[Show abstract][Hide abstract] ABSTRACT: The combination of natural and synthetic biomaterials leads to the formation of advanced Drug Delivery nano Systems (aDDnSs). The aDDnSs can be classified as hybridic (hy‐) or chimeric (chi‐) based on the nature – same or different respectively ‐ of biomaterials used. Such advanced bio complexes can alter the pharmacokinetic properties of the encapsulated drug and consequently its effectiveness. Numerous studies regarding the usage of natural or synthetic biomaterials as drug carriers have been performed, while only few studies concerning the combination of different kinds of biomaterials have been published. Carriers produced by the combination of liposomes and dendrimers were recently characterized as chi‐aDDnSs belonging to the class of Modulatory Liposomal Controlled Released Systems (MLCRSs) where the polymeric or the dendritic component act as modulator of the drug's release from the carrier. A small but significant number of studies have begun to shed light on the interactions between the components of the bio complexes that seem to be of utmost importance for the pharmacological effectiveness of the final formulation. This review deals with the categorization of the aDDnSs, the nature of the interacting forces between them and their potential biomedical applications.
Dendrimers in Biomedical Applications, Edited by Barbara Klajnert, Ling Peng, Valentin Cena, 05/2013: pages 30-39; RSC Publishung., ISBN: 978-1-84973-611-4
[Show abstract][Hide abstract] ABSTRACT: The aim of this work is to study the morphological characteristics via fractal analysis and the alterations of the thermotropic behavior of dipalmitoylphosphatidylcholine (DPPC) liposomes, caused by the incorporation of cholesterol, poly(amidoamine) (PAMAM) dendrimer, and MPOx (poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline)) gradient block copolymer (9:1 molar ratio). A gamut of light scattering techniques and differential scanning calorimetry were used in order to extract information on the morphological (in different dispersion media) and thermodynamic characteristics of liposomal drug nanocarriers, respectively. The vesicles’ structure of liposomes has a different thermodynamic content, which corresponds to a different thermotropic behavior, in comparison to pure lipid bilayers. The observed metastable phase only for DPPC liposomes has been considered as a “physical impurity”, which leads to “physical incompatibility” and consequently promotes the aggregation of DPPC liposomes in aqueous media. The incorporation of biomaterials such as PAMAM G4 and MPOx, caused alterations in the thermotropic behavior of DPPC liposomes affecting only the main transition specific enthalpy ΔH. All the other calorimetric parameters remained unaltered. These findings supported the hypothesis that the exceptional stability and transition cooperativity of the chimeric liposomal membrane might be due to the reduction of the vesicle size with the smaller membrane curvature that is indicated by the fractal dimensionality of the system. In conclusion, the results from the thermal analysis of the liposomal systems were in line with the picture of their structural characteristics, as indicated by the interplay between physicochemical and thermodynamical parameters, which determines their fractal morphology.
Journal of Thermal Analysis and Calorimetry 04/2013; · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: New nano-scale drug carriers offer the possibility of increasing the therapeutic index of drug molecules by increasing their effectiveness, diminishing their toxicity against physiological tissues and achieving controlled therapeutic levels for a prolonged time. This review gives an overview of approaches to the development of these novel complex nanocarriers with emphasis on those involving dendrimers and related systems. The combination of two of more nano-sized units for producing an overall system with unique properties could be advantageous compared to more simple nanotechnology-based carriers. Recent advances in medicinal chemistry offer the possibility of exact tailoring of the properties of such complex systems which, in conjunction with full physicochemical characterization, may lead to novel and highly effective drug products. An assessment is given of the potential of systems such as chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) for the delivery of drugs compared with conventional carriers. Rational synthesis of molecules that can act as modulators of the properties of chi-aDDnSs and may be the future in the design and development of nanocarriers, not only for the delivery of drug molecules but also for genetic material and imaging agents.
