Showing papers in "Molecular Pharmaceutics in 2012"
TL;DR: This review aims to particularly highlight the position of RGD-based nanoparticles in cancer therapy and imaging and the binding of the RGD peptide to this integrin.
Abstract: The integrin α(v)β(3) plays an important role in angiogenesis. It is expressed on tumoral endothelial cells as well as on some tumor cells. RGD peptides are well-known to bind preferentially to the α(v)β(3) integrin. In this context, targeting tumor cells or tumor vasculature by RGD-based strategies is a promising approach for delivering anticancer drugs or contrast agents for cancer therapy and diagnosis. RGD-based strategies include antagonist drugs (peptidic or peptidomimetic) of the RGD sequence, RGD-conjugates, and the grafting of the RGD peptide or peptidomimetic, as targeting ligand, at the surface of nanocarriers. Although all strategies are overviewed, this review aims to particularly highlight the position of RGD-based nanoparticles in cancer therapy and imaging. This review is divided into three parts: the first one describes the context of angiogenesis, the role of the integrin α(v)β(3), and the binding of the RGD peptide to this integrin; the second one focuses on RGD-based strategies in cancer therapy; while the third one focuses on RGD-based strategies in cancer diagnosis.
772 citations
TL;DR: The endomembrane trafficking pathways are overviewed, the methods used to determine and quantitate the intracellular fate of nanomedicines are discussed, and the current status of lysosomotropic and endOSomotropic delivery is reviewed.
Abstract: More than 40 nanomedicines are already in routine clinical use with a growing number following in preclinical and clinical development. The therapeutic objectives are often enhanced disease-specific targeting (with simultaneously reduced access to sites of toxicity) and, especially in the case of macromolecular biotech drugs, improving access to intracellular pharmacological target receptors. Successful navigation of the endocytic pathways is usually a prerequisite to achieve these goals. Thus a comprehensive understanding of endocytosis and intracellular trafficking pathways in both the target and bystander normal cell type(s) is essential to enable optimal nanomedicine design. It is becoming evident that endocytic pathways can become disregulated in disease and this, together with the potential changes induced during exposure to the nanocarrier itself, has the potential to significantly impact nanomedicine performance in terms of safety and efficacy. Here we overview the endomembrane trafficking pathway...
304 citations
TL;DR: Investigation of the influence of electrostatic surface potential distribution of monoclonal antibodies (MAbs) on intermolecular interactions and viscosity finds replacement of charge residues in the sequence of MAb-2, M-10, did not invoke charge distribution to the same extent as M Ab-1 and hence exhibited a similar viscolysis and self-association profile as Mab-2.
Abstract: The present work investigates the influence of electrostatic surface potential distribution of monoclonal antibodies (MAbs) on intermolecular interactions and viscosity. Electrostatic models suggest MAb-1 has a less uniform surface charge distribution than MAb-2. The patches of positive and negative potential on MAb-1 are predicted to favor intermolecular attraction, even in the presence of a small net positive charge. Consistent with this expectation, MAb-1 exhibits a negative second virial coefficient (B₂₂), an increase in static structure factor, S((q→0)), and a decrease in hydrodynamic interaction parameter, H((q→0)), with increase in MAb-1 concentration. Conversely, MAb-2 did not show such heterogeneous charge distribution as MAb-1 and hence favors intermolecular repulsion (positive B₂₂), lower static structure factor, S((q→0)), and repulsion induced increase in momentum transfer, H((q→0)), to result in lower viscosity of MAb-2. Charge swap mutants of MAb-1, M-5 and M-7, showed a decrease in charge asymmetry and concomitantly a loss in self-associating behavior and lower viscosity than MAb-1. However, replacement of charge residues in the sequence of MAb-2, M-10, did not invoke charge distribution to the same extent as MAb-1 and hence exhibited a similar viscosity and self-association profile as MAb-2.
242 citations
TL;DR: This work demonstrates that supersaturation via ASDs has a subtle yet powerful advantage over other solubility-enabling formulation approaches, and may be achieved without the expense of apparent intestinal membrane permeability.
Abstract: Recently, we have revealed a trade-off between solubility increase and permeability decrease when solubility-enabling oral formulations are employed. We have shown this trade-off phenomenon to be ubiquitous, and to exist whenever the aqueous solubility is increased via solubilizing excipients, regardless if the mechanism involves decreased free fraction (cyclodextrins complexation, surfactant micellization) or simple cosolvent solubilization. Discovering a way to increase drug solubility without concomitant decreased permeability represents a major advancement in oral delivery of lipophilic drugs and is the goal of this work. For this purpose, we sought to elucidate the solubility-permeability interplay when increased apparent solubility is obtained via supersaturation from an amorphous solid dispersion (ASD) formulation. A spray-dried ASD of the lipophilic drug progesterone was prepared in the hydrophilic polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS), which enabled supersaturation up to 4× the crystalline drug's aqueous solubility (8 μg/mL). The apparent permeability of progesterone from the ASD in HPMC-AS was then measured as a function of increasing apparent solubility (supersaturation) in the PAMPA and rat intestinal perfusion models. In contrast to previous cases in which apparent solubility increases via cyclodextrins, surfactants, and cosolvents resulted in decreased apparent permeability, supersaturation via ASD resulted in no decrease in apparent permeability with increasing apparent solubility. As a result, overall flux increased markedly with increasing apparent solubility via ASD as compared to the other formulation approaches. This work demonstrates that supersaturation via ASDs has a subtle yet powerful advantage over other solubility-enabling formulation approaches. That is, increased apparent solubility may be achieved without the expense of apparent intestinal membrane permeability. Thus, supersaturation via ASDs presents a markedly increased opportunity to maximize overall oral drug absorption.
