Biodegradable Networks Research Articles

Chitosan-EDTA-Cellulose network as a green, recyclable and multifunctional biopolymeric organocatalyst for the one-pot synthesis of 2-amino-4H-pyran derivatives

In this research, cellulose grafted to chitosan by EDTA (Cs-EDTA-Cell) bio-based material is reported and characterized by a series of various methods and techniques such as FTIR, DRS-UV–Vis, TGA, FESEM, XRD and EDX analysis. In fact, the Cs-EDTA-Cell network is more thermally stable than pristine cellulose or chitosan. There is a plenty of both acidic and basic sites on the surface of this bio-based and biodegradable network, as a multifunctional organocatalyst, to proceed three-component synthesis of 2-amino-4H-pyran derivatives at room temperature in EtOH. The Cs-EDTA-Cell nanocatalyst can be easily recovered from the reaction mixture by using filtration and reused for at least five times without significant decrease in its catalytic activity. In general, the Cs-EDTA-Cell network, as a heterogeneous catalyst, demonstrated excellent catalytic activity in an environmentally-benign solvent to afford desired products in short reaction times and required simple experimental and work-up procedure compared to many protocols using similar catalytic systems.

Injectable and In Situ Gelling Dextran Derivatives Containing Hydrolyzable Groups for the Delivery of Large Molecules.

Recently, we reported the synthesis and characterization of a new dextran derivative obtained by grafting polyethylene glycol methacrylate to a polysaccharide backbone through a carbonate bond. This moiety was introduced because it allows for the fabrication, through a photo-induced crosslinking reaction, of biodegradable hydrogels particularly suitable for the release of high molecular weight molecules. Here, we investigate the influence of the oxyethylene chain length and the molecular weight of the starting dextran on the main properties of the polymeric solutions as well as those of the corresponding hydrogels. All synthesized polymeric derivatives were characterized by FTIR, NMR, and rheological analyses. The photo-crosslinking reaction of the polymers allowed us to obtain biodegradable networks tested for their mechanical properties, swelling, and degradation behavior. The results showed that both the oxyethylene chain length as well as the molecular weight of the starting dextran influenced swelling and degradation of the hydrogel network. As a consequence, the different behaviors in terms of swelling and degradability were able to affect the release of a large model molecule over time, making these matrices suitable candidates for the delivery of high molecular weight drug substances.

Biodegradable poly(N-isopropylacrylamide-co-N-maleylgelatin) hydrogels with adjustable swelling behavior

This study describes the detailed investigation on dynamic swelling of biodegradable network system poly(N-isopropylacrylamide-co-N-maleylgelatin) P(NIPAAm-co-N-MAGEL) prepared by N-isopropylacrylamide (NIPAAm) and N-maleylgelatin (MAGEL) with N,N′-methylene bis(acrylamide) (BIS) as a cross-linking agent. Effects of MAGEL content on the swelling behavior were investigated. The results showed that the swelling kinetics were dependent on the content of MAGEL and the maximum swelling rate was observed at 30% content of MAGEL. The swelling process follows second-order kinetics, and the mechanism of water transport is pseudo-Fickian type of diffusion. Swelling kinetics under different concentrations of NaCl was also studied. The swelling rate decreased with increasing the concentration of NaCl.

Photo‐Crosslinked Elastomeric Bimodal Poly(trimethylene carbonate) Networks

AbstractUsing methacrylated poly(trimethylene carbonate) oligomers unimodal (prepared from one macromer) and bimodal (prepared from two macromers with different molecular weights) photo‐crosslinked networks and structures are prepared by stereolithography. The obtained biodegradable networks are flexible and elastic. Compared to the corresponding unimodal networks, the tensile properties of bimodal poly(trimethylene carbonate) (PTMC) network films are significantly enhanced. Resilient materials with increased toughness and suture retention strengths are obtained. The mechanical properties of the bimodal networks compare favorably with those of unimodal networks prepared previously from PTMC macromers with much higher molecular weights. Tough porous PTMC structures with designed diamond pore network architectures can also be readily prepared by stereolithography. Upon swelling of these PTMC structures in a solvent, the pore sizes and pore size distribution increases while the porosity decreases.

