells differentiation. In this study, we investigated the effect of exogenous NO on the kinetics of movement and morphological changes in adult bone marrow stromal cells (BMSCs) in a wound healing model of cellular migration. Cellular migration and morphological changes were determined by measurement of changes in the area and fractal dimension of BMSCs monolayer as a function of time in the presence of an NO donor (S-Nitroso-N-Acetyl-D,l-Penicillamine, SNAP) compared to untreated BMSCs. Response of the BMSCs’ actin cytoskeleton and desmin to NO was assessed by determining changes in their integrated optical density (IOD) and fractal dimension at 24 h and 7 days. NO suppressed BMSCs’ migration accompanied by a reduction in cell size, with maintenance of their stellate to polygonal morphology. In response to NO, the actin cytoskeleton expressed an increase in randomness but maintained a constant amount of F-actin relative to the cell size. The presence of NO also induced an increase in randomly organized cytoplasmic desmin. These data suggest that NO has an apparent inductive effect on adult BMSCs and is capable of initiating phenotypic change at the gross cellular, cytoskeletal and molecular levels. It is apparent, however, that additional factors or conditions are required to further drive the differentiation of adult BMSCs into specific phenotypes, such as cardiomyocytes.

Keywords: Bone marrow stromal cells; Mesenchymal stem cells; Adult stem cell migration; Nitric oxide; Actin; Desmin


The mechanical stimulation of cells in 3D culture within a self-assembling peptide hydrogel by Yusuke Nagai; Hidenori Yokoi; Keiko Kaihara; Keiji Naruse (pp. 1044-1051).
The aim of this present study was to provide a scaffold as a tool for the investigation of the effect of mechanical stimulation on three-dimensionally cultured cells. For this purpose, we developed an artificial self-assembling peptide (SPG-178) hydrogel scaffold. The structural properties of the SPG-178 peptide were confirmed by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and transmission electron microscopy (TEM). The mechanical properties of the SPG-178 hydrogel were studied using rheology measurements. The SPG-178 peptide was able to form a stable, transparent hydrogel in a neutral pH environment. In the SPG-178 hydrogel, mouse skeletal muscle cells proliferated successfully (increased by 12.4 ± 1.5 times during 8 days of incubation; mean ± SEM). When the scaffold was statically stretched, a rapid phosphorylation of ERK was observed (increased by 2.8 ± 0.2 times; mean ± SEM). These results demonstrated that the developed self-assembling peptide gel is non-cytotoxic and is a suitable tool for the investigation of the effect of mechanical stimulation on three-dimensional cell culture.

Keywords: Cell proliferation; Self-assembly; Hydrogel; Scaffold; Mechanical strain


Influence of perfusion and compression on the proliferation and differentiation of bone mesenchymal stromal cells seeded on polyurethane scaffolds by Chaoxu Liu; Reza Abedian; Roland Meister; Carl Haasper; Christof Hurschler; Christian Krettek; Gabriela von Lewinski; Michael Jagodzinski (pp. 1052-1064).
In the present study, a porous meniscal-shaped scaffold consisting of polyurethane (PU)-based 1, 4-butanediisocyanate (BDI), which provided a 3-D culture condition for human bone mesenchymal stromal cells (hBMSC) was employed. A bioreactor was utilized to produce perfusion and mechanical stimulations. The viability, proliferation and fibro-cartilaginous differentiation of the hBMSC cultured on the PU-based meniscal scaffold were investigated during the perfusion and mechanical stimulation process. In addition, the mechanical properties of the cell-laden scaffolds were examined as well. Our finding indicated that the perfusion (10 ml/min) and on-off cyclic compressions mechanical stimulation (10% strain, 0.5 Hz, 4 times/day, 2 h/time with 4 h of rest thereafter) maintained the viability and promoted the proliferation of hBMSC over 2 weeks. The on-off cyclic compression caused a 1.85 fold increase in equilibrium modulus. Meanwhile, type I procollagen produced by hBMSC was increased for 3.02-fold after 2 weeks culture. On the other hand, the irrigating medium enhanced the synthesis of type III procollagen for 2.24-fold after 2 weeks. Tensile modulus was elevated for 2.02-fold in perfusion group after 1 week, which was decreased after 2 weeks unexpectedly. Our study suggests that the perfusion and on-off compression are promising to enhance the functional properties of the hBMSC-laden PU-based meniscal scaffold.

