Karol Ciepluch

In vivo toxicity of poly(propyleneimine) dendrimers

Dendrimers are highly branched macromolecules with the potential to be used for biomedical applications. Several dendrimers are toxic owing to their positively charged surfaces. However, this toxicity can be reduced by coating these peripheral cationic groups with carbohydrate residues. In this study, the toxicity of three types of 4th generation poly (propyleneimine) dendrimers were investigated in vivo; uncoated (PPI-g4) dendrimers, and dendrimers in which 25% or 100% of surface amino groups were coated with maltotriose (PPI-g4-25%m or PPI-g4-100%m), were administered to Wistar rats. Body weight, food and water consumption, and urine excretion were monitored daily. Blood was collected to investigate biochemical and hematological parameters, and the general condition and behavior of the animals were analyzed. Unmodified PPI dendrimers caused changes in the behavior of rats, a decrease in food and water consumption, and lower body weight gain. In the case of PPI-g4 and PPI-g4-25%m dendrimers, disturbances in urine and hematological and biochemical profiles returned to normal during the recovery period. PPI-g4-100%m was harmless to rats. The PPI dendrimers demonstrated dose- and sugar-modification-degree dependent toxicity. A higher dose of uncoated PPI dendrimers caused toxicity, but surface modification almost completely abolished this toxic effect.

Biological properties of new viologen-phosphorus dendrimers.

Some biological properties of eight dendrimers incorporating both phosphorus linkages and viologen units within their cascade structure or at the periphery were investigated for the first time. In particular cytotoxicity, hemotoxicity, and antimicrobial and antifungal activity of these new macromolecules were examined. Even if for example all these species exhibited good antimicrobial properties, it was demonstrated that their behavior strongly depends on several parameters as their size and molecular weight, the number of viologen units and the nature of the terminal groups.

The biodistribution of maltotriose modified poly(propylene imine) (PPI) dendrimers conjugated with fluorescein—proofs of crossing blood–brain–barrier

Oligosaccharide-modified poly(propylene imine) dendrimers are promising candidates as drug carriers and as anti-prion agents. Here, we report the biodistribution of maltotriose-modified 4th generation poly(propylene imine) (PPI) dendrimers and their ability to cross the blood–brain–barrier that is important if these glycodendrimers are considered as potential therapeutic agents in the central nervous system (CNS).

Complexation of HIV derived peptides with carbosilane dendrimers

Dendrimers have been proposed as new carriers for selected HIV-1 peptides. This paper reports on the complexation behaviour of the three HIV-derived-peptides: Gp160, NH-EIDNYTNTIYTLLEE-COOH; P24, NH-DTINEEAAEW-COOH and Nef, NHGMDDPEREVLEWRFDSRLAF-COOH with second generation cationic carbosilane dendrimers (CBD) branched with carbonsilicon bonds (CBD-CS) or oxygensilicon bonds (CBD-OS). Studies on the formation of complexes between HIV peptides and CBDs by fluorescence polarization, zeta-potential, electrophoresis and transmission electron microscopy have shown that both studied dendrimers form complexes with HIV peptides. At a molar ratio of (2.5-3):1 (dendrimer:peptide), the complexes formed were in the size range of 180-275 nm and with significant positive surface charge. The results suggest that interactions between dendrimers and HIV peptides have electrostatic nature due to the negative charge of peptides backbone and positive charge of dendrimer functional groups. Dendriplex stability depended on the type of studied dendrimers. Time of peptides release from the complexes ranged from 1 (CBD-OS) to ~36 (CBD-CS)h. Basing on the obtained results, we propose that the water-soluble cationic carbosilane dendrimers can be considered for delivery of HIV peptides to dendritic cells.

Effect of viologen–phosphorus dendrimers on acetylcholinesterase and butyrylcholinesterase activities

The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is the first step in checking whether new compounds can be considered as drugs for treating neurodegenerative diseases. The effect of viologen-phosphorus dendrimers on AChE and BChE activities was studied. The results show that the effects on the cholinesterase activities depend on dendrimer type and size. Viologen dendrimers can interact with the enzymes in two ways: they can bind either to a peripheral site of the enzyme or to amino acids located near the active site, inhibiting catalysis by both cholinesterases. All tested non-toxic viologen-phosphorus dendrimers inhibited the activities of both cholinesterases, showing their potential as new drugs for treating neurodegenerative diseases.

Dendrimers complexed with HIV-1 peptides interact with liposomes and lipid monolayers.

AIMS We have investigated the effect of surface charge of model lipid membranes on their interactions with dendriplexes formed by HIV-derived peptides and 2 types of positively charged carbosilane dendrimers (CBD). METHODS Interaction of dendriplexes with lipid membranes was measured by fluorescence anisotropy, dynamic light scattering and Langmuir-Blodgett techniques. The morphology of the complexes was examined by transmission electron microscopy. RESULTS All dendriplexes independent of the type of peptide interacted with model lipid membranes. Negatively charged vesicles composed of a mixture of DMPC/DPPG interacted more strongly, and it was accompanied by an increase in anisotropy of the fluorescent probe localized in polar domain of lipid bilayers. There was also an increase in surface pressure of the lipid monolayers. Mixing negatively charged liposomes with dendriplexes increased liposome size and made their surface charges more positive. CONCLUSIONS HIV-peptide/dendrimer complexes interact with model lipid membranes depending on their surface charge. Carbosilane dendrimers can be useful as non-viral carriers for delivering HIV-peptides into cells.

Biophysical Characterization of Glycodendrimers As Nano-carriers for HIV Peptides

This paper examines the formation and stability of nano-complexes that could provide a new therapeutic approach against HIV-1 infection. Poly(propylene imine) glycodendrimers decorated with 2(nd) generation cationic carbosilane dendrons were generated and their use in polyplex formation checked. Owing to their positively-charged terminal amino groups the hybrid glycodendrimers can bind anionic peptides. It was shown that they form nano-complexes with the HIV-derived peptides P24, Gp160 and Nef. Complexes 130-190 nm in size were formed in molar ratios (dendrimer/ peptide) of (3-4):1. These were sufficiently stable over time and at different pHs. The results obtained suggest that the hybrid dendrimers studied can be considered as alternative carriers for delivering HIV peptides to dendritic cells.

Modulation of biogenic amines content by poly(propylene imine) dendrimers in rats

Biogenic amines and polyamines participate in all vital organism functions, their levels being important function determinants. Studies were performed to check whether repeated administration of poly(propylene imine) (PPI) dendrimers, synthetic macromolecules with diaminobutane core, and peripheral primary amine groups, may influence the endogenous level of amines, as represented by the two of them: spermidine, a natural derivative of diaminobutane, and histamine. The experiment was carried out on Wistar rats. Fourth generation PPI dendrimer, as well as maltotriose-modified fourth generation PPI dendrimers with (a) cationic open sugar shell and (b) neutral dense sugar shell that possess a higher biocompatibility, was used. Applying the combination of column chromatography on Cellex P and spectrofluorimetric assays of o-phthaldialdehyde, the final amine condensation products were employed to analyze tissue spermidine and histamine outside the central nervous system. Furthermore, radioenzymatic assay was used to measure histamine levels in the brain. The obtained results indicate that in some tissues, the endogenous concentrations of histamine and spermidine may be affected by dendrimers depending on their dose and type of dendrimers.