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In spite of its wide and beneficial pharmacological potential, resveratrol lags behind other compounds because of its comparatively less impressive pharmacokinetic profile. Resveratrol has very low oral bioavailability and, from a formulation perspective, it has low solubility in water, which leads to its poor absorption upon oral administration. Apart from low aqueous solubility, resveratrol has poor metabolic stability and instability at high pH, and is photosensitive. The pharmacokinetic and formulation-related limitations of resveratrol can be controlled by entrapping the small resveratrol molecule inside highly water-soluble poly(amidoamine) dendrimer nanostructures, which provide spherical architecture and polyvalency at the nanoscale level, thus leading to novel features. Dendrimer architecture is used to entrap resveratrol for enhancement of its solubility and stability in aqueous solution; they can be engineered to control pharmacokinetics and targeting for oral, mucosal, transdermal, or parenteral administration. Dendrimers have the potential to work as excipients with multifunctional capability by enhancing solubility, dissolution, stability, permeability, multiple drug/cosmetic entrapment, controlled delivery, bioavailability, and efficacy of drugs., (© 2015 New York Academy of Sciences.)

The association of the anti-tuberculosis drug rifampicin (RIF) with a 4th-generation poly(amidoamine) (G4-PAMAM) dendrimer was investigated by means of molecular dynamics simulations. The RIF load capacity was estimated to be around 20 RIF per G4-PAMAM at neutral pH. The complex formed by 20 RIF molecules and the dendrimer (RIF20-PAMAM) was subjected to 100 ns molecular dynamics (MD) simulations at two different pH conditions (neutral and acidic). The complex was found to be significantly more stable in the simulation at neutral pH compared to the simulation at low pH in which the RIF molecules were rapidly and almost simultaneously expelled to the solvent bulk. The high stability of the RIF-PAMAM complex under physiological pH and the rapid release of RIF molecules under acidic medium provide an interesting switch for drug targeting since the Mycobacterium resides within acidic domains of the macrophage. Altogether, these results suggest that, at least in terms of stability and pH-dependent release, PAMAM-like dendrimers may be considered suitable drug delivery systems for RIF and derivatives., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Dendrimers are hyperbranched macromolecules with well-defined topological structures and multivalent functionalization sites, but they may cause cytotoxicity due to the presence of cationic charge. Recently, we have introduced alkyne-terminated poly(amidoamine) (PAMAM) dendrons of different generations (G=2,3) into chitosan to obtain dendronized chitosan derivatives [Cs-g-PAMAM (G=2,3)], which exhibited a better water solubility and enhanced plasmid DNA transfection efficiency. In this study, we attempted to examine the impact of Cs-g-PAMAM (G=2,3) at different concentrations (25 μg/mL, 50 μg/mL, and 100 μg/mL) on the morphology, surface structure, and viability of rat red blood cells (RBCs). The results showed that treatment of RBCs with Cs-g-PAMAM (G=2,3) at 50 μg/mL and 100 μg/mL induced a slightly higher hemolysis than Cs, and Cs-g-PAMAM (G=3) caused a slightly higher hemolysis than Cs-g-PAMAM (G=2), but all values were <5.0%. Optical microscopic and atomic force microscopic examinations indicated that Cs-g-PAMAM (G=2,3) caused slight RBC aggregation and lysis. Treatment of RBCs with 100 μg/mL Cs-g-PAMAM (G=3) induced echinocytic transformation, and RBCs displayed characteristic irregular contour due to the folding of the periphery. Drephanocyte-like RBCs were observed when treated with 100 μg/mL Cs-g-PAMAM (G=3). Erythrocytes underwent similar shape transition upon treatment with Cs-g-PAMAM (G=2) or Cs. The roughness values (Rms) of RBCs incubated with Cs-g-PAMAM (G=2,3) were significantly larger than those for RBCs incubated with physiological saline (P<0.01), but the Rms showed no difference for Cs and Cs-g-PAMAM (G=2,3) (P>0.05). Furthermore, Cs-g-PAMAM (G=2,3) exhibited a lower cytotoxicity in human kidney 293T cells. These results indicate that Cs-g-PAMAM (G=2,3) are hemocompatible but may disturb membrane and lipid structures at higher concentrations. Further safety and biocompatibility evaluations are warranted for Cs-g-PAMAM. Our findings prove helpful for a better understanding of the advantages of combining PAMAM dendrimers and chitosan to design and develop new, safe, and effective drug delivery vehicles.