Current Medicinal Chemistry 09/2012; · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Large unilamellar liposomes and multilamellar vesicles consisting of DMPC interacted with cationic phosphorus-containing dendrimers CPDs G3 and G4. DSC and ζ-potential measurements have shown that liposomal-dendrimeric molecular recognition probably occurs due to the interaction between the complementary surface groups. Calorimetric studies indicate that the enthalpy of the transition of the lipids that interact with CPDs is dependent on the dendrimers generation. These results can be used in order to rationally design mixed modulatory liposomal locked-in dendrimeric, drug delivery nano systems.
Chemistry and Physics of Lipids 12/2011; 165(4):408-13. · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) could be defined as mixed nanosystems due to the combination process of nanobiomaterials and can offer advantages as drug carriers. The role of the release modulator from the liposomal system is undertaken by the dendrimer molecules leading to new pharmacokinetic and, probably, pharmacological properties of the chimeric system. In this work, a conventional DOPC/DPPG liposomal system and a new chi-aDDnS composed of liposomes (DOPC/DPPG) incorporating PAMAM G3,5 has been developed, Doxorubicin (Dox) was loaded in the systems and the final formulations were lyophilized. The physicochemical (spectroscopic and calorimetric) investigation concerning the chi-aDDnS, revealed a strong interaction between both lipophilic and hydrophilic parts of the liposomal membrane and the dendrimer, with the induction of multiple energetic states. These states are probably the basis of higher Dox encapsulation and slower release rate compared to the respective conventional liposome. These results, in conjunction with the increase in TI observed in two investigated cancer cell lines (i.e., MB231 and MCF7), compared to the respective conventional liposomal system and to the free Dox, make this new chi-aDDnS the basic candidate for further in vivo investigations.
Journal of Nanoscience and Nanotechnology 05/2011; 11(5):3764-72. · 1.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The influence of cationic phosphorus-containing dendrimers generation 3 and 4 on model DMPC or DPPC lipid membranes was studied. Measurements of fluorescence anisotropy and differential scanning calorimetry (DSC) were applied to assess changes in lipid bilayer parameters, including fluidity, anisotropy, and phase-transition temperature. Interaction with both hydrophobic and hydrophilic regions of the bilayer was followed by these methods. Dendrimers of both generations influence lipid bilayers by decreasing membrane fluidity. The results suggest that dendrimers can interact both with the hydrophobic part and the polar head-group region of the phospholipid bilayer. Higher generation dendrimers interact more strongly with model membranes, and the concentration, as well as the generation, is of similar importance.
Biochimica et Biophysica Acta 03/2011; 1811(3):221-6. · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the rapid development of modern pharmaceutics, delivery of drugs to sites of action is not always effective. The research on new targeting delivery systems of pharmacologically active molecules is of great importance. Surface properties such as surface charge of drug delivery particles frequently define their pharmacokinetic profile; hence the efficiency of drugs can be increased by application of nanoparticles having appropriate surface properties. The aim of the present work was to study the interactions of cationic phosphorus-containing dendrimers (CPD) with model lipid membranes with no charge or bearing surface charge. The interactions of two generations of phosphorus dendrimers on the thermotropic behavior of model lipid membranes composed of DMPC (uncharged) or DMPC/DPPG (negatively charged) were studied using differential scanning calorimetry (DSC). The results of this study showed that CPDs can alter the thermotropic behaviour of the bilayer by reducing the cooperativity of phospholipids and this effect strongly depends on membrane surface charge. The information resulting from this study may be applied to the rational design of new drug carriers combining liposomal and dendrimeric technology.