Thermally reversible and biodegradable polyglycolic-acid-based networks

The furan-maleimide Diels-Alder (DA) reaction was used to synthesize thermally reversible and biodegradable networks based on functionalized polyglycolic acid precursors. Hydroxyl-telechelic polyglycolic acid (PGA) with a well-controlled molar mass was first obtained by ring-opening polymerization (ROP) of glycolide catalyzed by Sn(Oct)2 and using 1,4-butanediol as initiator. Functional furan polyglycolic acids with different functionalities were prepared by the isocyanate-alcohol condensation reaction from multi-alcohols such as glycerol and pentaerythritol, H12MDI, PGA-diol and furfuryl alcohol. For a more effective control of the DA reaction conversion and before approaching the synthesis of the networks, a Diels-Alder adduct and a coupling agent bearing maleimide functions on its extremities were synthesized separately. At different stages, the obtained products were characterized by FTIR, NMR, DSC and SEC techniques. The thermoreversible networks were then obtained via two different methods: first, one in which the Diels-Alder adduct gives rise to the networks (method 1) and then via a one-shot process where the alcoholysis reaction of the coupling agent is responsible for the crosslinking (method 2). Thermomechanical analyses were used to verify the thermal reversible character of PGA-based networks. Furthermore, biodegradability studies such as in vitro degradation as well as aerobic biodegradability revealed that an increase in the polymer crosslinking density and a decrease in glycolide content typically lead to a slower degradation.

Abstract 2143: Mechanistic study of the relative cytotoxicity of doxorubicin loaded nanoparticle formulation compared to free doxorubicin in hepatocellular carcinoma (HCC) cell lines

Abstract Background and Aims Efficacy of doxorubicin encapsulated into a biodegradable network (NP) is currently studied in phase III compared to Best Standard of Care in patients with advanced HCC (Relive study). Preclinical studies demonstrated that NP allowed the reversion of chemo-resistance and enhanced cytotoxicity compared to free doxorubicin on resistant human hepatoma and mestastatic liver cells. In this study the mechanism of action of NP in overcoming HCC cellular resistance as well as the mechanisms of cellular uptake were investigated in representative cell lines. Methods Determination of IC20 of NP in the presence of influx drug inhibitors targeting endocytosis (clathrin or caveolae-dependent; sucrose and Genistein respectively), phagocytosis (LY-294002) or macropinocytosis (Cytochalasin D) were performed on two HCC cell lines (HuH7 and HepG2) using a proliferation assay. Each uptake inhibitor was added 30 min before incubation with NP on cultured cells for measurement of proliferation followed by cellular quantification of free doxorubicin by HPLC. The same assays were also performed using Verapamil as an inhibitor of the major multidrug resistance protein P-glycoprotein (P-gp). The P-gp ATPase activity in plasma membrane preparations from vehicle, doxorubicin and NP-treated cells was determined using the Pgp-Glo assay system. Results NP showed lower IC20 than free doxorubicin in HCC proliferation assays. None of the influx inhibitors used in combination with NP impaired the inhibitory effect of NP on the rate of proliferation of HCC cell lines. Similarly, Verapamil did not modulate the cellular potency of NP on the rate of proliferation in these cell lines. Doxorubicin quantification in cellular extracts and supernatant of NP-treated cells confirmed these results. Furthermore, NP had no effect on P-gp ATPase activity in isolated plasma membrane samples. Conclusions All these results demonstrated that NP did not enter into the HCC cell via an active transport mechanism, but by passive diffusion as occurs with free Doxorubicin. The absence of inhibition of the P-gp ATPase by NP implies that the Doxorubicin-nanoparticle conjugate (ion pair) probably ‘hinders’ the doxorubicin from being a substrate for the pump rather than by a direct interaction. The implication of these data on the role of NP in the treatment of HCC will be discussed. Citation Format: Véronique Trochon-joseph, Caroline Lemarchand, Vincent Hayes, Yamina Rayah, Jean-Louis Labernardière, Graham Dixon. Mechanistic study of the relative cytotoxicity of doxorubicin loaded nanoparticle formulation compared to free doxorubicin in hepatocellular carcinoma (HCC) cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2143.

Tough biodegradable mixed-macromer networks and hydrogels by photo-crosslinking in solution

The preparation of polymeric networks that are both tough and biodegradable remains a challenge. Here we show a very straightforward method to produce tough biodegradable networks from low molecular weight macromers for applications such as tissue engineering. Photo-crosslinking combinatorial mixtures of methacrylate-functionalized poly(1,3-trimethylene carbonate) (PTMC), poly(d,l-lactide) (PDLLA), poly(ε-caprolactone) (PCL) and poly(ethylene glycol) (PEG) oligomers in propylene carbonate (PC) allowed the preparation of network films with excellent tensile characteristics and resistance to tearing. This method enabled the production of both very tough mixed-macromer elastomers as well as mixed-macromer hydrogels. A mixed-macromer hydrogel prepared from 33wt.% PTMC, 33wt.% PCL and 33wt.% PEG had a very high tearing energy of 0.81kJ/m2, which is comparable to tearing energies determined for articular cartilage.