219 citations
TL;DR: In vivo fluorescence-microscopic results demonstrate that insulin could be absorbed into the systemic circulation, while most CS was retained in the microvilli scaffolds, and that CS is a safe permeation enhancer and is an effective carrier for oral protein delivery.
Abstract: This study investigates the effects of chitosan (CS) on the opening of epithelial tight junctions (TJs) and paracellular transport at microscopic, ultrastructural, and computed-tomographic levels in Caco-2 cell monolayers and animal models. Using immunofluorescence staining, CS treatment was observed to be associated with the translocation of JAM-1 (a trans-membrane TJ protein), resulting in the disruption of TJs; the removal of CS was accompanied by the recovery of JAM-1. Ultrastructural observations by TEM reveal that CS treatment slightly opened the apical intercellular space, allowing lanthanum (an electron-dense tracer) to stain the intercellular surface immediately beneath the TJs, suggesting the opening of TJs. Following the removal of CS, the TJs were completely recovered. Similar microscopic and ultrastructural findings were obtained in animal studies. CS nanoparticles were prepared as an insulin carrier. The in vivo fluorescence-microscopic results demonstrate that insulin could be absorbed into...
203 citations
TL;DR: This is the first time an ICG-containing nanostructure has been used through systemic administration to achieve an efficient in vivo photothermal effect for cancer treatment and could be used as a fluorescent marker as well as a light-absorber for imaging-guided photothermal therapy.
Abstract: Indocyanine green (ICG) is a conventional dye that can be used in clinical near-infrared (NIR) imaging, and it is also an effective light absorber for laser-mediated photothermal therapy. However, applications of ICG were limited due to its fast degradation in aqueous media and quick clearance from the body. Herein, an ICG-containing nanostructure, ICG-PL-PEG, was developed for photothermal therapy, which was self-assembled by ICG and phospholipid-polyethylene glycol (PL-PEG). Our in vitro and in vivo experiments demonstrated that ICG-PL-PEG suspension was more efficient in producing a NIR-dependent temperature increase than ICG alone, due to the increase of ICG monomers from the addition of PL-PEG to match the central wavelength of the 808 nm laser. When conjugated with integrin αvβ3 monoclonal antibody (mAb), ICG-PL-PEG could be selectively internalized and retained in target tumor cells. Irradiation of an 808 nm laser after intravenous administration of ICG-PL-PEG-mAb resulted in tumor suppression in m...
201 citations
TL;DR: The data suggest that large cationic PAMAM dendrimers induce platelet aggregation through disruption of membrane integrity, as well as a variety of chemical and biological inhibitors known to interfere with various pathways of platelet activation.
Abstract: Nanoparticles are finding growing applications in medicine because they may reduce toxicity and improve the solubility, pharmacokinetics and biodistribution profiles1 of traditional pharmaceuticals. In the bloodstream, nanoparticles encounter a very complex environment of plasma proteins and immune cells 2-4. Some nanoparticles intended for drug delivery applications are intentionally engineered so as to reduce their clearance from the bloodstream to extend systemic circulation times and to increase drug delivery to a target site. When blood clearance is fast, nanoparticle interaction with blood components is minimized, however an increase in the circulation time respectively increases the duration of contact with blood components, including those of the coagulation system. Such extended exposure to coagulation factors and thrombocytes may amplify adverse effects such as activation of the blood clotting and occlusion of blood vessels by thrombi. This is why the initial characterization of nanomaterials often includes evaluation of nanoparticle hematocompatibility.
Platelets represent cellular components of the blood coagulation system. They are small anucleated cells derived from bone marrow megakaryocytes. Under physiological conditions, 150-450 × 109 platelets per liter circulate in the peripheral blood in 10 days 5. There is also a reservoir of platelets in the spleen which can be rapidly distributed into circulation when needed to maintain hemostasis. Platelets are very sensitive to changes in the blood microenvironment; they can be activated by different physiological agonists such as thrombin, collagen, adenosine-diphosphate (ADP), but also by various microorganisms, immunoglobulins, drugs and some nanomaterials 5. Although several studies have shown that certain nanoparticles, such as, iron-oxide nanoparticles 6, and silver nanoparticles 7, can activate platelets and induce platelet aggregation, no comprehensive structure activity relationship study evaluating the effects of nanoparticle size and surface properties on thrombogenic properties has been conducted.
