Exploring the mucoadhesive behavior of sucrose acetate isobutyrate : a novel excipient for oral delivery of biopharmaceuticals

Oral drug delivery is an attractive noninvasive alternative to injectables. However, oral delivery of biopharmaceuticals is highly challenging due to low stability during transit in the gastrointestinal tract (GIT), resulting in low systemic bioavailability. Thus, novel formulation strategies are essential to overcome this challenge. An interesting approach is increasing retention in the GIT by utilizing mucoadhesive biomaterials as excipients. Here, we explored the potential of the GRAS excipient sucrose acetate isobutyrate (SAIB) to obtain mucoadhesion in vivo. Mucoadhesive properties of a 90% SAIB/10% EtOH (w/w) drug delivery system (DDS) were assessed using a biosimilar mucus model and evaluation of rheological behavior after immersion in biosimilar intestinal fluid. To ease readability of this manuscript, we will refer to this as SAIB DDS. The effect of SAIB DDS on cell viability and epithelial membrane integrity was tested in vitro prior to in vivo studies that were conducted using SPECT/CT imaging in rats. When combining SAIB DDS with biosimilar mucus, increased viscosity was observed due to secondary interactions between biosimilar mucus and sucrose ester predicting considerable mucoadhesion. Mucoadhesion was confirmed in vivo, as radiolabeled insulin entrapped in SAIB DDS, remained in the small intestine for up to 22 h after administration. Moreover, the integrity of the system was investigated using the dynamic gastric model under conditions simulating the chemical composition of stomach fluid and physical shear stress in the antrum under fasted conditions. In conclusion, SAIB is an interesting and safe biomaterial to promote high mucoadhesion in the GIT after oral administration.Peer reviewe

Structure and Dynamics of Thermosensitive pDNA Polyplexes Studied by Time-Resolved Fluorescence Spectroscopy

Combining multiple stimuli-responsive functionalities into the polymer design is an attractive approach to improve nucleic acid delivery. However, more in-depth fundamental understanding how the multiple functionalities in the polymer structures are influencing polyplex formation and stability is essential for the rational development of such delivery systems. Therefore, in this study the structure and dynamics of thermosensitive polyplexes were investigated by tracking the behavior of labeled plasmid DNA (pDNA) and polymer with time-resolved fluorescence spectroscopy using fluorescence resonance energy transfer (FRET). The successful synthesis of a heterofunctional poly(ethylene glycol) (PEG) macroinitiator containing both an atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain-transfer (RAFT) initiator is reported. The use of this novel PEG macroinitiator allows for the controlled polymerization of cationic and thermosensitive linear triblock copolymers and labeling of the chain-end with a fluorescent dye by maleimide-thiol chemistry. The polymers consisted of a thermosensitive poly(N-isopropylacrylamide) (PNIPAM, N), hydrophilic PEG (P), and cationic poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA, D) block, further referred to as NPD. Polymer block D chain-ends were labeled with Cy3, while pDNA was labeled with FITC. The thermosensitive NPD polymers were used to prepare pDNA polyplexes, and the effect of the N/P charge ratio, temperature, and composition of the triblock copolymer on the polyplex properties were investigated, taking nonthermosensitive PD polymers as the control. FRET was observed both at 4 and 37 degrees C, indicating that the introduction of the thermosensitive PNIPAM block did not compromise the polyplex structure even above the polymer's cloud point. Furthermore, FRET results showed that the NPD- and PD-based polyplexes have a less dense core compared to polyplexes based on cationic homopolymers (such as PEI) as reported before. The polyplexes showed to have a dynamic character meaning that the polymer chains can exchange between the polyplex core and shell. Mobility of the polymers allow their uniform redistribution within the polyplex and this feature has been reported to be favorable in the context of pDNA release and subsequent improved transfection efficiency, compared to nondynamic formulations.Peer reviewe

Статеві особливості метаболізму міокарда в динаміці розвитку експериментального гіпертиреозу

