Towards dendrimers as biomimetic macromolecules

Dendrimers can be obtained in precise molecular weights even at high generations. This feature, as well as the inherent globular shape of high generation dendrimers, makes them ideal candidates for macromolecular biomimetics. In this account, we discuss the synthesis and use of dendrimers that are reminiscent of macromolecular architectures present in nature. In particular, we focus the use of dendrimers in the areas of encapsulation, functionalization, and sequencing. To cite this article: S. Thayumanavan et al., C. R. Chimie 6 (2003).     

Self‐immolative dendrimers as novel drug delivery platforms

Self‐immolative dendrimers were recently developed and introduced as a potential platform for a single‐triggered multi‐prodrug. These unique structural dendrimers can release all of their tail units through domino‐like chain fragmentation, which is initiated by a single cleavage at the dendrimer core. The incorporation of drug molecules as the tail units and an enzyme substrate as the trigger generates a multi‐prodrug unit that is activated with a single enzymatic cleavage. We have demonstrated several examples of self‐immolative dendritic prodrug systems and have shown significant advantages with respect to the appropriate monomeric prodrug. We anticipate that single‐triggered, dendritic prodrugs will be exploited to further improve selective chemotherapeutic approaches in cancer therapy. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 1569–1578, 2006     

Computational studies on the doped graphene quantum dots as potential carriers in drug delivery systems for isoniazid drug

In this study, the application of graphene quantum dots (GQDs) and doped GQDs as potential carriers for the delivery of isoniazid (Iso) drug has been investigated, using density functional theory (DFT) calculations. For this purpose, the hexa-peri-hexabenzocoronene (as a GQD model) and its BN-, BP-, AlN-, and AlP-doped (C₃₆X₃Y₃H₁₈ where X = B, Al and Y = N, P) forms were selected. Our results indicated that the adsorption energies of isoniazid on doped GQDs were more negative than that of pure GQD. Moreover, the calculations showed that adsorption of isoniazid on AlN- and AlP-doped GQDs was thermodynamically favorable. The dipole moments of BP-, AlN-, and AlP-doped GQDs were much greater (5.799, 1.860, and 3.312 D, respectively) than that of pristine GQD (0 D). The AlN-Iso and AlP-Iso complexes had small energy gaps, low chemical potentials, and low global hardnesses, which were appropriate for their attachments to the target site. The nature of interactions was analyzed by the quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI) analyses. Overall, the results confirmed that the AlN- and AlP-doped GQDs could be used as potential carriers for drug delivery application.     

肽类树枝状大分子:自组装胶束及药物释放研究

本文以三代聚谷氨酸肽类树枝状分子(G3-Glu)为大分子引发剂,引发N-羧基-L-苯丙氨酸-环内酸酐(NCA-Phe)的开环聚合反应,制备聚谷氨酸树枝状大分子-聚苯丙氨酸嵌段共聚物.嵌段共聚物通过自组装形成以聚苯丙氨酸链段为核,聚谷氨酸树枝状大分子为壳的胶束.将抗肿瘤药物阿霉素负载到高分子胶束中,研究其药物释放性能及体外抗肿瘤效果.结果表明,共聚物胶束具有良好的生物相容性.载药胶束具有药物缓释效果,药物持续释放时间可达60h.载药胶束的体外抗肿瘤实验表明其对肝癌细胞HepG2具有很好的杀灭效果,共培养48h后对癌细胞的杀死率可高达75%.     

Polypeptide dendrimers: Self-assembly and drug delivery

Amphiphilic dendritic poly(glutamic acid)-b-polyphenylalanine copolymers were synthesized using generation 3 dendritic poly(glutamic acid) as the macroinitiator in the ring-opening polymerization of NCA-Phe.The block copolymers self-assembled micelles with polyphenylalanine segments as core and dendritic poly(glutamic acid) segments as shell.The biocompatibility of the micelles was studied.The release of the anticancer drug doxorubicin from the micelles was investigated in vitro.The results showed that the ...     