Keywords: Polyurethane scaffold; Mesenchymal stromal cells; Physical stimulations; Mechanical properties; Cytotoxicity; Meniscus tissue engineering


Three-dimensional cancer-bone metastasis model using ex-vivo co-cultures of live calvarial bones and cancer cells by Paul Curtin; Helen Youm; Erdjan Salih (pp. 1065-1078).
One of the major limitations of studying cancer-bone metastasis has been the lack of an appropriate ex-vivo model which can be used under defined conditions that simulates closely the in vivo live bone microenvironment in response to cancer-bone interactions. We have developed and utilized a three-dimensional (3D) cancer-bone metastasis model using free-floating live mouse calvarial bone organs in the presence of cancer cells in a roller tube system. In such co-cultures under hypoxia and a specifically defined bone remodeling stage, viz., resorption system, cancer cells showed a remarkable affinity and specificity for the “endosteal side” of the bone where they colonize and proliferate. This was concurrent with differentiation of resident stem/progenitor cells to osteoclasts and bone resorption. In contrast, under bone formation conditions this model revealed different pathophysiology where the breast cancer cells continued to induce osteoclastic bone resorption whereas prostate cancer cells led to osteoblastic bone formation. The current 3D model was used to demonstrate its application to studies involving chemical and biochemical perturbations in the absence and presence of cancer cells and cellular responses. We describe proof-of-principle with examples of the broad versatility and multi-faceted application of this model that adds another dimension to the ongoing studies in the cancer-bone metastasis arena.

Keywords: Breast and prostate cancer cells; Bone resorption; Bone formation; Calvarial bone organ cultures; Indomethacin; Cancer-Bone metastasis model; Prostaglandin E2Abbreviations; ECM; Extracellular matrix; PGE2; prostaglandin E2; 2D; two-dimensional; 3D; three-dimensional; PTH; parathyroid hormone; MMP-3; matrix metaloproteinase 3; NR; neutral red; Cox2; cyclo-oxygenase-2; ELISA; enzyme-linked immunosobent assay; DMEM; Dulbecco’s Modified Eagle’s Medium; EDTA; ethylene diamine tetraacetic acid; IL-6; interleukin-6


Multifunctional nanoprobes for upconversion fluorescence, MR and CT trimodal imaging by Huaiyong Xing; Wenbo Bu; Shengjian Zhang; Xiangpeng Zheng; Ming Li; Feng Chen; Qianjun He; Liangping Zhou; Weijun Peng; Yanqing Hua; Jianlin Shi (pp. 1079-1089).
Early diagnosis probes that combine fluorescence, X-ray computed tomography (CT) and magnetic resonance (MR) imagings are anticipated to give three dimensional (3D) details of tissues and cells of high resolution and sensitivity. However, how to combine these three modalities together within a sub-50 nm sized structure is technically challenging. Here we report a trimodal imaging probe of PEGylated NaY/GdF4: Yb, Er, Tm @SiO2-Au@PEG5000 nanopaticles of uniform size of less than 50 nm. The as-designed nanoprobes showed (1) strong emissions ranging from the visible (Vis) to near infrared (NIR) for fluorescent imaging, (2) T1-weighted MRI by shorting T1 relaxation time and (3) enhanced HU value as a CT contrast agent. The structure was optimized based on a comprehensive investigation on the influence of the distance between the NaY/GdF4: Yb, Er, Tm core and Au nanoparticles (NPs) at the surface. The potential of trimodal imaging for cancerous cells and lesions was further demonstrated both in vitro and in vivo.