[Show abstract][Hide abstract] ABSTRACT: A new Liposomal-Locked in-Dendrimer (LLD) formed by DPPC-DPPG and PAMAM 3.5 incorporating the anticancer drug DOX was studied by means of spectroscopic and DSC investigations. Multilamellar Lipid Bilayers were also considered for the sake of comparison. The results were in line with a picture of phase separation between DPPC-DPPG lipids and dendrimer that promotes the stability of the liposome membrane and the cooperativity of the relevant gel-to-liquid-crystal transition, which is enhanced in the presence of the dendrimer and the drug. As a result, the inner core of the liposome contained large amounts of dendrimer-DOX complex and was protected by a very stable membrane. This view was given a more general validation through investigations performed with other types of dendrimers, namely PG1 and PG2. The thermodynamic interpretation of the DSC data allowed a better understanding of the physico-chemical factors that justify this behaviour that makes these LLDs very promising as a new class of Modulatory Liposomal Controlled Release System (MLCRS) that could lead to drug formulations with higher safety and efficacy profiles.
[Show abstract][Hide abstract] ABSTRACT: Since the late 1960s, the field of drug delivery has focused on the creation of new formulations with improved properties, taking much attention to drug release from the carrier. Liposomes and dendrimers represent two of the most studied drug carriers. A Modulatory Liposomal Controlled Release System (MLCRS) combining liposomal and dendrimeric technology has been recently published as well as Liposomal locked-in Dendrimers (LLDs) technology which was considered to be a class of MLCRSs. Chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) can be defined as mixed nanosystems due to the combination of the bionanomaterials used and can offer advantages as drug carriers. This work deals with the production of two new chi-aDDnSs incorporating the newly synthesized dendrimer PG1. One of the two formulations bears the exact lipidic composition as the commercial liposomal drug "Myocet". Doxorubicin (Dox) was incorporated into conventional (free of dendrimer) liposomal formulations and into the corresponding chi-aDDnSs, and the physicochemical characteristics, the in vitro drug release and the in vitro cytotoxicity against human cancer cell lines were assessed. The results revealed a different modulation release effect of doxorubicin from the chi-aDDnS, compared to the Myocet replica. Pharmacological cytotoxicity concerning all the chi-aDDnSs was very close to that of the conventional liposomal systems.
International Journal of Pharmaceutics 10/2010; 402(1-2):231-7. · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Liposomal locked-in dendrimers (LLDs), the combination of liposomes and dendrimers in one formulation, represents a relatively new term in the drug carrier technology. LLDs undergone appropriate physicochemical investigation can merge the benefits of liposomal and dendrimeric nanocarriers. In this study generation 1 and 2 hydroxy-terminated dendrimers were synthesized and were then "locked" in liposomes consisting of DOPC/DPPG. The anticancer drug doxorubicin (Dox) was loaded into pure liposomes or LLDs and the final products were subjected to lyophilization. The loading of Dox as well as its in vitro release rate from all systems was determined and the interaction of liposomes with dendrimers was assessed by thermal analysis and fluorescence spectroscopy. The results were very promising in terms of drug encapsulation and release rate, factors that can alter the therapeutic profile of a drug with low therapeutic index such as Dox. Physicochemical methods revealed a strong, generation dependent, interaction between liposomes and dendrimers that probably is the basis for the higher loading and slower drug release from the LLDs comparing to pure liposomes.
Journal of Pharmaceutical Sciences 08/2010; 99(8):3561-71. · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Curcumin is a natural compound with biological activities and potent anticancer effects that has the drawback of poor water solubility which leads to low bioavailability. In this work curcumin was formulated in new physicochemically characterized micellar carriers composed of new synthetic block copolymers. The study of the in vitro release rate of curcumin from the formulas, as well as the in vitro activity of free curcumin and of curcumin-loaded into micelles, against a panel of colorectal cancer cell lines was also part of this study. New β—lactam functionalized poly(isoprene-b-ethylene oxide) amphiphilic block copolymers, were synthesized by the combination of anionic polymerization and selective postpolymerization functionalization of the polyisoprene block with chlorosulfonylisocyanate. Micelles composed of the synthetic copolymers were formulated in order to incorporate curcumin. As the results revealed, increase in the percentage of the lipophilic block of micelles, led to higher encapsulation efficiency and loading capacity while the size was found to be smaller and the in vitro release rate slower. In vitro cytotoxicity results showed similar or slightly higher activity for curcuminloaded into micelles than free curcumin, a fact that could be attributed to the similar in vitro cellular uptake profiles of curcumin and of curcumin-loaded into micelles.
