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1.
Interactions between Clinically Used Bisphosphonates and Bone Mineral: from Coordination Chemistry to Biomedical Applications and Beyond.
Gałęzowska, J
ChemMedChem. 2018;(4):289-302
Abstract
Bisphosphonates (BPs) are well-established, widely used first-choice drugs for bone-related diseases and are one of the few classes of molecules for selective bone targeting. Their binding to calcium cations within hydroxyapatite (HA) is a key physicochemical event that takes place on the bone surface. It is the starting point for a cascade of biochemical reactions and cellular effects that lead to the pharmacological activity of BPs. The phenomenon has been known for years, yet its physicochemical nature is still not fully understood. In particular, the adsorption/release processes and structure-function relationships of BPs remain to be clarified. These are elementary, yet crucial factors, which should influence the design and development of new delivery tools or drugs with improved characteristics. This review summarizes the current understanding of the chemical interactions between clinically used BPs and bone mineral, starting from basic Ca2+ coordination chemistry through to interactions with hydroxyapatite, nanocrystalline apatites, and natural bone mineral.
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2.
Molecular Insight into Drug-Loading Capacity of PEG-PLGA Nanoparticles for Itraconazole.
Wilkosz, N, Łazarski, G, Kovacik, L, Gargas, P, Nowakowska, M, Jamróz, D, Kepczynski, M
The journal of physical chemistry. B. 2018;(28):7080-7090
Abstract
Nanoparticles made of amphiphilic block copolymers comprising biodegradable core-forming blocks are very attractive for the preparation of drug-delivery systems with sustained release. Their therapeutic applications are, however, hindered by low values of the drug-loading content (DLC). The compatibility between the drug and the core-forming block of the copolymer is considered the most important factor affecting the DLC value. However, the molecular picture of the hydrophobic drug-copolymer interaction is still not fully recognized. Herein, we examined this complex issue using a range of experimental techniques in combination with atomistic molecular dynamics simulations. We performed an analysis of the interaction between itraconazole, a model hydrophobic drug, and a poly(ethylene glycol)-poly(lactide- co-glycolide) (PEG-PLGA) copolymer, a biodegradable copolymer commonly used for the preparation of drug-delivery systems. Our results clearly show that the limited capacity of the PEG-PLGA nanoparticles for the accumulation of hydrophobic drugs is due to the fact that the drug molecules are located only at the water-polymer interface, whereas the interior of the PLGA core remains empty. These findings can be useful in the rational design and development of amphiphilic copolymer-based drug-delivery systems.
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3.
Calcium phosphate-based nanosystems for advanced targeted nanomedicine.
Degli Esposti, L, Carella, F, Adamiano, A, Tampieri, A, Iafisco, M
Drug development and industrial pharmacy. 2018;(8):1223-1238
Abstract
Synthetic calcium phosphates (CaPs) are the most widely accepted bioceramics for the repair and reconstruction of bone tissue defects. The recent advancements in materials science have prompted a rapid progress in the preparation of CaPs with nanometric dimensions, tailored surface characteristics, and colloidal stability opening new perspectives in their use for applications not strictly related to bone. In particular, the employment of CaPs nanoparticles as carriers of therapeutic and imaging agents has recently raised great interest in nanomedicine. CaPs nanoparticles, as well as other kinds of nanoparticles, can be engineered to specifically target the site of the disease (cells or organs), thus minimizing their dispersion in the body and undesired organism-nanoparticles interactions. The most promising and efficient approach to improve their specificity is the 'active targeting', where nanoparticles are conjugated with a targeting moiety able to recognize and bind with high efficacy and selectivity to receptors that are highly expressed only in the therapeutic site. The aim of this review is to give an overview on advanced targeted nanomedicine with a focus on the most recent reports on CaP nanoparticles-based systems, specifically designed for the active targeting. The distinctive characteristics of CaP nanoparticles with respect to the other kinds of nanomaterials used in nanomedicine are also discussed.
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4.
Nrp-1 receptor targeting peptide-functionalized TPGS micellar nanosystems to deliver 10-hydroxycampothecin for enhanced cancer chemotherapy.
Mozhi, A, Ahmad, I, Kaleem, QM, Tuguntaev, RG, Eltahan, AS, Wang, C, Yang, R, Li, C, Liang, XJ
International journal of pharmaceutics. 2018;(1-2):582-592
Abstract
Mitochondria are considered the power house of cells where ATP is generated for cellular metabolism, and they also act as a crucial regulator of the intrinsic apoptosis pathway. During ATP synthesis, reactive oxygen species (ROS) are produced as secondary products. Overproduction of ROS can promote mitochondrial DNA mutation, dysfunction and depolarization of the mitochondrial membrane, ultimately resulting in cell death. Therefore, the destruction of mitochondria would be an effective therapeutic approach to kill malignant tumors. Herein, we formulated a PEGylated α-TOS polymeric micellar system loaded with 10-hydroxycamptothecin (HCPT) drug to inhibit the nuclear topoisomerase I enzyme and disrupt the mitochondrial membrane to induce apoptosis. In addition, tumor-penetrating CRGDK peptide-functionalized TPGS2k specifically bound to the Nrp-1 receptor to facilitate higher cell uptake of polymeric micelles by tumor cells. Experimental studies confirmed that HCPT-loaded and peptide-functionalized TPGS2k-TOS micelles (HLPFTTM) showed an enhanced anti-cancer effect in A549 cancer cells.