Keywords: Multifunctional nanoprobes; Upconversion fluorescence; MRI; CT imaging; Surface plasmon resonance


Simultaneous electrochemical detection of multiple analytes based on dual signal amplification of single-walled carbon nanotubes and multi-labeled graphene sheets by Lijuan Bai; Ruo Yuan; Yaqin Chai; Ying Zhuo; Yali Yuan; Yan Wang (pp. 1090-1096).
In this work, a sandwich-type electrochemical aptasensor for simultaneous sensitive detection of platelet-derived growth factor (PDGF) and thrombin is fabricated. Reduced graphene oxide sheets (rGS) are used as matrices to immobilize the redox probes, which are subsequently coated with platinum nanoparticles (PtNPs) to form the PtNPs-redox probes-rGS nanocomposites. With the employment of the as prepared nanocomposites, a signal amplification strategy was described based on bienzyme (glucose oxidase and horseradish peroxidase) modified PtNPs-redox probes-rGS nanocomposites as the tracer labels for secondary aptamers (Apt II) through sandwiched assay. Gold nanoparticles functionalized single-walled carbon nanotubes (AuNPs@SWCNTs) as the biosensor platform enhance the surface area to capture a large amount of primary aptamers (Apt I), thus amplifying the detection response. The experiment results show that the multi-labeled PtNPs-redox probes-rGS nanocomposites display satisfying electrochemical redox activity and highly electrocatalytic activity of PtNPs and bienzyme, which exhibit high sensitivity for detection of proteins. The linear range of PDGF is 0.01–35 nM with a detection limit of 8 pM, while the linear ranges from 0.02 to 45 nM and a detection limit of 11 pM for thrombin are obtained.

Keywords: Electrochemical aptasensor; Simultaneous detection; Signal amplification; Multi-labeled graphene sheets


Decorated graphene sheets for label-free DNA impedance biosensing by Yuwei Hu; Kaikai Wang; Qixian Zhang; Fenghua Li; Tongshun Wu; Li Niu (pp. 1097-1106).
An efficient DNA impedance biosensing platform is constructed, in which positively charged N,N-bis-(1-aminopropyl-3-propylimidazol salt)-3,4,9,10-perylene tetracarboxylic acid diimide (PDI) is anchored to graphene sheets. The π–π stacking and electronic interactions are elucidated by the distinct absorption features in UV–vis spectra and by quenching perylene fluorescence in contact with graphene. The rational design and tailoring of graphene surface invest it with desired properties (dispersive, structural, photoelectrical and conductive, etc.) and boost its application. Electrostatic interaction between PDI’s positively charged imidazole rings and negatively charged phosphate backbones of single-stranded DNA (ssDNA) facilitates ssDNA immobilization. This manner is different from these mainly based on the attraction between the rings in DNA bases and the hexagonal cells of graphene, which is disturbed after hybridization and causes the leaving of formed double-stranded DNA from graphene surface. The electrostatic ssDNA grafting occupies phosphate backbones and particularly leaves the bases available for efficient hybridization. DNA immobilization and hybridization lead to PDI/graphene interfacial property changes, which are monitored by electrochemical impedance spectroscopy and adopted as the analytical signal. The conserved sequence of the pol gene of human immunodeficiency virus 1 is satisfactorily detected via this PDI/graphene platform and shows high reproducibility, selectivity.