Amine-terminated dendrimers as biomimetic templates for silica nanosphere formation

In diatoms, silica synthesis occurs by use of complex posttranslationally modified peptides, termed silaffins, and highly complex biological polyamine structures. Silaffin peptides have lysine residues that are modified to long-chain polyamine moieties of N-methyl derivatives of polypropylenimine to drive silica synthesis at slightly acidic pH conditions. Using polypropylenimine (PPI) and PAMAM amine-terminated dendrimers as a biomimetic analogue of the polyamine modifications of silaffins, we have demonstrated the condensation of silica nanospheres. We have shown that the dendrimers react in an amine concentration-dependent fashion yielding silica nanospheres with a distinct size distribution reminiscent of the structures produced from both the modified and nonmodified peptides extracted from diatoms. Additionally, the templates were encapsulated by the growing nanospheres and precipitated from solution in a manner similar to that previously described for the bioactive peptides and polyamines.     

Functional and site-specific macromolecular micelles as high potential drug carriers

Since several years, macromolecular micelles based on amphiphilic block copolymers have attracted much interest as drug carriers. These micelles show a long term blood circulation time resulting from their small diameter and the steric repulsion created by the poly(ethylene oxide) chains which constitute micelle corona, as well as from their high thermodynamic stability. Besides this long term blood circulation time generating a passive targeting, an active targeting, chemical or physical affinity targeting, might allow the preparation of more efficient drug carriers. In order to obtain such double targeting properties, we have prepared two kinds of macromolecular micelles. The first one is based on amphiphilic poly(ethylene oxide)/poly(β-benzyl -aspartate) ---PEO/PBLA--- block copolymers having hydroxy groups at the free end of PEO chains. As a result of their structure, such micelles have hydroxy groups on their outer-shell which can be further modified in order to introduce a targeting moiety (sugar, etc.). The characteristics (diameter, critical micellar concentration (cmc), drug loading capacity) have been determined. Moreover, doxorubicin loaded -hydroxy PEO/PBLA micelles have been shown to be slightly more cytotoxic than the corresponding -methoxy PEO/PBLA micelles. The second type of micelles is based on thermosensitive amphiphilic poly(N-isopropyl acrylamide)/polystyrene ---PIPAAm/PSt--- block copolymers. Such micelles have a small diameter and a low cmc in addition to thermosensitivity properties which are similar to those of PIPAAm.     

Submicron particles of SBA-15 modified with MgO as carriers for controlled drug delivery

Submicron particles with modified surface were synthesized by a simple one-pot synthesis approach and used as drug carrier for controlled release. Due to the alkalinity of MgO species on the surface, the amount of a model drug, ibuprofen, adsorbed on the modified surface was increased as compared to pure silica SBA-15 although the surface area was decreased by the surface modification. FTIR investigation indicated that the adsorption state of ibuprofen on MgO modified SBA-15 was different from that on pure silica SBA-15 and pure crystal ibuprofen. The result obtained from in vitro release test exhibited that the surface modification greatly decreased the ibuprofen release rate. In first 6 h in vitro release test, only 63% of the adsorbed ibuprofen was released from the MgO/SBA-15 (Si/Mg=20). In contrast, the release of ibuprofen was complete in 1 h from the pure silica SBA-15 under the same release conditions. The surface modified with MgO created affinity with acidic ibuprofen molecules and retarded the release rate from the mesoporous matrix. In addition, the release rate of ibuprofen could be modulated by varying the content of MgO, and was found to decrease with increasing amount of MgO on surface of SBA-15 submicron particles.     

Harnessing the full potential of extracellular vesicles as drug carriers

Extracellular vesicles are natural delivery systems widely implicated in cellular communication. However, to fully utilize these vehicles as nanocarriers, we must explore various methods to modify their applicability as drug delivery vehicles. In this review, we outline and discuss techniques to engineer extracellular vehicles for enhanced loading, targeting, circulation, and tracking. We highlight cutting-edge methods to amplify extracellular vesicle secretion and production and optimize storage conditions to improve their clinical suitability. Moreover, we focus on reverse engineering as an important step in controlling their biological function. By taking a reductionist approach to characterize and understand the individual components of these carriers, we can not only elucidate complex mechanisms of action but also advance the field through the creation of synthetic drug delivery vehicles. Finally, we propose current challenges and future directions of the field.     