Current Nanoscience 05/2010; 6(3):277-284. · 1.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the present work was to study the interaction between PAMAM generation 4 (G4) dendrimer with model lipid membranes (DPPC) for designing new controlled released systems for bioactive molecules by combining dendrimer and liposomal technologies. Thermal analysis and Raman spectroscopy were applied to assess the thermodynamic changes caused by PAMAM G4 (polyamidoamines) dendrimer and to specify the exact location of this dendrimer into the DPPC lipid bilayer. DSC thermograms indicated that the maximum percent of PAMAM G4 that can be incorporated in the DPPC membrane without deranging its integrity is 5%. The Raman intensity ratios I 2935 / 2880 and I 1090/1130 cm 1 showed the degree of the fluidity of the lipid bilayer, while the absorption at 715 cm 1 showed a strong interaction of PAMAM G4 with the polar head group of phospholipid. The results showed that the incorporation of the PAMAM G4 dendrimer in DPPC bilayers causes a concentration dependent increase of the membrane fluidity and they interact strongly with both the lipophilic part and the polar head group of the phospholipids. Additionally, due to the current weak knowledge of how dendrimers interact with lipidic membranes these results may justify the tendency of dendrimers to disrupt biological membranes.
[Show abstract][Hide abstract] ABSTRACT: The interaction between PAMAM (polyamidoamine) dendrimer generation 4 (G4) and 3,5 (G3,5) with model lipid membranes composed of dipalmytoylphosphatidylcholine (DPPC) has been investigated. Differential scanning calorimetry (DSC) and Raman spectroscopy were applied to assess the thermodynamic changes caused by PAMAM G4 and G3,5 and to specify the exact location of these dendrimers into the DPPC lipid bilayer. DSC thermograms indicated that the maximum percentages of PAMAM G4 and of G3,5 that can be incorporated in the DPPC membrane without deranging its integrity were 5% and 3%, respectively. The Raman intensity ratios I(2935/2880), I(2844/2880) and I(1090/1130) cm(-1) showed the degree of the fluidity of the lipid bilayer, while the absorption at 715 cm(-1) showed a strong interaction of PAMAM G4 and G3,5 with the polar head group of phospholipid. The results showed that the incorporation of the PAMAM G4 and G3,5 dendrimers in DPPC bilayers causes a concentration dependent increase of the membrane fluidity and that the bilayers interact strongly with both the lipophilic part and the polar head group of the phospholipids. Due to the current weak knowledge relating to the mechanism(s) under which dendrimers interact with lipidic membranes and transport through cells, these results may justify the tendency of dendrimers to disrupt biological membranes. The findings from this study could also prove helpful to rationally design new liposomal drug carriers for bioactive molecules by combining dendrimeric and liposomal technologies.
International Journal of Pharmaceutics 09/2006; 318(1-2):118-23. · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the molecular interaction of amyloid beta peptides Aβ1–28 or Aβ25–40 with model lipid membranes differential scanning calorimetry (DSC) and DPH and TMA DPH fluorescence anisotropy approaches were used. The main transition temperature (T
m) and enthalpy change (ΔH) of model lipid membranes composed of DMPC/DPPG on addition of Aβ25–40 or Aβ25–40 at 10:1 (w/w) phospholipid/peptide ratio either non-aggregated or previously aggregated were examined. The effect of Aβ1–28 and Aβ25–40 on the membrane fluidity of liposomes made of DMPC/DPPG (98:2 w/w) was determined by fluorescence anisotropy of incorporated DPH and TMA DPH. The results of this study provide information that Aβ1–28 preferentially interacts with the hydrophilic part of the model membranes, while Aβ25–40 rather locates itself in the hydrophobic core of the bilayer where it reduces the order of the phospholipids packing.
Journal of Thermal Analysis and Calorimetry 99(3). · 2.21 Impact Factor