Some trends in particle thrombogenic properties have been described. Interestingly, the reported trends were different for different type of nanoparticles. For example, Koziara et al. have shown anionic cetyl alcohol/polysorbate-based nanoparticles inhibit platelet activation and aggregation, and that this property is decreased when particle surface is modified with polyethylene glycol (PEG), however, the same strongly anionic particles (zeta potential of -40.2mV) neither activated platelets nor induced their aggregation 8. In contrast, Zbiden et al reported that only anionic liposomes activated platelets and induced platelet aggregation 9. In agreement with this, another study reported that platelet activation and aggregation by latex nanoparticles was stronger for most anionic particles and weaker for particles with less negative zeta potentials 10, 11. Both anionic and cationic polystyrene particles activated platelets and induced platelet aggregation, and these effects were stronger with the smaller particles12. These limited and contradictory data do not allow for a clear determination of whether nanoparticle size, surface charge, or composition determines thrombogenic properties. The mechanisms through which nanoparticles induce platelet activation and aggregation are also largely unknown, and the mechanisms may be different for different classes of particles. For example, when various carbon-based particles (fullerene derivatives and nanotubes) and polystyrene nanobeads were studied, only single- walled carbon nanotubes (SWCNT), and multi-walled carbon nanotubes (MWCNT) activated platelets, and this activation could be prevented by inhibitors known to block extracellular calcium influx 13. Another study comparing five different types of carbon-based materials (water soluble fullerene derivative, nanotubes and mixed carbon nanoparticles) reported that all of these particles required activation of glycoprotein integrin receptor GPIIb/IIIa in order to cause platelet aggregation. However, pathways leading to this receptor depended on the size of the particles, with micron-sized particles, but not nanoparticles, requiring protein kinase C (PKC) for the activation of the integrin pathway14. The same study suggested that unlike classical platelet aggregation, carbon-based nanoparticle-induced platelet aggregation did not require thromboxane A2 and ADP release. These data suggest that: 1) nanosized particles may induce platelet aggregation via untraditional pathways, which could render common anti-thrombotic drugs less efficient at reducing aggregation; and 2) platelet activating/aggregating activity and its underlying mechanisms may vary significantly, even within the same class of nanomaterials.
One attractive feature of nanotechnology is that nanoparticles can be engineered to either promote platelet aggregation15-17 or inhibit it 18, 19, which can aid in treatment of various blood coagulation disorders.
Dendrimers are nanomaterials which have been tested in clinical studies for various applications20. These materials became attractive to drug delivery scientists because they are monodisperse, uniform, and hyperbranched materials with a well-defined and reproducible synthesis and modifiable protein-like structures21. In addition to these properties polyamidoamine (PAMAM) dendrimers are also available through several commercial sources to any laboratory without synthetic capabilities, and can be synthesized and purchased in large quantities. We used 12 formulations of PAMAM dendrimers, varying in size and surface charge, and studied their effects on human platelets in vitro. We verified our findings using several different methods including traditional light transmission aggregometry, and scanning electron microscopy (SEM). The results demonstrated that only large (G4-G6) cationic dendrimers, but not their small (G3) cationic couterparts or anionic or neutral dendrimers, were capable of inducing platelet aggregation. We also showed that platelet aggregation caused by large cationic PAMAM dendrimers is not associated with the release of membrane microparticles, and is not sensitive to a variety of inhibitors known to interrupt different pathways established as triggering platelet activation by physiological agonists. Collectively with published studies reporting dendrimer interaction with and disruption of supported lipid bilayers22-26, and computer simulation 27, our data suggest that large cationic PAMAM dendrimers induce platelet aggregation by disturbing the integrity of cell membranes.
199 citations
TL;DR: At least one human antimicrobial peptide, protegrin-1, which kills microbes by a channel-forming mechanism, has been shown to possess the ability to form extended amyloid fibrils very similar to those of classic disease-forming amyloids.
Abstract: More than two dozen clinical syndromes known as amyloid diseases are characterized by the buildup of extended insoluble fibrillar deposits in tissues. These amorphous Congo red staining deposits known as amyloids exhibit a characteristic green birefringence and cross-β structure. Substantial evidence implicates oligomeric intermediates of amyloids as toxic species in the pathogenesis of these chronic disease states. A growing body of data has suggested that these toxic species form ion channels in cellular membranes causing disruption of calcium homeostasis, membrane depolarization, energy drainage, and in some cases apoptosis. Amyloid peptide channels exhibit a number of common biological properties including the universal U-shape β-strand–turn−β-strand structure, irreversible and spontaneous insertion into membranes, production of large heterogeneous single-channel conductances, relatively poor ion selectivity, inhibition by Congo red, and channel blockade by zinc. Recent evidence has suggested that inc...
192 citations
TL;DR: The β ratio is introduced, which is derived from the commonly used α ratio but is more fundamental since it additionally takes into account structural details of the oligomers.
Abstract: This work reports details pertaining to the formation of chitosan nanoparticles that we prepare by the ionic gelation method. The molecular interactions of the ionic cross-linking of chitosan with tripolyphosphate have been investigated and elucidated by means of all-electron density functional theory. Solvent effects have been taken into account using implicit models. We have identified primary-interaction ionic cross-linking configurations that we define as H-link, T-link, and M-link, and we have quantified the corresponding interaction energies. H-links, which display high interaction energies and are also spatially broadly accessible, are the most probable cross-linking configurations. At close range, proton transfer has been identified, with maximum interaction energies ranging from 12.3 up to 68.3 kcal/mol depending on the protonation of the tripolyphosphate polyanion and the relative coordination of chitosan with tripolyphosphate. On the basis of our results for the linking types (interaction energ...