Biodegradable interpenetrating polymer network hydrogel membranes for controlled release of anticancer drug

Biodegradable interpenetrating polymer network hydrogel membranes of chitosan and gelatin were prepared by solvent casting evaporation method for the controlled release of 5‐fluorouracil (5‐FU), an anticancer drug. The membraneswere characterized by Fourier Transform Infrared Spectroscopy (FTIR), differential scanning calorimeter (DSC), X‐ray diffraction (XRD), scanning electron microscopy (SEM) and Tensile strength measurements.The FTIR was used to understand the formation of crosslinking and to confirm the absence of chemical interactions between drug and membranes. DSC and XRD studies were performed to understand the crystalline nature of drug after encapsulation into the membranes. SEM was used to study the surface morphology of the membranes. The in vitro studies were carried out in phosphate buffer pH 7.4 at 37°C.The results of controlled release tests showed that the amount of 5‐FU release increased with the increasing the amount of gelatin in the membrane. Moreover, the release rate of drug increased as the amount of drug loaded in the membranes increased. All the results indicated that the prepared membrane was potentially useful in drug‐delivery systems, and the prolonged release rate was observed up to 12 h. Key words: 5‐flurouracil, chitosan, drug‐delivery systems, gelatin, hydrogel membrane

New biodegradable dextran-based hydrogels for protein delivery: Synthesis and characterization

A new derivative of dextran grafted with polyethylene glycol methacrylate through a carbonate bond (DEX–PEG–MA) has been synthesized and characterized. The photo-crosslinking reaction of DEX–PEG–MA allowed the obtainment of biodegradable networks tested for their mechanical and release properties. The new hydrogels were compared with those made of dextran methacrylate (DEX–MA), often employed as drug delivery systems of small molecules. The inclusion of PEG as a spacer created additional interactions among the polymeric chains improving the extreme fragility and lack of hardness typical of gels made of DEX–MA. Moreover, the different behavior in terms of swelling and degradability of the networks was able to affect the release of a model macromolecule over time, making DEX–PEG–MA matrices suitable candidates for the delivery of high molecular weight peptides. Interestingly, the combination of the two dextran derivatives showed intermediate ability to modulate the release of high molecular weight macromolecules.

Biodegradable networks for soft tissue engineering by thiol–yne photo cross-linking of multifunctional polyesters

Degradable and biocompatible networks have been prepared via thiol–yne photochemistry from novel alkyne multifunctional PCL. The mechanical properties of these cross-linked biomaterials could make them good candidates for soft tissues scaffolds.

Reconfigurable Biodegradable Shape-Memory Elastomers via Diels–Alder Coupling

Synthetic biodegradable elastomers are a class of polymers that have demonstrated far-reaching utility as biomaterials for use in many medical applications. Biodegradable elastomers can be broadly classified into networks prepared by either step-growth or chain-growth polymerization. Each processing strategy affords distinct advantages in terms of capabilities and resulting properties of the network. This work describes the synthesis, processing, and characterization of cross-linked polyester networks based on Diels-Alder coupling reactions. Hyperbranched furan-modified polyester precursors based on poly(glycerol-co-sebacate) are coupled with bifunctional maleimide cross-linking agents. The chemical and thermomechanical properties of the elastomers are characterized at various stages of network formation. Experimental observations of gel formation are compared to theoretical predictions derived from Flory-Stockmayer relationships. This cross-linking strategy confers unique advantages in processing and properties including the ability to fabricate biodegradable reconfigurable covalent networks without additional catalysts or reaction byproducts. Reconfigurable biodegradable networks using Diels-Alder cycloaddition reactions permit the fabrication of shape-memory polymers with complex permanent geometries. Biodegradable elastomers based on polyester networks with molecular reconfigurability achieve vastly expanded properties and processing capabilities for potential applications in medicine and beyond.

Abstract 4523: Targeted delivery to tumor cells by using tunable nano-delivery system with chlorotoxin.