В экспериментах на половозрелых самцах и самках крыс исследовано активность перекисного окислення липидов, антиоксидантной защиты и энергообразования в динамике развития тироксиновой кардиомиопатии, которую моделировали введением L-тироксина (500 мг/кг, внутрижелудочно, ежедневно). В миокарде желудочков через 5, 10 и 15 дней с начала эксперимента определяли содержание диеновых и триеновых коньюгат (ДК, ТК), ТБК-активных продуктов (ТБК-АП), активность супероксиддисмутазы (СОД), каталазы, глутатионпероксидазы (ГП) и глутатионредуктазы (ГР), сукцинатдегидрогеназы (СДГ), цитохромоксидазы (ЦО). Установили, что гипертироксинемия визывала накопление в миокарде желудочков крыс ДК, ТК и ТБК-АП, что в самок было более существенным, чем у самцов, несмотря на большую активность ГП та ГР. Недостаточная протекторная эффективность ферментов системы глутатиона была результатом значительного угнетения активности СОД и каталазы, что свидетельствовало о существенном накоплении активных форм кислорода. Активность энергообразования в таких условиях уменьшалась, о чем свидетельствовало угнетение активности СДГ, которое было аналогичным в самцов и самок, и ЦО, что было более существенным в самок. Полученные результаты свидетельствуют о том, что развитие тироксиновой кардиомиопатии вызывает существенный метаболический дисбаланс в миокарде желудочков самок крыс, что разрешает ожидать болем интенсивные структурные нарушения.Lipid peroxidation, antioxidant protection and energy production were studied in adult male and female rats with thyroxin cardiomyopathy, which simulated by introduction of L-thyroxine (500 mg / kg, intraperitoneally, daily). In the myocardium of the ventricles after 5, 10 and 15 days from the start of the experiment determined the content of diene and triene conjugate (DC, TC), TBA-active metabolits (TBA-am), activity of superoxide dismutase (SOD), catalase, glutathione peroxidase (GP) and glutathione reductase (GR), succinate dehydrogenase (SDH), cytochrome oxidase (CO). Found that hyperthyroxinemia caused accumulation in myocardium of the ventricles DC, TC and TBA-am mostly in females despite the higher activity of GP and GR. Lack of protective effects of glutathione system enzymes resulted from significant inhibition of SOD and catalase, indicating a significant accumulation of reactive species of oxygen. Activity of the energy production in these conditions decreased. That was proved by the inhibition of SDH in myocardium both sex animals and CO mostly in females. We conclude that the development of thyroxin cardiomyopathy causes metabolic disbalance in myocardium of the ventricles mostly in female rats, which can results in more intense structural damage

Three-dimensional cathodoluminescence imaging and electron backscatter diffraction: tools for studying the genetic nature of diamond inclusions

As a step towards resolving the genesis of inclusions in diamonds, a new technique is presented. This technique combines cathodoluminescence (CL) and electron backscatter diffraction (EBSD) using a focused ion beam-scanning electron microscope (FIB-SEM) instrument with the aim of determining, in detail, the three-dimensional diamond zonation adjacent to a diamond inclusion. EBSD reveals that mineral inclusions in a single diamond have similar crystallographic orientations to the host, within ±0. 4°. The chromite inclusions record a systematic change in Mg# and Cr# from core to the rim of the diamond that corresponds with a ~80°C decrease of their formation temperature as established by zinc thermometry. A chromite inclusion, positioned adjacent to a boundary between two major diamond growth zones, is multi-faceted with preferred octahedral and cubic faces. The chromite is surrounded by a volume of non-luminescent diamond (CL halo) that partially obscures any diamond growth structures. The CL halo has apparent crystallographic morphology with symmetrically oriented pointed features. The CL halo is enriched in ~200 ppm Cr and ~80 ppm Fe and is interpreted to have a secondary origin as it overprints a major primary diamond growth structure. The diamond zonation adjacent to the chromite is complex and records both syngenetic and protogenetic features based on current inclusion entrapment models. In this specific case, a syngenetic origin is favoured with the complex form of the inclusion and growth layers indicating changes of growth rates at the diamond-chromite interface. Combined EBSD and 3D-CL imaging appears an extremely useful tool in resolving the ongoing discussion about the timing of inclusion growth and the significance of diamond inclusion studies. © 2010 The Author(s)

