Biomedical subjects

Constantinos M Paleos

Publications and source records attributed to Constantinos M Paleos.

14 recordsLinked to original sources

PubMed2007

Molecular engineering of dendritic polymers and their application as drug and gene delivery systems.

This review discusses the development of functional and multifunctional dendrimeric and hyperbranched polymers, collectively called dendritic polymers, with the objective of being applied as drug and gene delivery systems. In particular, using as starting materials known and well-characterized basic dendritic polymers, the review deals with the type of structural modifications to which these dendritic polymers were subjected for the development of drug carriers with low toxicity, high encapsulating capacity, a specificity for certain biological cells, and the ability to be transported through their membranes. Proceeding from functional to multifunctional dendritic polymers, one is able to prepare products that fulfill one or more of these requirements, which an effective drug carrier should exhibit. A common feature of the dendritic polymers is the exhibition of polyvalent interactions, while for multifunctional derivatives, a number of targeting ligands determine specificity, another type of group secures stability in biological milieu and prolonged circulation, while others facilitate their transport through cell membranes. Furthermore, dendritic polymers employed for gene delivery should be or become cationic in the biological environment for the formation of complexes with the negatively charged genetic material.

Animals↗

PubMed2006

Modeling cell membrane transport: interaction of guanidinylated poly(propylene imine) dendrimers with a liposomal membrane consisting of phosphate-based lipids.

Mixed anionic liposomes consisting of dihexadecyl phosphate, phosphatidylcholine, and cholesterol were employed as model systems for assessing the ability of a series of functionalized dendrimers, bearing a varying number of guanidinium groups at their surface, to translocate across the liposomal bilayers. At low guanidinium/phosphate molar ratios or when weakly guanidinylated dendrimeric derivatives were employed, the dendrimeric derivative acted as a kind of "molecular glue" leading to a simple adhesion of the liposomes. Liposomal fusion occurred to a certain extent at high guanidinium/phosphate molar ratios or when highly guanidinylated dendrimeric derivatives were employed. Furthermore, translocation of these dendrimeric derivatives to the liposomal core was observed for low to medium guanidinylation and at low guanidinium/phosphate molar ratios which was, however, enhanced when the lipid bilayer was in its fluid liquid-crystalline phase. Thus, an optimum balance is required between the binding strength of guanidinium with the phosphate groups and the degree of hydrophilicity of the guanidinylated dendrimers for the transport of the latter to the liposomal core to occur.

Biological Transport↗

PubMed2006

Synthesis and characterization of guanidinylated poly(propylene imine) dendrimers as gene transfection agents.

Fourth generation poly(propylene imine) dendrimer has been completely or partially functionalized with guanidinium groups. In the second case, the remaining toxic primary amino groups of the dendrimers were reacted with propylene oxide affording the corresponding hydroxylated derivatives. Five derivatives have been prepared bearing 0, 6, 12, 24 or 32 guanidinium groups. These guanidinylated dendrimers were interacted with plasmid DNA affording the corresponding dendriplexes. The complexes were physicochemically characterized by dynamic light scattering, zeta-potential measurements and AFM, while the extent of complexation was evaluated by agarose gel electrophoresis. Furthermore, their transfection efficiency was assessed employing HEK 293 and COS-7 cell lines, while the serum effect was studied in HEK 293 cells. It was found that complete replacement of primary amino groups with the hydroxylated moieties resulted in complete loss of transfection efficiency. On the contrary, guanidinylation of the parent dendrimer resulted to significant enhancement of its transfection efficiency, this enhancement being dependent on the number of guanidinium groups per dendrimer, the cell line used and the presence or absence of FBS. The fully guanidinylated dendrimer exhibited the best transfection efficiency under all the conditions studied. This efficiency has been attributed to the enhanced penetrating ability of the guanidinylated dendrimers due to the accumulation of the guanidinium group at the dendrimeric surface. It was also found that the derivative with 12 guanidinium groups exhibited the lowest toxicity. The reduction of toxicity was apparently attributed to the decrease of the external primary amino groups coupled with the presence of hydroxylated moieties located at the dendrimeric surface. The functionalization strategy employed leads to dendrimeric derivatives that combine satisfactory transfection efficiency and cytotoxicity.

Animals↗

PubMed2006

Novel functional hyperbranched polyether polyols as prospective drug delivery systems.

Multifunctional hyperbranched polyether polyols bearing protective poly(ethylene glycol) (PEG) chains with or without the folate targeting ligand at their end have been prepared. Solubilization in these polymers of a fluorescent probe, pyrene, and an anticancer drug, tamoxifen, was physicochemically investigated. It was found that PEG chains attached at the surface of these hyperbranched polymers, in addition to their well-established protective role, enhance the encapsulation efficiency of the polymers. The release of pyrene and tamoxifen observed upon addition of sodium chloride is, in most of the cases, significant only at concentrations exceeding the physiological extracellular concentration. Thus, a significant amount of the probe or drug remains solubilized inside the carriers, which is an encouraging result if the polymers are to be used for drug delivery.