175 citations
TL;DR: The model drug permeability studies in the human colon carcinoma (Caco-2) cell lines indicated that MSNs could significantly enhance TEL permeability and reduce rate of drug efflux, and MSNs offer the potential to achieve enhanced oral bioavailability of poorly soluble drugs via improved drug dissolution rate and enhancedDrug permeability.
Abstract: We investigate the effects of spherical mesoporous silica nanoparticles (MSNs) as an oral drug delivery system to improve the oral bioavailability of the model drug telmisartan (TEL) and examine their cellular uptake and cytotoxicity. Further, we explore the mechanisms behind the improved oral absorption of poorly soluble drugs promoted by MSNs. An investigation of intestinal epithelial cellular binding, association and uptake was carried out by laser scanning confocal microscopy, transmission electron microscopy and fluorescence activated cell sorting. The results show that the cellular uptake is highly time-, concentration- and size-dependent. The model drug permeability studies in the human colon carcinoma (Caco-2) cell lines indicated that MSNs could significantly enhance TEL permeability and reduce rate of drug efflux. After loading TEL into MSNs, its oral bioavailability was compared with that of the marketed product Micardis and TEL-loaded ordered mesoporous silica microparticles (MSMs) in beagle dogs. The relative bioavailability of TEL-loaded MSN formulation and TEL-loaded MSM formulation was 154.4 ± 28.4% and 129.1 ± 15.6%, respectively. MSNs offer the potential to achieve enhanced oral bioavailability of poorly soluble drugs via improved drug dissolution rate and enhanced drug permeability.
166 citations
TL;DR: A thorough understanding of the polymer and its modification has a huge potential to be the future trend for drug delivery and tissue engineering applications.
Abstract: Biodegradable polymers provided the opportunity to explore beyond conventional drug delivery and turned out to be the focus of current drug delivery In spite of availability of diverse class of polymers, several of these polymers lack important physicochemical and biological properties, limiting their widespread application in pharmaceutical drug delivery However, most polymers in the form of blends, copolymers and functionally modified polymers have exhibited their applicability to overcome specific limitations and to produce novel and/or functionalized formulations for drug delivery as well as tissue engineering This review aims to provide the need of polymeric modification, approaches adopted to modify and their scope Special emphasis has been given to synthetic polyester PCL, as it is widely demonstrated in its modified form to overcome its problem of hydrophobicity and much slower degradation over the past decade Past studies show a significantly higher utility of modified form of PCL in compari
TL;DR: Western blotting and semiquantitative PCR analysis clearly indicate that COP bandage can efficiently quench free radicals leading to reduced antioxidative enzyme activity and indicates that such a versatile approach may seed new arena for topical wound healing in the near future.
Abstract: Wound healing is an intricate multistage process that includes inflammation, cell proliferation, matrix deposition and remodeling phases. It is often associated with oxidative stress and consequent prolonged inflammation, resulting in impaired wound healing. Curcumin has been reported to improve wound healing in different animal models. In order to increase the efficacy of curcumin in the healing arena a curcumin loaded oleic acid based polymeric (COP) bandage was formulated. The in vivo wound healing potency was compared with void bandage and control (cotton gauze treatment) in a rat model. Biochemical parameters and histological analysis revealed increased wound reduction and enhanced cell proliferation in COP bandage treated groups due to its efficient free radical scavenging properties. Comparative acceleration in wound healing was due to early implementation of fibroblasts and its differentiation (increased level of α-smooth muscle actin). Western blotting and semiquantitative PCR analysis clearly indicate that COP bandage can efficiently quench free radicals leading to reduced antioxidative enzyme activity. Further evidence at mRNA and protein level indicates that our system is potent enough to reduce the inflammatory response mediated by the NFκB pathway during wound healing. With this background, we anticipate that such a versatile approach may seed new arena for topical wound healing in the near future.
TL;DR: How various classes of dendrimers have the potential to improve upon or replace certain antibiotics are described and how the unexplored areas in this field of research will be mentioned to present opportunities for additional studies regarding the use of dendedrimers as antimicrobial agents.
Abstract: The emergence and re-emergence of bacterial strains that are resistant to current antibiotics reveal the clinical need for new agents that possess broad-spectrum antibacterial activity. Furthermore, bacteriophobic coatings that repel bacteria are important for medical devices, as the lifetime, reliability, and performance of implant devices are hindered by bacterial adhesion and infection. Dendrimers, a specific class of monodisperse macromolecules, have recently shown potential to function as both antibacterial agents and antimicrobial surface coatings. This review discusses the limitations with currently used antibacterial agents and describes how various classes of dendrimers, including glycodendrimers, cationic dendrimers, anionic dendrimers, and peptide dendrimers, have the potential to improve upon or replace certain antibiotics. Furthermore, the unexplored areas in this field of research will be mentioned to present opportunities for additional studies regarding the use of dendrimers as antimicrobial agents.
TL;DR: A general evolutionary game theory framework of a double bind is presented to study the effect that such an approach would have in cancer and an explanation for its effectiveness based on the commensalistic relationship between the tumor phenotypes is provided.