Drug delivery with living cells

The field of drug delivery has grown tremendously in the past few decades by developing a wide range of advanced drug delivery systems. An interesting category is cell-based drug delivery, which includes encapsulation of drugs inside cells or attached to the surface and subsequent transportation through the body. Another approach involves genetic engineering of cells to secrete therapeutic molecules in a controlled way. The next-generation systems integrate expertise from synthetic biology to generate therapeutic gene networks for highly advanced sensory and output devices. These developments are very exciting for the drug delivery field and could radically change the way we administer biological medicines to chronically ill patients. This review is covering the use of living cells, either as transport system or production-unit, to deliver therapeutic molecules and bioactive proteins inside the body. It describes a wide range of approaches in cell-based drug delivery and highlights exceptional examples

Drug delivery with living cells

The field of drug delivery has grown tremendously in the past few decades by developing a wide range of advanced drug delivery systems. An interesting category is cell-based drug delivery, which includes encapsulation of drugs inside cells or attached to the surface and subsequent transportation through the body. Another approach involves genetic engineering of cells to secrete therapeutic molecules in a controlled way. The next-generation systems integrate expertise from synthetic biology to generate therapeutic gene networks for highly advanced sensory and output devices. These developments are very exciting for the drug delivery field and could radically change the way we administer biological medicines to chronically ill patients. This review is covering the use of living cells, either as transport system or production-unit, to deliver therapeutic molecules and bioactive proteins inside the body. It describes a wide range of approaches in cell-based drug delivery and highlights exceptional examples

Heterofunctional Poly(ethylene glycol) (PEG) Macroinitiator Enabling Controlled Synthesis of ABC Triblock Copolymers

ABC triblock copolymers with a poly­(ethylene glycol) (PEG) midblock have attractive properties for biomedical applications because of PEG’s favorable properties regarding biocompatibility and hydrophilicity. However, easy strategies to synthesize polymers containing a PEG midblock are limited. In this study, the successful synthesis of a heterofunctional PEG macroinitiator containing both an azoinitiator and an atom transfer radical polymerization (ATRP) initiator is demonstrated. This novel PEG macroinitiator allows the development of elegant synthesis routes for PEG midblock-containing ABC copolymers that does not require protection of initiating sites or polymer end-group postmodification. Polymers with outer blocks composed of different monomers were synthesized to illustrate the versatility of this macroinitiator. <i>N</i>-Isopropylacrylamide (NIPAM) was included to obtain thermosensitive polymers, 2-(dimethylamino)­ethyl methacrylate (DMAEMA) provided pH-sensitive properties, and 2-hydroxyethyl acrylate (HEA) functioned as a noncharged hydrophilic block that also allows for postmodifications reactions. This synthesis approach can further contribute to the design of high-precision polymers with tailorable block compositions and polymer topologies, which is highly attractive for applications in nanotechnology

Heterofunctional Poly(ethylene glycol) (PEG) Macroinitiator Enabling Controlled Synthesis of ABC Triblock Copolymers

ABC triblock copolymers with a poly(ethylene glycol) (PEG) midblock have attractive properties for biomedical applications because of PEG's favorable properties regarding biocompatibility and hydrophilicity. However, easy strategies to synthesize polymers containing a PEG midblock are limited. In this study, the successful synthesis of a heterofunctional PEG macroinitiator containing both an azoinitiator and an atom transfer radical polymerization (ATRP) initiator is demonstrated. This novel PEG macroinitiator allows the development of elegant synthesis routes for PEG midblock-containing ABC copolymers that does not require protection of initiating sites or polymer end-group postmodification. Polymers with outer blocks composed of different monomers were synthesized to illustrate the versatility of this macroinitiator. N-Isopropylacrylamide (NIPAM) was included to obtain thermosensitive polymers, 2-(dimethylamino)ethyl methacrylate (DMAEMA) provided pH-sensitive properties, and 2-hydroxyethyl acrylate (HEA) functioned as a noncharged hydrophilic block that also allows for postmodifications reactions. This synthesis approach can further contribute to the design of high-precision polymers with tailorable block compositions and polymer topologies, which is highly attractive for applications in nanotechnology