Two new classes of dendrimers bearing 8 and 32 fluorene donor groups have been synthesized. The first and second generations of these porphyrin-PAMAM-fluorene dendrimers were characterized by 1H-NMR, 13C-NMR, FTIR, UV-vis spectroscopy, elemental analyses and MALDI-TOF mass spectrometry. The UV-vis spectra showed that the individual properties of donor and acceptor moieties were preserved, indicating that the new dendrimers could be used as photosynthetic antennae. Furthermore, for fluorescent spectroscopy, these dendrimers showed good energy transfer.

Herein, the synthesis of five novel ionic dendrimers and their evaluation as biological carriers is reported. The compounds include an ionic bis-MPA dendrimer and four PAMAM dendrimers of different generations decorated with negatively charged hydrophilic chains of 2-[2-(2-methoxyethoxy)ethoxy]acetic acid as counter ions in order to increase their biocompatibility. The ionic dendrimers derived from bis-MPA have a low cytotoxicity at 0.5 mg · mL(-1) against U251MG and are even less toxic against mesenchymal stem cells; however, the PAMAM derivatives show high cytotoxicity at the same concentration. The five compounds are able to form complexes with plasmid DNA at different N/P ratios. The cytotoxicity and complexation ability of the new dendrimers were also compared with jetPEI, a linear polyethylenimine derivative commercially available as transfection reagent. The results indicate that the cytotoxicity of the ionic PAMAM dendrimers remains as an important drawback, whereas the ionic I-bis-MPA compound exhibits a high ability to complex pDNA and very low toxicity compared with jetPEI., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This paper presents a novel hormone-based impedimetric biosensor to determine parathyroid hormone (PTH) level in serum for diagnosis and monitoring treatment of hyperparathyroidism, hypoparathyroidism and thyroid cancer. The interaction between PTH and the biosensor was investigated by an electrochemical method. The biosensor was based on the gold electrode modified by 12-mercapto dodecanoic (12MDDA). Antiparathyroid hormone (anti-PTH) was covalently immobilized on to poly amidoamine dendrimer (PAMAM) which was bound to a 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide/N-hydroxysuccinimide (EDC/NHS) couple, self-assembled monolayer structure from one of the other NH2 sites. The immobilization of anti-PTH was monitored by electrochemical impedance spectroscopy, cyclic voltammetry and scanning electron microscope techniques. After the optimization studies of immobilization materials such as 12MDDA, EDC-NHS, PAMAM, and glutaraldehyde, the performance of the biosensor was investigated in terms of linearity, sensitivity, repeatability, and reproducibility. PTH was detected within a linear range of 10-60 fg/mL. Finally the described biosensor was used to monitor PTH levels in artificial serum samples., (© 2015 American Institute of Chemical Engineers.)