Abstract: Although many anticancer therapies are successful in killing a large percentage of tumor cells when initially administered, the evolutionary dynamics underpinning tumor progression mean that, often, resistance is an inevitable outcome. Research in the field of ecology suggests that an evolutionary double bind could be an effective way to treat tumors. In an evolutionary double bind two therapies are used in combination such that evolving resistance to one leaves individuals more susceptible to the other. In this paper we present a general evolutionary game theory framework of a double bind to study the effect that such an approach would have in cancer. Furthermore we use this mathematical framework to understand recent experimental results that suggest a synergistic effect between a p53 cancer vaccine and chemotherapy. Our model recapitulates the latest experimental data and provides an explanation for its effectiveness based on the commensalistic relationship between the tumor phenotypes.
TL;DR: Study of the effect of folic acid functionalization on transcellular transport of nanoparticle-encapsulated paclitaxel and surface-functionalized poly(D,L-lactide-co-glycolide) nanoparticles showed the potential to enhance the oral absorption of drugs with poor oral bioavailability.
Abstract: The oral absorption of drugs that have poor bioavailability can be enhanced by encapsulation in polymeric nanoparticles. Transcellular transport of nanoparticle-encapsulated drug, possibly through transcytosis, is likely the major mechanism through which nanoparticles improve drug absorption. We hypothesized that the cellular uptake and transport of nanoparticles can be further increased by targeting the folate receptors expressed on the intestinal epithelial cells. The objective of this research was to study the effect of folic acid functionalization on transcellular transport of nanoparticle-encapsulated paclitaxel, a chemotherapeutic with poor oral bioavailability. Surface-functionalized poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles loaded with paclitaxel were prepared by the interfacial activity assisted surface functionalization technique. Transport of paclitaxel-loaded nanoparticles was investigated using Caco-2 cell monolayers as an in vitro model. Caco-2 cells were found to express folate receptor and the drug efflux protein, p-glycoprotein, to high levels. Encapsulation of paclitaxel in PLGA nanoparticles resulted in a 5-fold increase in apparent permeability (Papp) across Caco-2 cells. Functionalization of nanoparticles with folic acid further increased the transport (8-fold higher transport compared to free paclitaxel). Confocal microscopic studies showed that folic acid functionalized nanoparticles were internalized by the cells and that nanoparticles did not have any gross effects on tight junction integrity. In conclusion, our studies indicate that folic acid functionalized nanoparticles have the potential to enhance the oral absorption of drugs with poor oral bioavailability.
TL;DR: The effect of a functional self-assembled protein coating on the intravenous biodistribution of (18)F-labeled thermally hydrocarbonized porous silicon (THCPSi) nanoparticles in rats is reported and it is revealed that certain opsonins and apolipoproteins are enriched in HFBII-functionalized nanoparticles, whereas the adsorption of abundant plasma components such as serum albumin and fibrinogen is decreased.
Abstract: Rapid immune recognition and subsequent elimination from the circulation hampers the use of many nanomaterials as carriers to targeted drug delivery and controlled release in the intravenous route. Here, we report the effect of a functional self-assembled protein coating on the intravenous biodistribution of 18F-labeled thermally hydrocarbonized porous silicon (THCPSi) nanoparticles in rats. 18F-Radiolabeling enables the sensitive and easy quantification of nanoparticles in tissues using radiometric methods and allows imaging of the nanoparticle biodistribution with positron emission tomography. Coating with Trichoderma reesei HFBII altered the hydrophobicity of 18F-THCPSi nanoparticles and resulted in a pronounced change in the degree of plasma protein adsorption to the nanoparticle surface in vitro. The HFBII-THCPSi nanoparticles were biocompatible in RAW 264.7 macrophages and HepG2 liver cells making their intravenous administration feasible. In vivo, the distribution of the nanoparticles between the l...
TL;DR: RPDSG/DOX nanoparticles display significantly higher anticancer efficacy than that of free DOX at concentrations higher than 5 μM and could be a promising nanotherapeutic for tumor-targeted chemotherapy.
Abstract: To mimic the clinic dosing pattern, initially administering high loading dose and then low maintenance dose, we designed a novel poly(2-(pyridin-2-yldisulfanyl)ethyl acrylate) (PDS) based nanoparticle delivery system. Side chain functional PDS was synthesized by free radical polymerization. Polyethylene glycol and cyclo(Arg-Gly-Asp-d-Phe-Cys) (cRGD) peptide was conjugated to PDS through thiol-disulfide exchange reaction to achieve RPDSG polymer. RPDSG/DOX, RPDSG nanoparticle loaded with doxorubicin, was fabricated by cosolvent dialysis method. The size of the nanoparticles was 50.13 ± 0.5 nm in PBS. The RPDSG/DOX nanoparticle is stable in physiological condition while quickly releasing doxorubicin with the trigger of acidic pH and redox potential. Furthermore, it shows a two-phase release kinetics, providing both loading dose and maintenance dose for cancer therapy. The conjugation of RGD peptide enhanced the cellular uptake and nuclear localization of the RPDSG/DOX nanoparticles. RPDSG/DOX exhibits IC(50) close to that of free doxorubicin for HCT-116 colon cancer cells. Due to the synergetic effect of RGD targeting effect and its two-phase release kinetics, RPDSG/DOX nanoparticles display significantly higher anticancer efficacy than that of free DOX at concentrations higher than 5 μM. These results suggest that RPDSG/DOX could be a promising nanotherapeutic for tumor-targeted chemotherapy.