Keywords: Graphene; Perylene; DNA; Non-covalent; Impedance; Biosensing


PEGylated dendrimer-entrapped gold nanoparticles for in vivo blood pool and tumor imaging by computed tomography by Chen Peng; Linfeng Zheng; Qian Chen; Mingwu Shen; Rui Guo; Han Wang; Xueyan Cao; Guixiang Zhang; Xiangyang Shi (pp. 1107-1119).
We report the synthesis and characterization of dendrimer-entrapped gold nanoparticles (Au DENPs) modified by polyethylene glycol (PEG) with enhanced biocompatibility for computed tomography (CT) imaging applications. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) modified by PEG monomethyl ether (G5.NH2- mPEG20) were used as templates to synthesize Au DENPs, followed by acetylation of the remaining dendrimer terminal amines to generate PEGylated Au DENPs. The partial PEGylation modification of dendrimer terminal amines allows high loading of Au within the dendrimer interior, and consequently by simply varying the Au salt/dendrimer molar ratio, the size of the PEGylated Au DENPs can be controlled at a range of 2–4 nm with a narrow size distribution. The formed PEGylated Au DENPs are water-dispersible, stable in a pH range of 5–8 and a temperature range of 0–50 °C, and non-cytotoxic at a concentration as high as 100 μm. X-ray absorption coefficient measurements show that the attenuation intensity of the PEGylated Au DENPs is much higher than that of Omnipaque with iodine concentration similar to Au. With the sufficiently long half-decay time demonstrated by pharmacokinetics studies, the PEGylated Au DENPs enabled not only X-ray CT blood pool imaging of mice and rats after intravenous injection of the particles, but also effective CT imaging of a xenograft tumor model in nude mice. These findings suggest that the designed PEGylated Au DENPs can be used as a promising contrast agent with enhanced biocompatibility for CT imaging of various biological systems, especially in cancer diagnosis.

Keywords: Dendrimers; Gold nanoparticles; Polyethylene glycol; In vivo; CT imaging; Blood pool CT imaging; Tumors


The CD44/integrins interplay and the significance of receptor binding and re-presentation in the uptake of RGD-functionalized hyaluronic acid by Sihem Ouasti; Paul J. Kingham; Giorgio Terenghi; Nicola Tirelli (pp. 1120-1134).
We have studied the interplay between two endocytic receptors for a carrier structure bearing two complementary ligands. Hyaluronic acid (HA; three different molecular weights) was functionalized with an RGD-containing peptide; this ancillary ligand allows the macromolecule to bind to αv integrins in addition to the classical HA internalization receptor (CD44). The uptake of HA-RGD and of native HA was assessed in a phagocytic cell model (J774.2 murine macrophages), studying the kinetics of internalization and its mechanistic details. Indications of a synergic binding to integrins and CD44 emerged for HA-RGD; possibly, a first binding to integrins allows for a pre-concentration of the macromolecule on the cell surface, which is then followed by its binding to CD44. The endocytic mechanism and kinetics appeared then dominated by CD44, which has a much slower turnover than integrins. In this study we have demonstrated that the knowledge of the rate-determining steps of the internalization of a carrier is necessary for assessing its performance. In this case, the presence of multiple ligands on a carrier was beneficial in some respect (e.g. in improved binding/targeting), but may not be sufficient to overcome penetration barriers that arise from slow receptor re-presentation.

Keywords: Hyaluronic acid; Macrophages; CD44; Integrin; RGD


Intracellular pathways and nuclear localization signal peptide-mediated gene transfection by cationic polymeric nanovectors by Qinglian Hu; Jinlei Wang; Jie Shen; Min Liu; Xue Jin; Guping Tang; Paul K. Chu (pp. 1135-1145).
Polyethylenimine (PEI) - based polymers are promising cationic nanovectors. A good understanding of the mechanism by which cationic polymers/DNA complexes are internalized and delivered to nuclei helps to identify which transport steps may be manipulated in order to improve the transfection efficiency. In this work, cell internalization and trafficking of PEI-CyD (PC) composed of β-cyclodextrin (β-CyD) and polyethylenimine (PEI, Mw 600) are studied. The results show that the PC transfected DNA is internalized by binding membrane-associated proteoglycans. The endocytic pathway of the PC particles is caveolae- and clathrin-dependent with both pathways converging to the lysosome. The intracellular fate of the PC provides visual evidence that it can escape from the lysosome. Lysosomal inhibition with chloroquine has no effect on PC mediated transfection implying that blocking the lysosomal traffic does not improve transfection. To improve the nuclear delivery of PC transfected DNA, nuclear localization signal (NLS) peptides are chosen to conjugate and combine with the PC. Compared to PC/pDNA, PC-NLS/pDNA, and PC/pDNA/NLS can effectively improve gene transfection in dividing and non-dividing cells.