Background: Antibody-dendrimer conjugates have the potential to improve the targeting and release of chemotherapeutic drugs at the tumor site while reducing adverse side effects caused by drug accumulation in healthy tissues. In this study, trastuzumab (TMAB), which binds to human epidermal growth factor receptor 2 (HER2), was used as a targeting agent in a TMAB-polyamidoamine (PAMAM) conjugate carrying paclitaxel (PTX) specifically to cells overexpressing HER2., Methods: TMAB was covalently linked to a PAMAM dendrimer via bifunctional polyethylene glycol (PEG). PTX was conjugated to PAMAM using succinic anhydride as a cross-linker, yielding TMAB-PEG-PAMAM-PTX. Dynamic light scattering and transmission electron microscopy were used to characterize the conjugates. The cellular uptake and in vivo biodistribution were studied by fluorescence microscopy, flow cytometry, and Carestream In Vivo FX, respectively., Results: Nuclear magnetic resonance spectroscopy demonstrated that PEG, PTX, fluorescein isothiocyanate, and cyanine7 were conjugated to PAMAM. Ultraviolet-visible spectroscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that TMAB was conjugated to PEG-PAMAM. Dynamic light scattering and transmission electron microscopy measurements revealed that the different conjugates ranged in size between 10 and 35 nm and had a spherical shape. In vitro cellular uptake demonstrated that the TMAB-conjugated PAMAM was taken up by HER2-overexpressing BT474 cells more efficiently than MCF-7 cells that expressed lower levels of HER2. Co-localization experiments indicated that TMAB-conjugated PAMAM was located in the cytoplasm. The in vitro cytotoxicity of TMAB-conjugated PAMAM was lower than free PTX due to the slow release of PTX from the conjugate. In vivo targeting further demonstrated that TMAB-conjugated PAMAM accumulated in the BT474 tumor model more efficiently than non-conjugated PAMAM., Conclusion: TMAB can serve as an effective targeting agent, and the TMAB-conjugated PAMAM can be exploited as a potential targeted chemotherapeutic drug delivery system for tumors that overexpress HER2.

We present a novel, insoluble, low-generation polyamidoamine (PAMAM)-based polymer. The monomer and polymer were characterized by fourier transform infrared spectroscopy, electrospray ionization mass spectrometry and thermogravimetric measurement, revealing that G0 acryloyl-terminated PAMAM were synthesized and polymerized using ammonium persulfate as an initiator, producing a high-density PAMAM derivative (PAMAM-HD). PAMAM-HD was tested for its ability to remove Na(I), K(I), Ca(II), Mg(II), Cu(II), Mn(II), Cd(II), Pb(II) and Zn(II) ions from acidic, neutral and basic aqueous solutions. PAMAM-HD efficiently removed metals ions from all three solutions. The greatest absorption efficiency at neutral pH was observed against Cu(II), Cd(II) and Pb(II), and the experimental data were supported by the calculated Kd values. Our data could have a significant impact on water purification by providing an inexpensive and efficient polymer for the removal of metal ions., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

As a problem in open non-equilibrium phenomena, small-angle scattering (SAS) studies of chemical reactions at specific sites and reaction-induced self-assembly of a system which is obtained by mixing two stable solutions of palladium acetate [Pd(OAc)2] in N,N-dimethylformamide and the second-generation polyamidoamine dendrimer in methanol are presented. The self-assembly was studied using a combination of neutron and X-ray SAS. The results revealed that the self-assembly involves the initial formation of aggregates of an average radius of 20 nm composed of the dendrimers and Pd(OAc)2 followed by formation of palladium nanoparticles of a radius of 2.0 nm inside the aggregates. The aggregates were found to provide a special field for a chemical reaction for reduction of Pd(II) ions with methanol and for the self-assembly of the reduction products of Pd(0) atoms into nanoparticles. The nanoparticles are found to be trapped and stabilized in the aggregates. [ABSTRACT FROM AUTHOR]