TL;DR: The positive results of the study strengthen the expectation that the developed formulation strategy can be fruitfully exploited to improve the oral deliverability of poorly bioavailable drugs and can open new vistas for oral chemotherapy.
Abstract: The present study explores the potential of polyelectrolyte-coated liposomes for improving the oral deliverability of doxorubicin (Dox). As a part of formulation strategy, stearyl amine was selecte...
TL;DR: The Bayesian classifier, employing molecular fingerprints, highlights the important structural fragments favorable or unfavorable for hERG potassium channel blockage, which offers extra valuable information for the design of compounds avoiding undesirable hERG activity.
Abstract: Inhibition of the human ether-a-go-go related gene (hERG) potassium channel may result in QT interval prolongation, which causes severe cardiac side effects and is a major problem in clinical studies of drug candidates. The development of in silico tools to filter out potential hERG potassium channel blockers in early stages of the drug discovery process is of considerable interest. Here, a diverse set of 806 compounds with hERG inhibition data was assembled, and the binary hERG classification models using naive Bayesian classification and recursive partitioning (RP) techniques were established and evaluated. The naive Bayesian classifier based on molecular properties and the ECFP_8 fingerprints yielded 84.8% accuracy for the training set using the leave-one-out (LOO) cross-validation procedure and 85% accuracy for the test set of 120 molecules. For the two additional test sets, the model achieved 89.4% accuracy for the WOMBAT-PK test set, and 86.1% accuracy for the PubChem test set. The naive Bayesian cl...
TL;DR: These studies further elucidate the role of polymer structure for gene delivery and highlight that small molecule end-group modification of a linear polymer can be critical for cellular uptake in a manner that is largely independent of polymer/DNA binding, particle size, and particle surface charge.
Abstract: Development of nonviral particles for gene delivery requires a greater understanding of the properties that enable gene delivery particles to overcome the numerous barriers to intracellular DNA delivery. Linear poly(beta-amino) esters (PBAE) have shown substantial promise for gene delivery, but the mechanism behind their effectiveness is not well quantified with respect to these barriers. In this study, we synthesized, characterized, and evaluated for gene delivery an array of linear PBAEs that differed by small changes along the backbone, side chain, and end group of the polymers. We examined particle size and surface charge, polymer molecular weight, polymer degradation rate, buffering capacity, cellular uptake, transfection, and cytotoxicity of nanoparticles formulated with these polymers. Significantly, this is the first study that has quantified how small differential structural changes to polymers of this class modulate buffering capacity and polymer degradation rate and relates these findings to ge...
TL;DR: Low molecular-weight chitosan (LMWC) is proposed as an alternative surface coating, which can protect the nanomedicine in neutral pH but allow cellular interactions in the weakly acidic pH of tumors.
Abstract: When a nanoparticle is developed for systemic application, its surface is typically protected by polyethylene glycol (PEG) to help their prolonged circulation and evasion of immune clearance. On the other hand, PEG can interfere with interactions between nanocarriers and target cells and negatively influence the therapeutic outcomes. To overcome this challenge, we propose low molecular-weight chitosan (LMWC) as an alternative surface coating, which can protect the nanomedicine in neutral pH but allow cellular interactions in weakly acidic pH of tumors. LMWCs with a molecular weight of 2–4 kDa, 4–6.5 kDa, and 11–22 kDa were produced by hydrogen peroxide digestion and covalently conjugated with poly(lactic-co-glycolic acid) (PLGA). Nanoparticles created with PLGA-LMWC conjugates showed pH-sensitive cell interactions, which enabled specific drug delivery to cells in a weakly acidic environment. The hydrophilic LMWC layer reduced opsonization and phagocytic uptake. These properties qualify LMWCs as a promising biomaterial for pH-sensitive stealth coating.
TL;DR: The potential use of pbFGF-loaded electrospun fibrous mats to accelerate the healing of skin ulcers for patients with diabetic mellitus is demonstrated.
Abstract: Deep or chronic skin wounds are difficult to heal spontaneously due to the lack of scaffold to guide cell growth and reduced levels and activities of endogenous growth factors. Emulsion electrospinning process integrated with DNA condensation techniques indicated potentials to gradually release DNA, but no attempt has been made to clarify the advantages in promoting tissue regeneration and wound recovery. In this study, polyplexes of basic fibroblast growth factor-encoding plasmid (pbFGF) with poly(ethylene imine) were incorporated into electrospun fibers with a core-sheath structure, and poly(ethylene glycol) was included into the fiber sheath to allow a sustained release of pbFGF for 4 weeks. In vitro tests on mouse embryo fibroblasts indicated that pbFGF-loaded fibrous mats enhanced cell proliferation by the autocrine bFGF, and an effective cell transfection proceeded for over 28 days. Skin wounds were created in the dorsal area of diabetic rats for in vivo evaluation of skin regeneration after being covered with pbFGF-loaded fibrous mats. The gradual pbFGF release revealed significantly higher wound recovery rate with improved vascularization, enhanced collagen deposition and maturation, complete re-epithelialization and formation of skin appendages. The above results demonstrate the potential use of pbFGF-loaded electrospun fibrous mats to accelerate the healing of skin ulcers for patients with diabetic mellitus.