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5.
Characterization of the interaction forces in a drug carrier complex of doxorubicin with a drug-binding peptide.
Gocheva, G, Ilieva, N, Peneva, K, Ivanova, A
Chemical biology & drug design. 2018;(4):874-884
Abstract
Polypeptide-based materials are used as building blocks for drug delivery systems aimed at toxicity decrease in chemotherapeutics. A molecular-level approach is adopted for investigating the non-covalent interactions between doxorubicin and a recently synthesized drug-binging peptide as a key part of a system for delivery to neoplastic cells. Molecular dynamics simulations in aqueous solution at room and body temperature are applied to investigate the structure and the binding modes within the drug-peptide complex. The tryptophans are outlined as the main chemotherapeutic adsorption sites, and the importance of their placement in the peptide sequence is highlighted. The drug-peptide binging energy is evaluated by density functional theory calculations. Principal component analysis reveals comparable importance of several types of interaction for the binding strength. π-Stacking is dominant, but other factors are also significant: intercalation, peptide backbone stacking, electrostatics, dispersion, and solvation. Intra- and intermolecular H-bonding also stabilizes the complexes. The influence of solvent molecules on the binding energy is mild. The obtained data characterize the drug-to-peptide attachment as a mainly attractive collective process with interactions spanning a broad range of values. These results explain with atomistic detail the experimentally registered doxorubicin-binging ability of the peptide and outline the complex as a prospective carrying unit that can be employed in design of drug delivery systems.
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6.
Green Reduced Graphene Oxide Toughened Semi-IPN Monolith Hydrogel as Dual Responsive Drug Release System: Rheological, Physicomechanical, and Electrical Evaluations.
Ganguly, S, Das, P, Maity, PP, Mondal, S, Ghosh, S, Dhara, S, Das, NC
The journal of physical chemistry. B. 2018;(29):7201-7218
Abstract
Macroporous hydrogel monoliths having tailor-made features, conductivity, superstretchability, excellent biocompatibility, and biodegradability, have become the most nurtured field of interest in soft biomaterials. Green method assisted reduced graphene oxide has been inserted by in situ free radical gelation into semi-IPN hydrogel matrix to fabricate conducting hydrogel. Mechanical toughness has been implemented for the graphene-polymer physisorption interactions with graphene basal planes. Moreover, the as-prepared 3D scaffold type monolith hydrogel has been rheologically superior regarding their high elastic modulus and delayed gel rupturing. κ-Carragenaan, one of the components of the hydrogel, has biodegradable nature. The most significant outcome is their low electrical percolation threshold and reversibly ductile nature. Reversible ductility provides them with rubber-like consistency in flow conditions. Surprising, the hydrogels showed dual stimuli-responsiveness, that is, environmental pH and external electrical stimulation. Electro-stimulation has been adopted here for the first time in semi-IPN systems, which could be an ideal alternative for iontopheretic devices and pulsatile drug release through skin. Regarding this, the hydrogel also has been passed to biocompatibility assay; they are noncytotoxic and show cell proliferation without negligible cell death in live-dead assay. The porosity of the nanocomposite scaffold-like gels was also analyzed by microcomputed tomography (μ-CT), which exhibited their connectivity in cell/voids inside the matrix. Thus, the experimentations are on the support of biocompatible soft material for dual-responsive tunable drug delivery.
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7.
Loading studies of the anticancer drug camptothecin into dual stimuli-sensitive nanoparticles. Stability scrutiny.
Iglesias, N, Galbis, E, Díaz-Blanco, MJ, de-Paz, MV, Galbis, JA
International journal of pharmaceutics. 2018;(1-2):429-438
Abstract
In recent years, the preparation of valuable drug delivery systems (DDS) from self-assembled amphiphilic copolymers has attracted much attention since these nanomaterials provide new opportunities to solve problems such as the lack of solubility in water of lipophilic drugs, improve their bioavailability, prolong their circulation time and decrease the side effects associated with their administration. In the current study two types of biocompatible pH-responsive nanoparticles derived from poly(2-hydroxyethyl methacrylate) (pHEMA) have been used as drug nano-carriers, being one of them core cross-linked to circumvent their instability upon dilution in human fluids. The present paper deals with the optimization of the loading process of the labile, hydrophobic and highly active anticancer drug, Camptothecin (CPT) into the nanoparticles with regard to four independent variables: CPT/polymer ratio, sonication, temperature and loading time. Forty experiments were carried out and a Box-Behnken experimental design was used to evaluate the significance of the independent variables related to encapsulation efficiency and drug retention capacity. The enhanced drug loading and encapsulation efficiency values (58% and >92%, respectively) of CPT were achieved by the core cross-linked NPs in 2 h at 32 °C at CPT/polymer ratio 1.5:1 w/w and 14 min of sonication. The optimized CPT-loaded NPs were studied by dynamic light scattering and scanning electron microscopy, and an increase in size of the loaded-NP compared to the unloaded counterparts was found. Other twenty experiments were conducted to study the enability to retain CPT into the conjugates at different ionic strength values and times. The stability studies demonstrated that the core cross-linked nanocarriers displayed an excellent drug retention capacity (>90%) at 25 °C for 15 days in every ionic-strength environments whereas the non-cross-linked ones were more stable at physiological ionic strength. The optimized systems proved to be a major step forward to encapsulate and retain CPT in the NP nuclei, what makes them ideal devices to control the delivery of CPT upon the triggered acidic conditions of solid tumors.