Cationic micellar nanoparticles for chemotherapeutic drugs and therapeutic gene co-delivery were prepared based on a poly-(N-ε-carbobenzyloxy-l-lysine) (PZLL) and dendritic polyamidoamine (PAMAM) block copolymer (PZLL-D3). PZLL-D3 was synthesized by a copper-catalyzed azide alkyne cyclization (click) reaction between α-alkyne-PZLL and azide focal point PAMAM dendrons. Its structure was characterized by (1)H NMR and FTIR, and its buffering capability was determined by acid-base titration. MTT, agarose gel electrophoresis and flow cytometry studies showed that PZLL-D3 revealed low in vitro cytotoxicity, strong pDNA condensation ability, protection of pDNA against deoxyribonuclease I degradation and high gene transfection efficiency in 293T and HeLa cells. In addition, the micellar nanoparticles delivered pDNA and anticancer drug doxorubicin (DOX) simultaneously and efficiently to tumor cells, and the DOX loaded nanoparticles showed sustained in vitro release at pH=7.4 and 5.8., (Copyright © 2014. Published by Elsevier B.V.)

Dendrimers are nano-sized, radially symmetric molecules with well-defined, homogeneous, and monodisperse structure that has a typically symmetric core, an inner shell, and an outer shell. Their three traditional macromolecular architectural classes are broadly recognized to generate rather polydisperse products of different molecular weights. A variety of dendrimers exist, and each has biological properties such as polyvalency, self-assembling, electrostatic interactions, chemical stability, low cytotoxicity, and solubility. These varied characteristics make dendrimers a good choice in the medical field, and this review covers their diverse applications.

Cancer treatment that uses a combination of approaches with the ability to affect multiple disease pathways has been proven highly effective in the treatment of many cancers. Combination therapy can include multiple chemotherapeutics or combinations of chemotherapeutics with other treatment modalities like surgery or radiation. However, despite the widespread clinical use of combination therapies, relatively little attention has been given to the potential of modern nanocarrier delivery methods, like liposomes, micelles, and nanoparticles, to enhance the efficacy of combination treatments. This lack of knowledge is particularly notable in the limited success of vectors for the delivery of combinations of nucleic acids with traditional small molecule drugs. The delivery of drug-nucleic acid combinations is particularly challenging due to differences in the physicochemical properties of the two types of agents. This review discusses recent advances in the development of delivery methods using combinations of small molecule drugs and nucleic acid therapeutics to treat cancer. This review primarily focuses on the rationale used for selecting appropriate drug-nucleic acid combinations as well as progress in the development of nanocarriers suitable for simultaneous delivery of drug-nucleic acid combinations., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In the realm of drug delivery, carbon nanotubes (CNTs) have gained tremendous attention as promising nanocarriers, owing to their distinct characteristics, such as high surface area, enhanced cellular uptake and the possibility to be easily conjugated with many therapeutics, including both small molecules and biologics, displaying superior efficacy, enhanced specificity and diminished side effects. While most CNT-based drug delivery system (DDS) had been engineered to combat cancers, there are also emerging reports that employ CNTs as either the main carrier or adjunct material for the delivery of various non-anticancer drugs. In this review, the delivery of small molecule drugs is expounded, with special attention paid to the current progress of in vitro and in vivo research involving CNT-based DDSs, before finally concluding with some consideration on inevitable complications that hamper successful disease intervention with CNTs., (© 2013.)

Platinum based anticancer drugs have revolutionized cancer chemotherapy, and continue to be in widespread clinical use especially for management of tumors of the ovary, testes, and the head and neck. However, several dose limiting toxicities associated with platinum drug use, partial anti-tumor response in most patients, development of drug resistance, tumor relapse, and many other challenges have severely limited the patient quality of life. These limitations have motivated an extensive research effort towards development of new strategies for improving platinum therapy. Nanocarrier-based delivery of platinum compounds is one such area of intense research effort beginning to provide encouraging preclinical and clinical results and may allow the development of the next generation of platinum chemotherapy. This review highlights current understanding on the pharmacology and limitations of platinum compounds in clinical use, and provides a comprehensive analysis of various platinum-polymer complexes, micelles, dendrimers, liposomes and other nanoparticles currently under investigation for delivery of platinum drugs., (© 2013.)