Abstract The aim of this research is to develop the Tunable Nano-Delivery System (TNDS) for specific targeting of the tumor cells using Chlorotoxin (CTX). We present preliminary findings for the TNDS localized drug delivery system comprising of non-ionic surfactant vesicles (niosomes) with CTX embedded in a biodegradable and temperature sensitive chitosan network. The system demonstrates a new approach in the treatment of cancers, through the controlled and targeted delivery to tumor cells (the release time and dosage can be accurately controlled) while sparing normal cells. CTX is a scorpion-derived peptide that binds specifically to neuroectodermal tumors, e.g., glioma, but not to normal tissues. Previously, we have shown that there is a specific interaction between chitosan and Mucin1 (MUC1) receptors over expressed in epithelial ovarian carcinoma resulting in higher chitosan accumulation on the cancer cell surface than on normal ovarian epithelial cells. The current research addresses the incorporation of CTX embedded in Chitosan network to enhance specific targeting, which already benefits from the intrinsic interaction of MUC1 with Chitosan. Our current studies incorporating CTX in chitsoan resulting in TNDS-CTX complex are preformed in cell-free system. First, the release rates and release kinetics of TNDS-CTX are being measured in cell-free system using High Performance Liquid Chromatography (HPLC) and Attenuated Total Reflectance- Fourier Transform Infra-Red (ATR-FTIR) spectroscopy. Results are being compared to our established TNDS delivery system to better determine CTX specific chemical binding sites along with the sites already determined to be specific for MUC1. Next, we will be testing TNDS-CTX in vitro in glioma, epithelial ovarian carcinoma, and normal ovarian epithelial and astrocyte cells. The level of fluorescence of normal cells and tumor cells exposed to the TNDS-CTX-fluorescently labeled are evaluated in in vitro by confocal microscopy. The studies in cell-free system showed that the release rates could be finely controlled depending on the specific design of the TNDS-CTX e.g., ratio of niosomes to chitosan and amount of crosslinker for the chitosan network. We are currently evaluating TNDS-CTX containing benchmark chemotherapeutics such as Paclitaxel, and it is expected that the presence of CTX will enhance cellular uptake of chemotherapeutics when compared to the noisome-chitosan delivery system without CTX. Based on our preliminary data, it is anticipated that CTX will perform as a targeting ligand improving the TNDS-CTX's anti-tumor efficacy owing to enhanced tumor targeting and its tunable and localized delivery. Citation Format: Rana Falahat, Eva Christabel Williams, Marzenna Wiranowska, Ryan Toomey, Norma Alcantar. Targeted delivery to tumor cells by using tunable nano-delivery system with chlorotoxin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4523. doi:10.1158/1538-7445.AM2013-4523

Biodegradable cross-linked poly(trimethylene carbonate) networks for implant applications: Synthesis and properties

In order to avoid the deformation of poly(trimethylene carbonate) (PTMC) in vivo applications, bis(cyclic carbonate) was synthesized and used as cross-linker to prepare PTMC based biodegradable networks via ring-opening polymerization of TMC and/or CL with stannous octanoate as catalyst. The effect of the cross-linking on the resulted networks was studied. The results showed that the crosslinker had high reactivity and efficiency to form stable polymeric networks with high gel percentage, high decomposition temperature and good mechanical properties. These obtained networks were amorphous and elastic, and the glass transition temperatures were below physiological temperature (37 °C), which were expected to be rubbery for in vivo applications. The properties of the networks could be predictably controlled and tailed by varying the polymer composition and cross-linker amount in feed. The cross-linked PTMC based networks showed a potential biomedical application of loading drugs for implanted devices.

Controlling the kinetic chain length of the crosslinks in photo-polymerized biodegradable networks

Biodegradable polymer networks were prepared by photo-initiated radical polymerization of methacrylate functionalized poly(D,L-lactide) oligomers. The kinetic chains formed in this radical polymerization are the multifunctional crosslinks of the networks. These chains are carbon-carbon chains that remain after degradation. If their molecular weight is too high these poly(methacrylic acid) chains can not be excreted by the kidneys. The effect of the photo-initiator concentration and the addition of 2-mercaptoethanol as a chain transfer agent on the molecular weight of the kinetic chains was investigated. It was found that both increasing the initiator concentration and adding 2-mercaptoethanol decrease the kinetic chain length. However, the effect of adding 2-mercaptoethanol was much larger. Some network properties such as the glass transition temperature and the swelling ratio in acetone are affected when the kinetic chain length is decreased.