Keywords: Polyethylenimine (PEI) - cyclodextrin (CyD); Cell internalization; Lysosomal trafficking; Nuclear signal peptide


Highly dynamic biodegradable micelles capable of lysing Gram-positive and Gram-negative bacterial membrane by Yuan Qiao; Chuan Yang; Daniel J. Coady; Zhan Yuin Ong; James L. Hedrick; Yi-Yan Yang (pp. 1146-1153).
The development of biodegradable antimicrobial polymers adds to the toolbox of attractive antimicrobial agents against antibiotic-resistant microbes. To this end, the potential of polycarbonate polymers as such materials were explored. A series of random polycarbonate polymers consisting of monomers MTC-OEt and MTC-CH2CH3Cl were designed and synthesized using metal-free organocatalytic ring-opening polymerization. Random polycarbonate polymers self-assembled in solution but appeared highly dynamic; such behaviors are desirable as ready disassembly of polymers at the microbial membrane facilitates membrane disruption. Their activities against clinically relevant Gram-positive ( Staphylococcus aureus) and Gram-negative bacteria ( E.coli and Pseudomonas aeruginosa) revealed that the hydrophobic-hydrophilic composition balance in polymers are important to render antimicrobial potency. Scanning electron microscopy (SEM) studies indicated microbial cell surface damage after treatment with polymers, and confocal microscopy studies also showed entry of FITC-dextran dye in Escherichia coli as a result of membrane disruption. On the other hand, the polymers exhibited minimal toxicity against red blood cells in hemolysis tests. Therefore, these random polycarbonate polymers are promising antimicrobial agents against both Gram-positive and Gram-negative bacteria for various biomedical applications.

Keywords: Random copolymers; Polycarbonates; Self-assembly; Antimicrobial; Charge density; Amphiphilicity


Sustained local delivery of siRNA from an injectable scaffold by Christopher E. Nelson; Mukesh K. Gupta; Elizabeth J. Adolph; Joshua M. Shannon; Scott A. Guelcher; Craig L. Duvall (pp. 1154-1161).
Controlled gene silencing technologies have significant, unrealized potential for use in tissue regeneration applications. The design described herein provides a means to package and protect siRNA within pH-responsive, endosomolytic micellar nanoparticles (si-NPs) that can be incorporated into nontoxic, biodegradable, and injectable polyurethane (PUR) tissue scaffolds. The si-NPs were homogeneously incorporated throughout the porous PUR scaffolds, and they were shown to be released via a diffusion-based mechanism for over three weeks. The siRNA-loaded micelles were larger but retained nanoparticulate morphology of approximately 100 nm diameter following incorporation into and release from the scaffolds. PUR scaffold releasate collected in vitro in PBS at 37 °C for 1–4 days was able to achieve dose-dependent siRNA-mediated silencing with approximately 50% silencing achieved of the model gene GAPDH in NIH3T3 mouse fibroblasts. This promising platform technology provides both a research tool capable of probing the effects of local gene silencing and a potentially high-impact therapeutic approach for sustained, local silencing of deleterious genes within tissue defects.

Keywords: RNA interference; Drug delivery; RAFT; Tissue engineering; Polyurethane; Controlled release