Oral delivery of camptothecin has a treatment advantage but is limited by low bioavailability and gastrointestinal toxicity. Poly(amido amine) or PAMAM dendrimers have shown promise as intestinal penetration enhancers, drug solubilizers and drug carriers for oral delivery in vitro and in situ. There have been very limited studies in vivo to evaluate PAMAM dendrimers for oral drug delivery. In this study, camptothecin (5 mg/kg) was formulated and co-delivered with cationic, amine-terminated PAMAM dendrimer generation 4.0 (G4.0) (100 and 300 mg/kg) and anionic, carboxylate-terminated PAMAM generation 3.5 (G3.5) (300 and 1000 mg/kg) in CD-1 mice. Camptothecin associated to a higher extent with G4.0 than G3.5 in the formulation, attributed to an electrostatic interaction on the surface of G4.0. Both PAMAM G4.0 and G3.5 increased camptothecin solubilization in simulated gastric fluid and caused a 2-3 fold increase in oral absorption of camptothecin when delivered at 2 h. PAMAM G4.0 and G3.5 did not increase mannitol transport suggesting that the oral absorption of camptothecin was not due to tight junction modulation. Histologic observations of the epithelial layer of small intestinal segments of the gastrointestinal tract (GIT) at 4 h post dosing supported no evidence of toxicity at the evaluated doses of PAMAM dendrimers. This study demonstrates that both cationic (G.4) and anionic (G3.5) PAMAM dendrimers were effective in enhancing the oral absorption of camptothecin. Results suggest that drug inclusion in PAMAM interior controlled solubilization in simulated gastric and intestinal fluids, and increased oral bioavailability., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The efficacy of chemotherapy is substantially limited by the resistance of cancer cells to anticancer drugs that fluctuates significantly in different patients. Under identical chemotherapeutic protocols, some patients may receive relatively ineffective doses of anticancer agents while other individuals obtain excessive amounts of drugs that induce severe adverse side effects on healthy tissues. The current review is focused on an individualized selection of drugs and targets to suppress multidrug resistance. Such selection is based on the molecular characteristics of a tumor from an individual patient that can potentially improve the treatment outcome and bring us closer to an era of personalized medicine., (© 2013. Published by Elsevier B.V. All rights reserved.)

Pumps of the ATP-binding cassette superfamily (ABCs) regulate the access of drugs to the intracellular space. In this context, the overexpression of ABCs is a well-known mechanism of multidrug resistance (MDR) in cancer and infectious diseases (e.g., viral hepatitis and the human immunodeficiency virus) and is associated with therapeutic failure. Since their discovery, ABCs have emerged as attractive therapeutic targets and the search of compounds that inhibit their genetic expression and/or their functional activity has gained growing interest. Different generations of pharmacological ABC inhibitors have been explored over the last four decades to address resistance in cancer, though clinical results have been somehow disappointing. "Generally Recognized As Safe" (GRAS) is a U.S. Food and Drug Administration designation for substances that are accepted as safe for addition in food. Far from being "inert", some amphiphilic excipients used in the production of pharmaceutical products have been shown to inhibit the activity of ABCs in MDR tumors, emerging as a clinically translatable approach to overcome resistance. The present article initially overviews the classification, structure and function of the different ABCs, with emphasis on those pumps related to drug resistance. Then, the different attempts to capitalize on the activity of GRAS nanopharmaceuticals as ABC inhibitors are discussed., (© 2013.)