Combinatorial Synthesis of Photo-Crosslinked Biodegradable Networks

Photo-crosslinking is a technique that can accelerate the development of novel polymeric biomaterials. Here we show the development of a combinatorial platform to synthesize numerous synthetic biodegradable and biocompatible networks by photo-crosslinking mixtures of macromers. Combinations of dimethacrylate-terminated macromers based on hydrophobic D,L-lactide (DLLA), trimethylene carbonate (TMC), epsilon-caprolactone (CL), and hydrophilic polyethylene glycol (PEG) were crosslinked into polymer networks with widely differing properties. The interaction of cells with the network surfaces was assessed by an in vitro cell seeding experiment in which cell proliferation was assessed using a DNA proliferation assay. In this way, a hydrophilic material was identified that unexpectedly supported the proliferation of cells very well.

Synthesis and properties of biodegradable network poly(ether‐urethane)s from L‐lysine triisocyanate and poly(alkylene glycol)s

AbstractBiodegradable network poly(ether‐urethane) films with different hydrophilicity were prepared from L‐lysine triisocyanate (LTI) and poly(ethylene glycol) (PEG), poly(1,4‐tetramethylene glycol) (PTMG) or poly (propyrene glycol) (PPG) with the molecular weights of 250–2000 g mol−1. Prepolymers prepared by a melt‐polycondensation were cast from tetrahydrofuran solution and heated at 65–80°C for 9 h, then postpolymerized at 150–180°C for 10–20 min to form a network. The resultant films were transparent to opaque and insoluble in water and organic solvents. These network films were fully characterized by FTIR, density measurement, wide‐angle X‐ray scattering (WAXS), differential scanning calorimetry, dynamic mechanical analysis, and tensile tests. WAXS intensity curves of LTI/PEG‐1000 and LTI/PEG‐2000 exhibited crystalline peaks due to PEG segments, while those of all other network films did amorphous halos. The molecular weights (Mw) between cross‐links increased, while the cross‐linking density decreased with increasing the Mws of the poly(alkylene glycol)s. Mechanical properties were strongly affected by the type and molecular weights of poly(alkylene glycol)s used. The weight losses of the LTI/PEG series network films that were degraded in a phosphate buffer solution (pH 7.2) at 37°C and the equilibrium water content in distilled water at 20°C were much larger than those of LTI/PTMG and LTI/PPG series ones. In contrast, LTI/PTMG‐1000 and LTI/PPG‐1000 network films absorbed 150–216% of organic solvents such as benzene and toluene under equilibrium state at 20°C. The use of poly(alkylene glycol)s with different types and the MWs allowed the preparation of novel network poly(ether‐urethane) films with a broad range of properties. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012

Preparation of porous structures with shape memory properties from biodegradable polymeric networks

ABSTRACTPreparing porous biodegradable structures from shape memory polymers can combine the structure-defining properties of porous structures with the minimally invasive implanting possibilities of shape memory polymers. In this study, porous biodegradable shape memory structures were prepared using photo-crosslinked networks based on poly(D,L-lactide-co-trimethylene carbonate). The characteristic shape memory properties of the structures, such as their shape fixity at a low temperature of 0 oC and their full shape recovery upon heating to physiological temperatures, were excellent. This makes these biodegradable and biocompatible structures very well-suited for use as self-deploying implants in medical applications like tissue engineering, drug delivery and the support of soft tissues.

Abstract 3229: Thermo-responsive double packaged system for localized drug delivery for cancer treatment

Abstract This research aims at developing a drug delivery system that will provide a plethora of benefits including cost effectiveness, reduction of toxicity and a control over the release of chemotherapeutics in Ovarian Cancer and Brain Tumor patients. We have designed a drug delivery system consisting of non-ionic surfactant vesicles (niosomes) packaged within a biodegradable, temperature and pH sensitive hydrogel (chitosan) network. Optimization of the release rates were accomplished by altering the molecular weight and cross-link density of the chitosan network and the size of the niosomes. Two chemotherapeutics Paclitaxel and Carboplatin were used for encapsulation. The interaction between niosome and chitosan were observed using Attenuated Total Reflectance- Fourier Transform Infrared (ATR-FTIR) spectroscopy. The drug delivery system was further investigated in human ovarian (OV2008) and human glioma (U373) cell lines. The concentration of the therapeutics used ranged from 0.04-0.4 µg/ml. Confocal imaging of the cells verified that the activity of the drugs remained intact within the niosome-chitosan drug delivery system and cell's toxicity was observed within two hours confirming cellular delivery of the drug. The effect of the niosome-chitosan without the chemotherapeutic drugs on normal cells was also examined indicating that this system is non-toxic. Our results showed that this route of drug delivery to the cancer cells was effective since microtubule stabilization, fragmentation of the nucleus, and condense morphology were noted. Moreover, the time release of the drugs can be finely controlled by varying the crosslinking ratio in the chitosan network from 3:1 (loose network which translates into high release) to 5:1 (tight network which translates into low release). In addition, this system is a liquid solution at room temperature and undergoes a change of phase to a soft, self-containing gel at physiological conditions. The system therefore, can be injected into a tumor site. The materials used to construct this system are low cost and biocompatible and provides a flexible method for drug delivery with applications to intracavitary ovarian cancer and glioma treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3229. doi:10.1158/1538-7445.AM2011-3229