TL;DR: The data suggest that digestion acts as a "trigger" for enhanced supersaturation and that solubilization/precipitation behavior is correlated with the degree of supersaturation on dispersion (S(M)DISP) or digestion (S (M)DIGEST).
Abstract: The generation of supersaturation in the gastrointestinal (GI) tract is an increasingly popular means of promoting oral absorption for poorly water-soluble drugs. The current study examined the impact of changes to the quantities of medium-chain (MC) lipid (Captex 300:Capmul MCM), surfactant (Cremophor EL) and cosolvent (EtOH), and the addition of polymeric precipitation inhibitors (PPI), on supersaturation during the dispersion and digestion of MC self-emulsifying drug delivery systems (SEDDS) containing danazol. The data suggest that digestion acts as a “trigger” for enhanced supersaturation and that solubilization/precipitation behavior is correlated with the degree of supersaturation on dispersion (SMDISP) or digestion (SMDIGEST). The ability of the formulation to maintain solubilization in vitro decreased as the SM of the formulation increased. PPI significantly increased supersaturation stabilization and precipitation was inhibited where SMDISP < 3.5 and SMDIGEST < 4. In the presence of polymer, som...
TL;DR: The results show that covalently linked pyropheophorbide a molecule not only is stable but also retains its spectroscopic and functional properties, and may provide a powerful alternative for near-infrared photodynamic therapy with an improved tumor targeting specificity.
Abstract: Near-infrared (NIR)-to-visible upconversion nanoparticle (UCNP) has shown promising prospects in photodynamic therapy (PDT) as a drug carrier or energy donor. In this work, a photosensitizer pyropheophorbide a (Ppa) and RGD peptide c(RGDyK) comodified chitosan-wrapped NaYF4:Yb/Er upconversion nanoparticle UCNP-Ppa-RGD was developed for targeted near-infrared photodynamic therapy. The properties of UCNP-Ppa-RGD, such as morphology, stability, optical spectroscopy and singlet oxygen generation efficiency, were investigated. The results show that covalently linked pyropheophorbide a molecule not only is stable but also retains its spectroscopic and functional properties. In vitro studies confirm a stronger targeting specificity of UCNP-Ppa-RGD to integrin αvβ3-positive U87-MG cells compared with that in the corresponding negative group. The photosensitizer-attached nanostructure exhibited low dark toxicity and high phototoxicity against cancer cells upon 980 nm laser irradiation at an appropriate dosage. The...
TL;DR: P pH-dependent permeability and solubility criteria that can be used to assign provisional biopharmaceutics class at early stage of the drug discovery process are identified.
Abstract: The Biopharmaceutics Classification System (BCS) is a scientific framework that provides a basis for predicting the oral absorption of drugs. These concepts have been extended in the Biopharmaceutics Drug Disposition Classification System (BDDCS) to explain the potential mechanism of drug clearance and understand the effects of uptake and efflux transporters on absorption, distribution, metabolism, and elimination. The objective of present work is to establish criteria for provisional biopharmaceutics classification using pH-dependent passive permeability and aqueous solubility data generated from high throughput screening methodologies in drug discovery settings. The apparent permeability across monolayers of clonal cell line of Madin–Darby canine kidney cells, selected for low endogenous efflux transporter expression, was measured for a set of 105 drugs, with known BCS and BDDCS class. The permeability at apical pH 6.5 for acidic drugs and at pH 7.4 for nonacidic drugs showed a good correlation with the...
TL;DR: A novel approach to synthesize a polyvalent G5-MTX(n) conjugate through click chemistry, attaching the MTX to the dendrimer through an esterase-stable amide linkage, which may serve as a FR-targeted chemotherapeutic with potential for cancer therapy.
Abstract: Our previous studies have demonstrated that a generation 5 dendrimer (G5) conjugated with both folic acid (FA) and methotrexate (MTX) has a higher chemotherapeutic index than MTX alone Despite this, batch-to-batch inconsistencies in the number of FA and MTX molecules linked to each dendrimer led to conjugate batches with varying biological activity, especially when scaleup synthesis was attempted Since the MTX is conjugated through an ester linkage, there were concerns that biological inconsistency could also result from serum esterase activity and differential bioavailability of the targeted conjugate In order to resolve these problems, we undertook a novel approach to synthesize a polyvalent G5–MTXn conjugate through click chemistry, attaching the MTX to the dendrimer through an esterase-stable amide linkage Surface plasmon resonance binding studies show that a G5–MTX10 conjugate synthesized in this manner binds to the FA receptor (FR) through polyvalent interaction showing 4300-fold higher affinity
TL;DR: The current work shows that 30 nm PEGylated gold NPs interact not only with blood proteins as thought before but also with blood cells (especially platelets and monocytes) in vivo and that longer blood circulation correlates strongly with tumor uptake.