Antineoplastic Agents↗

PubMed2005

Interaction of functional dendrimers with multilamellar liposomes: design of a model system for studying drug delivery.

Multilamellar liposomes consisting of phosphatidylcholine-cholesterol-dihexadecyl phosphate (19:9.5:1 molar ratio) and dispersed in aqueous or phosphate buffer solutions were interacted with poly(propylene imine) dendrimers which were partially functionalized with guanidinium groups. The remaining toxic external primary amino groups of the dendrimers were reacted with propylene oxide, affording the corresponding hydroxylated derivatives. Microscopic, zeta-potential, and dynamic light scattering techniques have shown that liposomal-dendrimeric molecular recognition occurs due to the interaction between the complementary phosphate and guanidinium groups. Calcein liposomal entrapment experiments demonstrate a limited leakage, i.e., less than 13%, following liposomes interaction with the modified dendrimers. Calorimetric studies indicate that the enthalpy of the interaction is dependent on the number of guanidinium groups present at the dendrimeric surface and the medium. The process is reversible, and redispersion of the aggregates occurs by adding concentrated phosphate buffer. Two corticosteroid drugs, i.e., betamethasone dipropionate and betamethasone valerate, were encapsulated into the functionalized dendrimers. Drug transport from guanidinylated dendrimers to multilamellar liposomes ranges from 40% to 85%, and it is also dependent on the medium and the degree of dendrimer guanidinylation.

Cholesterol↗

PubMed2005

Enhanced drug transport from unilamellar to multilamellar liposomes induced by molecular recognition of their lipid membranes.

Unilamellar PC-based liposomes bearing a recognizable moiety were loaded either with the hydrophilic drug doxorubicin (DXR) or with the hydrophobic drug tamoxiphen (TMX) and allowed to interact with multilamellar PC-based liposomes bearing complementary recognizable groups. It has been established that, due to molecular recognition of these complementary liposomes, effective and fast transport of the drugs occurs from unilamellar to multilamellar liposomes. The transport of TMX is more effective compared to that of DXR. This behavior was observed for both PEGylated and non-PEGylated unilamellar liposomes, and it was attributed to the different sites of solubilization of the drugs in the unilamellar liposomes. PEGylation reduces the transport of both drugs since it inhibits to some extent the molecular recognition effectiveness of the complementary moieties.

Liposomes↗

PubMed2005

Interaction of poly-L-arginine with dihexadecyl phosphate/phosphatidylcholine liposomes.

In the present study, mixed liposomes of dihexadecyl phosphate sodium salt:phosphatidylcholine:cholesterol at a 1:19:9.5 molar ratio were allowed to interact with poly-L-arginine at temperatures below and above the main phase transition of the liposomal membrane. The interaction led to the formation of aggregates, which gradually increased in size and eventually precipitated. It was, however, possible, during the initial stage of the experiments, when the ratio of guanidinium group relative to phosphate was smaller than ca. 40%, to determine their size and charge and observe their morphology in aqueous dispersion. Fluorescence experiments established that the liposomes are not ruptured during their interaction with poly-L-arginine. Instead, they are attached at the polypeptide chain through the guanidinium-phosphate complementary pair. Fluorescence quenching experiments indicated that the poly-L-arginine chain is accessible for interaction with iodides dissolved in the aqueous phase when the temperature of the liposomal dispersion is below the main lipid phase transition. It is, however, partitioned in the interior of the membrane at temperatures exceeding this main lipid phase transition.

Fluorescamine↗

PubMed2005

Interaction of L-arginine with dihexadecylphosphate unilamellar liposomes: the effect of the lipid phase organization.

The interaction of L-arginine with unilamellar liposomes of dihexadecylphosphate sodium salt (DHP-Na) has been investigated using calorimetric, light scattering, fluorescence spectroscopy and zeta-potential techniques. Heating from room temperature, the bilayer exhibits a phase transition from a subgel (L(c)) to the gel (L(beta')) phase as well as a pre-transition (L(beta')-P(beta')), which is followed by the main lipid phase transition (P(beta')-L(alpha)). Direct studies of the interaction of L-arginine with the DHP-Na bilayers via isothermal titration calorimetry at 27 degrees C depict significant differences between samples in the L(c) and the L(beta') phases reflecting the effect of molecular organization of the lipids upon the interaction. While L-arginine has only a small impact upon the L(c) to L(beta') phase transition, it affects more significantly the transition temperature as well as the shape of the DSC peaks of the main lipid phase transition. Based on fluorescence and zeta-potential studies, the permeability of L-arginine through the liposomal membrane is higher within the temperature range of the main lipid phase transition. Encapsulated l-arginine obstructs the formation of the subgel phase.

Arginine↗

PubMed2004

Interactions of complementary PEGylated liposomes and characterization of the resulting aggregates.