Regenerated keratin proteins as potential biomaterial for drug delivery

This work aims to preliminarily evaluate the reliability of regenerated keratins (RKs) in the design of microparticulate drug delivery systems by studying their processability and cytotoxicity. RKs were extracted by sulfitolysis from wool waste. A 4.5% w/w RK solution was spray‐dried, and microparticles were sterilized by steam vapor under pressure. Scanning electron microscope, sodium dodecyl sulfate‐polyacrylamide gel electrophoresis, and Fourier transform infrared spectroscopy were used to characterize RKs and microparticles thereof. The in vitro cytotoxicity was determined by assessing the release of lactate dehydrogenase in the human monocytic cell line Tamm–Horsfall glycoprotein‐1. RK‐based microparticles with a narrow and unimodal particle size distribution (~6 µm) were obtained. They had a raisin‐like structure with a smooth surface. Both microparticle morphology and RK molecular weight were well‐preserved after sterilization. The curve fitting of the amide I bands showed that RK in the microparticles was prevalently present in the disordered/α‐helix secondary structures which made the protein soluble in water. To promote crystallization in the β‐sheet secondary structure and, therefore, water insolubility, RK‐based microparticles were immersed in an aqueous solution of acetic acid at pH 3.5 overnight. RK did not induce any appreciable cellular cytotoxicity at any of the concentrations (from 1 up to 1000 µg sterile microparticles in 1 ml cell culture medium) or time‐points (24–72 h) tested. These preliminary data suggest the feasibility of producing RK biocompatible microparticles using waste wool as starting material. Copyright © 2013 John Wiley & Sons, Ltd.     

Fluorescent dendrimers with a peptide cathepsin B cleavage site for drug delivery applications

The synthesis of a multifunctionally equipped first generation (G1) dendrimer carrying a pentapeptide with a cathepsin[space]B cleavage site, chelating ligands for Pt2+-complexation, and a dansyl fluorescence marker is described and an investigation of its cellular uptake as well as intracellular localization by confocal fluorescence microscopy reported.     

Gadolinium containing photochromic micelles as potential magnetic resonance imaging traceable drug carriers

Novel photochromic amphipathic molecules, KMR‐AZn (Gd‐DTPA‐AZCn), composed of hydrophilic Gd‐DTPA and hydrophobic alkylated azobenzene were prepared. In aqueous environment, KMR‐AZn indicated self‐assembly. The resulting aggregates were demonstrated to be able to include a hydrophobic drug substitute (hydrophobic fluorescent dye) into the internal core, and to release the included compound upon photoirradiation within 10 min through the influence of azobenzene photoisomerization. This micellar MRI contrast agent exhibited three‐ to four‐fold higher r₁ relaxivity (r₁ = 14.5–16.5 mm ^?1 s^?1, 0.47 T at 40°C) than the widely applied small molecule contrast agent Gd‐DTPA (Magnevist^®r₁ = 4.1 mm ^?1 s^?1, 0.47 T at 40°C). This dual functionality of encapsulated compound release and increased MR imaging contrast indicates that KMR‐AZn is a potential candidate for application as a lipid‐based MRI‐traceable drug carrier.     

环糊精在药物控制释放系统中的应用研究进展

因为环糊精的生物相容性和多功能性,通过改性以及各种剂型的设计,能够扩展其在医药领域的应用。本文介绍了环糊精及其衍生物在药物控制释放体系中的作用机理及特点,并结合本课题组的研究工作,综述了近年来环糊精在该领域中的应用研究进展。     

Cationic polyhedral oligomeric silsesquioxane (POSS) units as carriers for drug delivery processes

Quaternary ammonium functionalized polyhedral oligomeric silsesquioxane (OctaAmmonium-POSS) units, widely employed as additives in ceramic and polymeric systems, possess many attributes which make them attractive as biocompatible drug carriers: nanoscale size, three-dimensional functionality, efficient cellular uptake, low toxicity, and high solubility.     