Abstract: Theranostic nanoparticles (NPs) cannot reach their target tissue without first passing through blood; however, the influence of blood protein and blood cell interactions on NP biodistribution are not well understood. The current work shows that 30 nm PEGylated gold NPs (GNPs) interact not only with blood proteins as thought before but also with blood cells (especially platelets and monocytes) in vivo and that longer blood circulation correlates strongly with tumor uptake. Further, GNP surface properties such as negative charge or lyophilization had either a minimal (i.e., charge) or 15-fold increase (i.e., fresh vs lyophilized) in blood retention times and tumor uptake. Tumor accumulation was increased over 10-fold by use of a bioactive ligand (i.e., TNF) on the lyophilized GNP surface. Resident macrophages were primarily responsible for the bulk of GNP uptake in liver while spleen uptake was highly surface property dependent and appears to involve macrophages and cellular interaction between the red and ...
TL;DR: Overall, this study for the first time reports a natural protein core based polymeric micelle and demonstrates its application for the delivery of hydrophobic anticancer drugs such as curcumin.
Abstract: Novel biodegradable micelles were synthesized by conjugating methoxy poly(ethylene glycol) (mPEG) to zein, a biodegradable hydrophobic plant protein. The mPEG–zein micelles were in the size range of 95–125 nm with a low CMC (5.5 × 10–2 g/L). The micelles were nonimmunogenic and were stable upon dilution with buffer as well as 10% serum. Curcumin, an anticancer agent with multiple delivery challenges, was encapsulated in mPEG–zein micelles. The micelles significantly enhanced the aqueous solubility (by 1000–2000-fold) and stability (by 6-fold) of curcumin. PEG–zein micelles sustained the release of curcumin up to 24 h in vitro. Curcumin-loaded mPEG–zein micelles showed significantly higher cell uptake than free curcumin in drug-resistant NCI/ADR-RES cancer cells in vitro. Micellar curcumin formulation was more potent than free curcumin in NCI/ADR-RES cancer cells, as evidenced from the 3-fold reduction in IC50 value of curcumin. Overall, this study for the first time reports a natural protein core based po...
TL;DR: Recommendations are proposed as to the suggested approach to develop dendrimers as tumor targeted drug-delivery vectors as a systematic review toward which drug association approach will provide the best outcomes in terms of antitumor efficacy and systemic toxicity.
Abstract: Cancer is a leading cause of death within developed nations, and part of this morbidity is due to difficulties associated with its treatment. Currently, anticancer therapy relies heavily upon the administration of small molecule cytotoxic drugs that attack both cancerous and noncancerous cells due to limited selectivity of the drugs and widespread distribution of the cytotoxic molecules throughout the body. The antitumor efficacy and systemic toxicity of existing chemotherapeutic drugs can, however, be improved by employing formulation and particle engineering approaches. Thus, drug delivery systems can be developed that more specifically target tumor tissue using both passive (such as the enhanced permeation and retention effect) and active (through the use of cancer targeting ligands) modalities. Dendrimers are one such system that can be developed with high structural monodispersity, long plasma circulation times and precise control over surface structure and biodistribution properties. Chemotherapeutic drugs can be associated with dendrimers via covalent conjugation to the surface, or via encapsulation of drugs within the structure. Each of these approaches has demonstrated therapeutic benefit relative to the administration of free drug. Thus far, however, there has not been a systematic review toward which drug association approach will provide the best outcomes in terms of antitumor efficacy and systemic toxicity. Hence, the current literature is reviewed here and recommendations are proposed as to the suggested approach to develop dendrimers as tumor targeted drug-delivery vectors.
TL;DR: In vitro macrophage uptake studies, cytotoxicity and in vitro TNF-α assays revealed promising biointeractions for the respirable/swellable nano-micro particles developed in this study as potential carriers for sustained pulmonary drug delivery.
Abstract: This study involves a promising approach to achieve sustained pulmonary drug delivery. Dry powder particulate carriers were engineered to allow simultaneous aerosol lung delivery, evasion of macrophage uptake, and sustained drug release through a controlled polymeric architecture. Chitosan grafted with PEG was synthesized and characterized (FTIR, EA, DSC and 2D-XRD). Then, a series of respirable amphiphilic hydrogel microparticles were developed via spray drying of curcumin-loaded PLGA nanoparticles with chitosan-grafted-PEG or chitosan. The nanoparticles and microparticles were fully characterized using an array of physicochemical analytical methods including particle size, surface morphology, dynamic swelling, density, moisture content and biodegradation rates. The PLGA nanoparticles and the hydrogel microspheres encapsulating the curcumin-loaded PLGA nanoparticles showed average size of 221-243 nm and 3.1-3.9 μm, respectively. The developed carriers attained high swelling within a few minutes and showed low moisture content as dry powders (0.9-1.8%), desirable biodegradation rates, high drug loading (up to 97%), and good sustained release. An aerosolization study was conducted using a next generation impactor, and promising aerosolization characteristics were shown. In vitro macrophage uptake studies, cytotoxicity and in vitro TNF-α assays were performed for the investigated particles. These assays revealed promising biointeractions for the respirable/swellable nano-micro particles developed in this study as potential carriers for sustained pulmonary drug delivery.