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8.
Current development in novel drug delivery systems of bioactive molecule plumbagin.
Rajalakshmi, S, Vyawahare, N, Pawar, A, Mahaparale, P, Chellampillai, B
Artificial cells, nanomedicine, and biotechnology. 2018;(sup1):209-218
Abstract
Plumbagin (PLB), a member of the quinine family, mainly found in the plant Plumbago zeylanica Linn., potentially exhibit anticancer, anti-inflammatory, anti-oxidant, antifungal, neuroprotective, hypolipidemic and antibacterial activities. However, it has been well known that the application of PLB was limited owing to its water insolubility, instability and poor bioavailability. For decades, many attempts have been made to compensate for these disadvantages with the development of improved delivery platforms as the feasible approaches. This review aims to describe the various studies supporting the biopharmaceutical aspects of PLB. In addition, it includes a section devoted to discussing the challenges associated with the drug and strategies to improve the properties of PLB such as solubility, stability and bioavailability. Also, this paper summarizes the recent works on the design and development of novel delivery systems of PLB such as liposomes, niosomes, microsphares, nanoparticles, micelles, complexization, metal nanoparticles, crystals modification, etc., with the goal of harnessing the true difficulties of this multifunctional agent in the clinical arena.
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9.
FLIM reveals alternative EV-mediated cellular up-take pathways of paclitaxel.
Saari, H, Lisitsyna, E, Rautaniemi, K, Rojalin, T, Niemi, L, Nivaro, O, Laaksonen, T, Yliperttula, M, Vuorimaa-Laukkanen, E
Journal of controlled release : official journal of the Controlled Release Society. 2018;:133-143
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Abstract
In response to physiological and artificial stimuli, cells generate nano-scale extracellular vesicles (EVs) by encapsulating biomolecules in plasma membrane-derived phospholipid envelopes. These vesicles are released to bodily fluids, hence acting as powerful endogenous mediators in intercellular signaling. EVs provide a compelling alternative for biomarker discovery and targeted drug delivery, but their kinetics and dynamics while interacting with living cells are poorly understood. Here we introduce a novel method, fluorescence lifetime imaging microscopy (FLIM) to investigate these interaction attributes. By FLIM, we show distinct cellular uptake mechanisms of different EV subtypes, exosomes and microvesicles, loaded with anti-cancer agent, paclitaxel. We demonstrate differences in intracellular behavior and drug release profiles of paclitaxel-containing EVs. Exosomes seem to deliver the drug mostly by endocytosis while microvesicles enter the cells by both endocytosis and fusion with cell membrane. This research offers a new real-time method to investigate EV kinetics with living cells, and it is a potential advancement to complement the existing techniques. The findings of this study improve the current knowledge in exploiting EVs as next-generation targeted drug delivery systems.
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10.
The promising future of nano-antioxidant therapy against environmental pollutants induced-toxicities.
Eftekhari, A, Dizaj, SM, Chodari, L, Sunar, S, Hasanzadeh, A, Ahmadian, E, Hasanzadeh, M
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2018;:1018-1027
Abstract
Developmental toxicity caused by exposure to a mixture of environmental pollutants has become a major health concern. Human-made chemicals, including xenoestrogens, pesticides, heavy metals, polycyclic aromatic hydrocarbons (PAHs) are major factors that increase formation of Reactive Oxygen Species (ROS) and adversely influence endogen antioxidant defense. Humans have evolved complex antioxidants systems that protect cells from prooxidant conditions. Deficiency of any these components can cause destruction in the overall antioxidant status of an individual. Antioxidants agents can be endogenous or obtained exogenously, as a part of a diet or through dietary supplements. Although oxidative damage contributes to many pathologies the use of naturally occurring, small-molecule exogenous antioxidants as therapies for these disorders has not been successful. An ideal exogenous antioxidant should be readily absorbed, enough delivered to intracellular location required to decrease pathological oxidative damage, positively affecting gene expression. To develop effective antioxidant therapies the best strategy may be to create new nanoscale drug delivery systems. This review highlights the role of environmental induced oxidative stress factors and novel nanoparticle design techniques of antioxidants.