Ferrocenyl amphiphilic Janus dendrimers as redox‐responsive micellar carriers

Amphiphilic Janus dendrimers have attracted increasing attention due to their asymmetric structures and various functional properties compared to the conventional symmetric macromolecules. Herein, a novel ferrocenyl‐terminated amphiphilic Janus dendrimer containing nine hydrophilic triethylene glycol branches was synthesized by two synthetic routes, namely the typical chemo selective coupling method and the mixed modular approach. Chemical redox triggers, namely Fe₂(SO₄)₃ as oxidant and ascorbic acid as reductant, could regulate the self‐assembly behavior of the Janus dendrimer in water through the redox‐switching between ferrocene and ferricinium cations, and the change of micelles formed were investigated and confirmed through scanning electron microscopy and dynamic light scattering. The cargo‐loading property of the micelles self‐assembled by the Janus dendrimer was further proved by the successful fabrication of Rhodamine B (RhB)‐loaded micelles, and the oxidation‐triggered release behavior of the encapsulated RhB could be mediated by changing the concentration of oxidants. This work provides an effective approach to prepare ferrocenyl‐terminated amphiphilic Janus dendrimers and the self‐assembled micelles might be used as a promising molecular carrier in areas such as drug delivery and catalysis.     

Synthesis of water-soluble, multiple functionalizable dendrons for the conversion of large dendrimers or other molecular objects into potential drug carriers

The synthesis of dendrons and dendrimers which carry OEG chains and bidentate ligands and/or fluorescence tags is described. The orthogonally protected functional groups of the dendrons allow modification of the substitution pattern and attachment to larger entities. Both dendrons and dendrimers are highly water-soluble. The dendrons should have considerable potential to convert, for example, commercially available, high-generation dendrimers into water-soluble, versatile support materials for antitumor therapy.     

Microgels as drug carriers for sonopharmacology

The ultrasound-induced cleavage of covalent and non-covalent bonds to activate drugs (sonopharmacology) is a promising concept to gain control over the action of active pharmaceutical ingredients by an external trigger. Previously, linear polymer architectures bearing drug payloads were exploited for drug release by using the principles of polymer mechanochemistry. In this work, the carrier design is altered by the polymer topology to improve the ultrasound-triggered release of covalently anchored drugs from polymer scaffolds. We use microgels crosslinked by mechanoresponsive disulfides and copolymerized with Diels-Alder adducts of furylated payload molecules and acetylenedicarboxylate. Force-induced thiol formation induces a Michael-type addition liberating the payload from the microgels. The use of microgels significantly reduces sonication times compared to linear polymer chains and shields the cargo efficiently from non-triggered activation using ultrasound that produces inertial cavitation at a frequency of 20 kHz as model condition.     

Controllable exploding microcapsules as drug carriers

Controllable exploding polyelectrolyte microcapsules were developed by layer-by-layer assembly of poly(allylamine hydrochloride) (PAH) and poly(sodium 4-styrenesulfonate) (PSS) on a dextran microgel core containing a cleavable disulfide bond fabricated via click chemistry. The microcapsules can explode upon the injection of DTT with an explosive release of the drug.     

Highly biocompatible, hollow coordination polymer nanoparticles as cisplatin carriers for efficient intracellular drug delivery

Highly biocompatible coordination polymer (Prussian Blue) nanoparticles (LC(50) > 1000 μg mL(-1)) with a hollow interior and a microporous framework (denoted as HPB) are utilized as an anticancer drug (i.e. cisplatin) capsule for chemotherapy of bladder cancer T24 cells.     

Synthesis of degradable functional poly(ethylene glycol) analogs as versatile drug delivery carriers

Poly(ethylene glycol) (PEG) is widely used as a water soluble carrier for polymer-drug conjugates. Herein, we report degradable linear PEG analogs (DPEGs) carrying multifunctional groups. The DPEGs were synthesized by a Michael addition based condensation polymerization of dithiols and PEG diacrylates (PEGDA) or dimethacrylates (PEGDMA). They were stable at pH 7.4 but quickly degraded at pH 6.0 and 5.0. Thus, DPEGs could be used as drug carriers without concern for their retention in the body. DPEGs could be made to carry such functional groups as terminal thiol or (meth)acrylate and pendant hydroxyl groups. The functional groups were used for conjugation of drugs and targeting groups. This new type of PEG analog will be useful for drug delivery and the PEGylation of biomolecules and colloidal particles.