The therapeutic efficacy of camptothecin-encapsulated supramolecular nanoparticles by Kuan-Ju Chen; Li Tang; Mitch André Garcia; Hao Wang; Hua Lu; Wei-Yu Lin; Shuang Hou; Qian Yin; Clifton K.-F. Shen; Jianjun Cheng; Hsian-Rong Tseng / (pp. 1162-1169).
Nanomaterials have been increasingly employed as drug(s)-incorporated vectors for drug delivery due to their potential of maximizing therapeutic efficacy while minimizing systemic side effects. However, there have been two main challenges for these vectors: (i) the existing synthetic approaches are cumbersome and incapable of achieving precise control of their structural properties, which will affect their biodistribution and therapeutic efficacies, and (ii) lack of an early checkpoint to quickly predict which drug(s)-incorporated vectors exhibit optimal therapeutic outcomes. In this work, we utilized a new rational developmental approach to rapidly screen nanoparticle (NP)-based cancer therapeutic agents containing a built-in companion diagnostic utility for optimal therapeutic efficacy. The approach leverages the advantages of a self-assembly synthetic method for preparation of two different sizes of drug-incorporated supramolecular nanoparticles (SNPs), and a positron emission tomography (PET) imaging-based biodistribution study to quickly evaluate the accumulation of SNPs at a tumor site in vivo and select the favorable SNPs for in vivo therapeutic study. Finally, the enhanced in vivo anti-tumor efficacy of the selected SNPs was validated by tumor reduction/inhibition studies. We foresee our rational developmental approach providing a general strategy in the search of optimal therapeutic agents among the diversity of NP-based therapeutic agents.

Keywords: Supramolecular assembly; Nanoparticles; Drug delivery; Positron emission tomography; Cancer therapeutics


Multifunctional nanocarrier mediated co-delivery of doxorubicin and siRNA for synergistic enhancement of glioma apoptosis in rat by Du Cheng; Nuo Cao; Jifeng Chen; Xingsu Yu; Xintao Shuai (pp. 1170-1179).
As the most fatal malignancy in brain, glioma cannot be effectively treated with the conventional chemotherapy and thus techniques which may improve the chemotherapeutic effect are of great importance in clinical glioma treatment. Based on the folate-targeted multifunctional nanocarrier developed in our lab, effective co-delivery of DOX and siRNA into rat C6 glioma cells over-expressing folate receptors was achieved. Although cell apoptosis was initiated even at low DOX doses such as 0.5 μg/mL in the DOX-alone treatment mediated by the folate-targeted nanocarrier, anti-apoptotic response in C6 cells was activated as well, as revealed by molecular biological investigations. Delivery of BCL-2 siRNA using the folate-targeted nanocarrier can effectively suppress the anti-apoptotic response and sensitized C6 cells to DOX treatment both in vitro and in vivo. In particular, animal studies using the in situ rat C6 glioma model showed that the folate-targeted co-delivery of BCL-2 siRNA and DOX caused not only an obvious down-regulation of the anti-apoptotic BCL-2 gene but also a remarkable up-regulation of the pro-apoptotic Bax gene, resulting in the significantly elevated level of caspase-3 activation and remarkable cell apoptosis in tumor tissues. Our results strongly demonstrated the synergistic effect of siRNA and DOX in inducing glioma C6 cell apoptosis, upon which an excellent therapeutic effect was achieved using the folate-targeted co-delivery strategy as indicated by the effective tumor growth inhibition and prolonged rat survival time in the animal test.

Keywords: Glioma treatment; Active targeting; Co-delivery of siRNA and drug; Gene silencing; Apoptosis; ChemotherapyAbbreviations; DOX; doxorubicin; siRNA; small interfering RNA; SCR; scrambled siRNA; BCL-2 siRNA; siRNA targeting Bcl-2 gene; PEI; linear poly(ethylene imine); PCL; poly(ε-caprolactone); PEG; poly(ethylene glycol); PGA; poly(glutamic acid); N/P ratio; molar ratio of PEI-PCL nitrogen to siRNA phosphate; C/N ratio; molar ratio of FA-PEG-PGA or PEG-PGA carboxyl to PEI-PCL amine; d; -PCE or B-PCE; DOX-loaded or blank PEI-PCL micelles; d; -PCE/BCL-2/FA or B-PCE/BCL-2/FA; DOX-loaded or blank PEI-PCL micelles complexing with BCL-2 siRNA and then with FA-PEG-PGA; d; -PCE/BCL-2/NFA; DOX-loaded PEI-PCL micelles complexing with BCL-2 siRNA and then with PEG-PGA; d; -PCE/FITC/FA; DOX-loaded PEI-PCL micelles complexing with FITC-labeled SCR and then with FA-PEG-PGA; d; -PCE/SCR/FA; DOX-loaded PEI-PCL micelles complexing with SCR and then with FA-PEG-PGA