Encapsulating anticancer drugs to synthetic polymer is a promising approach to improve the efficiency and reduce the side effects of anticancer drugs. In this study, novel chitosan derivatives with polyamidoamine moieties (CS-PAMAM) were synthesized and characterized by morphology, particle size, and zeta potential. Then the anticancer drug-methotrexate-encapsulated CS-PAMAM was prepared by hydrophobic-hydrophilic interactions. The drug release assay showed that the amount of the methotrexate release from CS-PAMAM was pH depended. Meanwhile, the cell viability assay illustrated that CS-PAMAM was suitable for the drug delivery because of its low cytotoxicity on cells. Moreover, our results showed that the CS-PAMAM could significantly improve the cytotoxicity of free methotrexate on A549 cells. These results demonstrate that CS-PAMAM may provide a suitable platform for the water-insoluble drug delivery., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In this study the ability of three polyamidoamine (PAMAM) dendrimers with different surface charge (positive, neutral and negative) to interact with a negatively charged protein (porcine pepsin) was examined. It was shown that the dendrimer with a positively charged surface (G4 PAMAM-NH2), as well as the dendrimer with a neutral surface (G4 PAMAM-OH), were able to inhibit enzymatic activity of pepsin. It was also found that these dendrimers act as mixed partially non-competitive pepsin inhibitors. The negatively charged dendrimer (G3.5 PAMAM-COOH) was not able to inhibit the enzymatic activity of pepsin, probably due to the electrostatic repulsion between this dendrimer and the protein. No correlation between changes in enzymatic activity of pepsin and alterations in CD spectrum of the protein was observed. It indicates that the interactions between dendrimers and porcine pepsin are complex, multidirectional and not dependent only on disturbances of the secondary structure., (© 2013.)

Among all the malignant brain tumors, glioma is the deadliest and most common form with poor prognosis. Gene therapy is regarded as a promising way to halt the progress of the disease or even cure the tumor and RNA interference (RNAi) stands out. However, the existence of the blood-brain barrier (BBB) and blood tumor barrier (BTB) limits the delivery of these therapeutic genes. In this work, the delivery system targeting to the transferrin (Tf) receptor highly expressed on both BBB and glioma was successfully synthesized and would not compete with endogenous Tf. U87 cells stably express luciferase were employed here to simulate tumor and the RNAi experiments in vitro and in vivo validated that the gene silencing activity was 2.17-fold higher with the targeting ligand modification. The dual-targeting gene delivery system exhibits a series of advantages, such as high efficiency, low toxicity, stability and high transaction efficiency, which may provide new opportunities in RNAi therapeutics and nanomedicine of brain tumors., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

Among innovative strategies developed for cancer treatments, gene therapies stand of great interest despite their well-known limitations in targeting, delivery, toxicity or stability. The success of any given gene-therapy is highly dependent on the carrier efficiency. New approaches are often revisiting the mythic trojan horse concept to carry therapeutic nucleic acid, i.e. DNAs, RNAs or small interfering RNAs, to pathologic tumor site. Recent investigations are focusing on engineering carrying modalities to overtake the above limitations bringing new promise to cancer patients. This review describes recent advances and perspectives for gene therapies devoted to tumor treatment, taking advantage of available knowledge in biotechnology and medicine., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The widespread use of various cyclodextrin (CyD)-appended polymers and polyrotaxanes as gene carriers has been reported. Among the various polyamidoamine dendrimer (dendrimer) conjugates with CyDs (CDE), the dendrimer (G3) conjugate with α-CyD having an average degree of substitution (DS) of 2.4 (α-CDE (G3, DS 2)) displayed remarkable properties as DNA carriers. In an attempt to develop cell-specific gene transfer carriers, we prepared some sugar-appended α-CDEs, e.g. mannosylated, galactosylated, and lactosylated α-CDEs. In addition, PEGylated Lac-α-CDEs (G3) were prepared and evaluated as a hepatocyte-selective and serum-resistant gene transfer carrier. Moreover, PEGylated-α-CDE/CyD polypseudorotaxane systems for novel sustained DNA release system have been developed. Interestingly, glucronylglucosyl-β-cyclodextrin (GUG-β-CyD) conjugates with dendrimer (G2) (GUG-β-CDE (G2)) had superior gene transfer activity to α-CDE (G2), expecting a development of new series of sugar-appended CDEs over α-CDEs (G2). Collectively, sugar-appended α-CDEs have the potential as novel cell-specific and safe carriers for DNA., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: Polyamidoamine (PAMAM) dendrimers are a unique family of dendritic polymers with numerous pharmaceutical and biomedical applications. One major problem with these polymers is their cytotoxicity. The purpose of this study was to synthesize novel dendrimers with aldehyde terminal groups and compare their cytotoxicity with that of dendri¬mers containing amine-terminated groups., Methods: G1(first generation) and G2 (second generation) dendrimers with amine-terminated groups were synthesized by divergent method and then the amine-terminated groups were converted to the aldehyde groups using surface modification of the functional group inversion (FGI) method. The cytotoxicity of the novel G1 and G2 polyamidoaldehyde (PAMAL) dendrimers together with that of G1 and G2 PAMAM-NH2 dendrimers was investigated by MTT assay using MCF-7 cell line., Results: The results showed that cytotoxicity of dendrimers with aldehyde-terminated groups is much lower than that of G1 and G2 PAMAM-NH2 dendri¬mers., Conclusion: Dendrimers with aldehyde-terminated groups could be used as novel and convenient carriers for drug delivery with low cytotoxic effect compared with the amine-terminated dendrimers. The results revealed that the same generations of the dendri¬mers with aldehyde-terminated groups are far less toxic than the corresponding amine-terminated dendrimers.