The interaction of complementary liposomes bearing both recognizable and protective ligands at their external surface has been investigated. Aggregation of hydrogenated phosphatidyl choline/cholesterol (2:1 molar ratio) based liposomes was mediated by the molecular recognition of the complementary phosphate and guanidinium groups incorporated in separate unilamellar liposomes. The phosphate group was incorporated in the bilayer employing dihexadecyl phosphate, while the guanidinium moiety was introduced in the membrane through the incorporation of various guanidinium lipids. For the latter, anchoring ability and primarily introduction of a spacer group between their lipophilic part and the guanidinium group was found to affect the ability for molecular recognition. Also, poly(ethylene glycol) (PEG) introduced in both types of liposomes at various concentrations and up to 15% with respect to cholesterol modifies the interaction effectiveness and morphology of the obtained aggregates. Interaction of these complementary liposomes leads to large precipitating aggregates or fused liposomes, as shown by phase contrast microscopy and dynamic light scattering. Specifically, fusion of liposomes takes place under a nonleaking process involving lipid mixing, as demonstrated by calcein entrapment and resonance energy transfer experiments. Calorimetric parameters also correlate with the processes of aggregation and fusion. The interactions of non-PEGylated liposomes involve exothermic processes of higher enthalpic content than those of the PEGylated counterparts.

Cholesterol↗

PubMed2004

Hydrogen bonding interactions of liposomes simulating cell-cell recognition. A review.

Amphiphiles bearing polar heads with the property to form hydrogen bond(s) exhibit unique organizational and aggregational behaviour. Thus appropriate amphiphilic molecules assemble and form liposomes, which further interact through hydrogen bonding with complementary molecules or liposomal counterparts affording larger and more elaborated aggregates. A number of examples are demonstrating the interaction mode of liposomes and of associated phenomena as related to the structural features of the supramolecular aggregates obtained. The recognition between cells incorporating recognizable amphiphiles in their membranes has shown similarities to the analogous interactions between liposomes. Thus molecular recognition between liposomes can be used in modeling recognitions occurring between cells. Designed experiments in this area can support the Lipid World Model proposed for the origin of life.

Hydrogen Bonding↗

PubMed2003

Effect of chirality on the structural behaviour of hydrogen-bonded n-alkylammonium pyroglutamates in the crystalline and smectic state.

A set of optically active and racemic n-alkylammonium pyroglutamates from dodecyl to octadecyl were synthesized and characterised. Their thermotropic polymorphism was investigated by polarizing optical microscopy, differential scanning calorimetry and dilatometry. Their structure in the crystalline and smectic state was analysed by X-ray diffraction. The hydrogen bonding of the molecules in the crystalline and smectic layers was examined by infrared spectroscopy. The chirality control over the supramolecular self-assembly of the molecules along with the homochiral and heterochiral architecture of the self-assembled dimers are briefly discussed.

Crystallization↗

PubMed2002

Complementary liposomes based on phosphatidylcholine: interaction effectiveness vs protective coating.

A prospective targeted drug delivery system was prepared by the introduction of complementary and protective moieties at the external surfaces of liposomes. Thus recognition between hydrogenated phosphatidylcholine-cholesterol-based liposomes was achieved by the interaction of the complementary phosphate and guanidinium groups incorporated in separate liposomes while polyethylene glycol chains (PEG) protected both liposomes from environmental factors. In general, protective coating of liposomes in the range of 5% molar incorporation exerted an inhibitory effect on their recognition but it also permitted effective interaction between complementary liposomes.

Cholesterol↗

PubMedDate not supplied

Interaction between complementary liposomes: a process leading to multicompartment systems formation.

Interaction of complementary liposomes induces a series of processes, involving reorganization of their membrane lipids, which lead to the formation of large aggregates. In several cases these aggregates exhibit multicompartment structures and only primitively mimic, in some aspects at least, the multicompartmental features of cells. Similar multicompartment structures were repeatedly obtained following the interaction of a diversity of complementary liposomal pairs. Thus, a working hypothesis is proposed, according to which, molecular recognition of liposomes induces the formation of multicompartment structures.

Cell Compartmentation↗

PubMedDate not supplied

Acid- and salt-triggered multifunctional poly(propylene imine) dendrimer as a prospective drug delivery system.

A novel dendrimeric compound is designed with the objective of simultaneously addressing issues commonly encountered in drug delivery, i.e., stability in biological milieu as well as targeting. For this purpose, a multifunctional dendrimeric system derived from diaminobutane poly(propylene imine) dendrimers (DAB) is prepared bearing at its external surface poly(ethylene glycol) chains and guanidinium moieties. For these moieties, it has been established that they exhibit protective and targeting properties, respectively. The release of encapsulated compounds is triggered by titration with acids followed by the addition of sodium chloride solution. Specifically for pyrene, the solubilization site of which can be clearly traced, protonation leads to a distribution between the core and the poly(ethylene glycol) chains in the periphery of the dendrimer while it is released to the aqueous bulk solution by the addition of sodium chloride. The release of betamethasone valerate is also triggered by the addition of sodium chloride solution.

Acids↗