Gold nanoparticles functionalized with therapeutic and targeted peptides for cancer treatment by Anil Kumar; Huili Ma; Xu Zhang; Keyang Huang; Shubin Jin; Juan Liu; Tuo Wei; Weipeng Cao; Guozhang Zou; Xing-Jie Liang (pp. 1180-1189).
Functionalization of nanostructures such as gold nanoparticles ( AuNPs) with different biological molecules has many applications in biomedical imaging, clinical diagnosis and therapy. Researchers mostly employed AuNPs larger than 10 nm for different biological and medicinal applications in previous studies. Herein, we synthesized a novel small (2 nm) AuNPs, which were functionalized with the therapeutic peptide, PMI (p12), and a targeted peptide, CRGDK for selective binding to neuropilin-1(Nrp-1) receptors which overexpressed on the cancer cells and regulated the process of membrane receptor-mediated internalization. It was found that CRGDK peptides increased intracellular uptake of AuNPs compared to other surface conjugations quantified by ICP-MS. Interestingly, CRGDK functionalized AuNPs resulted in maximal binding interaction between the CRGDK peptide and targeted Nrp-1 receptor overexpressed on MDA-MB-321 cell surface, which improved the delivery of therapeutic P12 peptide inside targeted cells. Au@p12 + CRGDK nanoparticles indicated with highly effective cancer treatment by increasing p53 expression upregulated with intracellular enhanced p12 therapeutic peptide. These results have implications to design and functionalize different molecules onto AuNPs surfaces to make hybrid model system for selective target binding as well as therapeutic effects for cancer treatment.

Keywords: Gold nanoparticles (; Au; NPs); Therapeutic peptide PMI (p12); Targeted peptide (CRGDK); Neuropilin-1 (Nrp-1) receptor; p53 mechanism; Cancer treatment


Polyethylene glycol-conjugated hyaluronic acid-ceramide self-assembled nanoparticles for targeted delivery of doxorubicin by Hyun-Jong Cho; In-Soo Yoon; Hong Yeol Yoon; Heebeom Koo; Yu-Jin Jin; Seung-Hak Ko; Jae-Seong Shim; Kwangmeyung Kim; Ick Chan Kwon; Dae-Duk Kim (pp. 1190-1200).
Polyethylene glycol (PEG)-conjugated hyaluronic acid-ceramide (HACE) was synthesized for the preparation of doxorubicin (DOX)-loaded HACE-PEG-based nanoparticles, 160 nm in mean diameter with a negative surface charge. Greater uptake of DOX from these HACE-PEG-based nanoparticles was observed in the CD44 receptor highly expressed SCC7 cell line, compared to results from the CD44-negative cell line, NIH3T3. A strong fluorescent signal was detected in the tumor region upon intravenous injection of cyanine 5.5-labeled nanoparticles into the SCC7 tumor xenograft mice; the extended circulation time of the HACE-PEG-based nanoparticle was also observed. Pharmacokinetic study in rats showed a 73.0% reduction of the in vivo clearance of DOX compared to the control group. The antitumor efficacy of the DOX-loaded HACE-PEG-based nanoparticles was also verified in a tumor xenograft mouse model. DOX was efficiently delivered to the tumor site by active targeting via HA and CD44 receptor interaction and by passive targeting due to its small mean diameter (<200 nm). Moreover, PEGylation resulted in prolonged nanoparticle circulation and reduced DOX clearance rate in an in vivo model. These results therefore indicate that PEGylated HACE nanoparticles represent a promising anticancer drug delivery system for cancer diagnosis and therapy.

Keywords: Doxorubicin; Hyaluronic acid-ceramide-polyethylene glycol; Prolonged circulation; Theranostic nanoparticle; Tumor-targeting

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