Background: Bioconjugates of a polyamidoamine (PAMAM) G3 dendrimer and an aldehyde were synthesized as carriers for vitamins A and B₆, and the bioavailability of these vitamins for skin nutrition was investigated., Methods: Nuclear magnetic resonance (NMR) and ultraviolet-visible methods were used to characterize the structure of the bioconjugates and for monitoring release of pyridoxal (Pyr) and pyridoxal phosphate (PLP) from these bioconjugates in vitro. A skin model permeation of bioconjugates was also studied in a Franz chamber., Results: A transdermal G3 PAMAM dendrimer was used to synthesize bioconjugates with trans-retinal (Ret), pyridoxal (Pyr), or PLP. These nanomolecules, containing up to four covalently linked Ret, Pyr, or PLP (G3(4Ret), G3(4Pyr), and G3(4PLP)), were able to permeate the skin, as demonstrated in vitro using a model skin membrane. PLP and Pyr bound to a macromolecular vehicle were active cofactors for glutamic pyruvic transaminase, as shown by ¹H NMR spectral monitoring of the progress of the L-alanine + α-ketoglutarate → glutamic acid + pyruvic acid reaction., Conclusion: PAMAM-PLP, PAMAM-Pyr, and PAMAM-Ret bioconjugates are able to permeate the skin. PLP and Pyr are available as cofactors for glutamic pyruvic transaminase.

To gain a deeper understanding of the physicochemical phenomenon of self-assembled nanoparticles of different generations and ratios of poly (amidoamine) dendrimer (PAMAM) dendrimer and a short-stranded DNA (antisense oligonucleotide), multiple methods were used to characterize these nanoparticles including photon correlation spectroscopy (PCS); zeta potential measurement; and atomic force microscopy (AFM). PCS and AFM results revealed that, in contrast to larger molecules of DNA, smaller molecules produce more heterodisperse and large nanoparticles when they are condensed with a cationic dendrimer. AFM images also showed that such nanoparticles were spherical. The stability of the antisense content of the nanoparticles was investigated over different charge ratios using polyacrylamide gel electrophoresis. It was clear from such analyses that much more than charge neutrality point was required to obtain stable nanoparticles. For cell uptake, self-assembled nanoparticles were prepared with PAMAM G5 and 5'-FITC labeled antisense and the uptake experiment was carried out in T47D cell culture. This investigation also shows that the cytotoxicity of the nanoparticles was dependent upon the generation and charge ratio of the PAMAM dendrimer, and the antisense concentration had no significant effect on the cytotoxicity.