Nano-NRTIs: Efficient Inhibitors of HIV Type-1 in Macrophages with a Reduced Mitochondrial Toxicity

Macrophages serve as a depot for HIV type-1 (HIV-1) in the central nervous system. To efficiently target macrophages, we developed nanocarriers for potential brain delivery of activated nucleoside reverse transcriptase inhibitors (NRTIs) called nano-NRTIs. Nanogel carriers consisting of poly(ethylene glycol) (PEG)- or Pluronic-polyethylenimine (PEI) biodegradable networks, star PEG-PEI or poly(amidoamine) dendrimer-PEI-PEG dendritic networks, as well as nanogels decorated with brain-targeting peptide molecules, specifically binding to the apolipoprotein E receptor, were synthesized and evaluated. Nano-NRTIs were obtained by mixing aqueous solutions of zidovudine 5'-triphosphate or didanosine 5'-triphosphate and nanocarriers, followed by freeze-drying. Intracellular accumulation, cytotoxicity and antiviral activity of nano-NRTIs were monitored in monocyte-derived macrophages (MDMs). HIV-1 viral activity in infected MDMs was measured by a reverse transcriptase activity assay following treatment with nano-NRTIs. Mitochondrial DNA depletion in MDMs and human HepG2 cells was assessed by quantitative PCR. Nanogels were efficiently captured by MDMs and demonstrated low cytotoxicity, and no antiviral activity without drugs. All nano-NRTIs demonstrated high efficacy of HIV-1 inhibition at drug levels as low as 1 μmol/l, representing a 4.9- to 14-fold decrease in 90% effective drug concentrations as compared with NRTIs, whereas 50% cytotoxicity effects started at 200× higher concentrations. Nano-NRTIs with a core-shell structure and decorated with brain-targeting peptides displayed the highest antiviral efficacy. Mitochondrial DNA depletion, a major cause of NRTI neurotoxicity, was reduced threefold compared with NRTIs at application of selected nano-NRTIs. Nano-NRTIs demonstrated a promising antiviral efficacy against HIV-1 in MDMs and showed strong potential as nanocarriers for delivery of antiviral drugs to macrophages harbouring in the brain.

Photo-Cross-Linked Poly(dl-lactide)-Based Networks. Structural Characterization by HR-MAS NMR Spectroscopy and Hydrolytic Degradation Behavior

To date, biodegradable networks and particularly their kinetic chain lengths have been characterized by analysis of their degradation products in solution. We characterize the network itself by NMR analysis in the solvent-swollen state under magic angle spinning conditions. The networks were prepared by photoinitiated cross-linking of poly(dl-lactide)−dimethacrylate macromers (5 kg/mol) in the presence of an unreactive diluent. Using diffusion filtering and 2D correlation spectroscopy techniques, all network components are identified. By quantification of network-bound photoinitiator fragments, an average kinetic chain length of 9 ± 2 methacrylate units is determined. The PDLLA macromer solution was also used with a dye to prepare computer-designed structures by stereolithography. For these networks structures, the average kinetic chain length is 24 ± 4 methacrylate units. In all cases the calculated molecular weights of the polymethacrylate chains after degradation are maximally 8.8 kg/mol, which is far below the threshold for renal clearance. Upon incubation in phosphate buffered saline at 37 °C, the networks show a similar mass loss profile in time as linear high-molecular-weight PDLLA (HMW PDLLA). The mechanical properties are preserved longer for the PDLLA networks than for HMW PDLLA. The initial tensile strength of 47 ± 2 MPa does not decrease significantly for the first 15 weeks, while HMW PDLLA lost 85 ± 5% of its strength within 5 weeks. The physical properties, kinetic chain length, and degradation profile of these photo-cross-linked PDLLA networks make them most suited materials for orthopedic applications and use in (bone) tissue engineering.