siRNA delivery remains a major challenge in RNAi- based therapy. Here, we report for the first time that an amphiphilic dendrimer is able to self-assemble into adaptive supramolecular assemblies upon interaction with siRNA, and effectively delivers siRNAs to various cell lines, including human primary and stem cells, thereby outperforming the currently available nonviral vectors. In addition, this amphi- philic dendrimer is able to harness the advantageous features of both polymer and lipid vectors and hence promotes effective siRNA delivery. Our study demonstrates for the first time that dendrimer-based adaptive supramolecular assemblies repre- sent novel and versatile means for functional siRNA delivery, heralding a new age of dendrimer-based self-assembled drug delivery in biomedical applications
The relative difference in polymeric architectures of dendrimer and linear bis(poly(ethylene glycol)) (PEG) polymer in conjugation with paclitaxel has been described. Paclitaxel, a poorly soluble anticancer drug, was covalently conjugated with PAMAM G4 hydroxyl-terminated dendrimer and bis(PEG) polymer for the potential enhancement of drug solubility and cytotoxicity. Both conjugates were characterized by 1NMR, HPLC, and MALDI/TOF. In addition, molecular conformations of dendrimer, bis(PEG), paclitaxel, and its polymeric conjugates were studied by molecular modeling. Hydrolysis of the ester bond in the conjugate was analyzed by HPLC using esterase hydrolyzing enzyme. In vitro cytotoxicity of dendrimer, bis(PEG), paclitaxel, and polymeric conjugates containing paclitaxel was evaluated using A2780 human ovarian carcinoma cells. Cytotoxicity increased by 10-fold with PAMAM dendrimer-succinic acid-paclitaxel conjugate when compared with free nonconjugated drug. Data obtained indicate that the nanosized dendritic polymer conjugates can be used with good success as anticancer drug carriers.
Poly(vinylcaprolactam) (PVCL)-based biodegradable microgels were prepared for the biomedical application as drug delivery system via precipitation polymerization, where N,N-bis(acryloyl) cystamine (BAC) served as cross-linker, methacrylic acid (MAA) and polyethylene glycol (PEG) methyl ether methacrylate acted as comonomers. The microgels with excellent stability had distinct temperature sensitivity as largely observed in the case of PVCL-based particles and their volume phase transition temperature (VPTT) shifted to higher temperature with increasing MAA content and ambient pH. In the presence of reducing agent glutathione (GSH) or dithiothreitol (DTT), the microgels could be degraded into individual linear polymer chains by the cleavage of the disulfide linkages coming from the cross-linker BAC. The microgels could effectively encapsulate Doxorubicin (DOX) inside and presented stimuli-triggered drug release in acidic or reducing environment. The results of the cytotoxicity assays further demonstrated that the blank microgels were nontoxic to normal cells while DOX-loaded microgels presented efficient antitumor activity to HeLa cells.
Intelligent gene delivery systems based on physiologically triggered reversible shielding technology have evinced enormous interest due to their potential in vivo applications. In the present work, an acid-labile block copolymer consisting of poly(ethylene glycol) and poly(2-(dimethylamino)ethyl methacrylate) segments connected through a cyclic ortho ester linkage (PEG- a-PDMAEMA) was synthesized by atom transfer radical polymerization of DMAEMA using a PEG macroinitiator with an acid-cleavable end group. PEG- a-PDMAEMA condensed with plasmid DNA formed polyplex nanoparticles with an acid-triggered reversible PEG shield. The pH-dependent shielding/deshielding effect of PEG chains on the polyplex particles were evaluated by zeta potential and size measurements. At pH 7.4, polyplexes generated from PEG- a-PDMAEMA exhibited smaller particle size, lower surface charge, reduced interaction with erythrocytes, and less cytotoxicity compared to PDMAEMA-derived polyplexes. At pH 5.0, zeta potential of polyplexes formed from PEG- a-PDMAEMA increased, leveled up after 2 h of incubation and gradual aggregation occurred in the presence of bovine serum albumin (BSA). In contrast, the stably shielded polyplexes formed by DNA and an acid-stable block copolymer, PEG- b-PDMAEMA, did not change in size and zeta potential in 6 h. In vitro transfection efficiency of the acid-labile copolymer greatly increased after 6 h incubation at pH 5.0, approaching the same level of PDMAEMA, whereas there was only slight increase in efficiency for the stable copolymer, PEG- b-PDMAEMA.
The design of bioresponsive controlled drug delivery systems is a promising approach in cancer therapy, but it still is a major challenge capable of optimum therapeutic efficacy, i.e. no premature drug leakage in blood circulation while having a rapid and complete release in tumor tissues. In this work, a kind of PEGylated core/shell structured composite nanoparticle was developed via precipitation polymerization, where a disulfide-cross-linked poly(N-vinylcaprolactam-co-methacrylic acid) (P(VCL-s-s-MAA)) polymer shell was created to act as sheddable thermo/pH-sensitive gatekeepers, and a carboxylic acid modified mesoporous silica nanoparticles (MSN-COOH) core was applicable as an accessible reservoir to encapsulate high drug doses. At physiological conditions, the P(VCL-s-s-MAA)-PEG shell underwent a distinct transition from a swollen state in pH 7.4 to a collapsed state in pH 5.0. Though sufficiently stable in water, composite nanoparticles were prone to fast dissociation and rupture when subjecting to 10 mM glutathione (GSH), due to the shedding of polymer walls through reductive cleavage of intermediate disulfide bonds, so that the polymer shell was active in moderating the diffusion of embedded drugs in-and-out of MSN channels. The cumulative in vitro release of DOX-loaded composite nanoparticles allowed a low trace of DOX diffusion below volume phase transition temperature (VPTT) and a significant release rate above its VPTT, while the most rapid and perfect release was achieved under a reductive environment (pH 6.5 and 10 mM GSH), mimicking that of intracellular cytosol compartments. The in vitro cell assay of blank carriers to normal cells indicated that the composite nanoparticles were suitable as drug carriers, but DOX-loaded carriers had a similar intensive toxicity to cancer cells compared with free DOX. Therefore, these stimuli-responsive composite nanoparticles with a reductively sheddable and thermo/pH-responsive polymer shell gate could, in principle, be applied for in vivo cancer therapy, and synergistic drug delivery can be accomplished “just in time” in a precise event over the location.
Small interfering RNA (siRNA) can efficiently silence disease-related genes in a sequencespecific manner, creating an entirely new siRNA-based gene therapy. [1][2] However, safe and effective siRNA delivery remains a major challenge. [2][3] Although viral vectors are very effective, increasing concerns over their safety and immunogenicity substantiate the need to develop alternative nonviral vectors. During the past years, myriads of natural and synthetic nonviral vectors differing in size, shape, structure, chemistry and mode of action have been developed for siRNA delivery. [4][5][6][7][8] These delivery systems can be generally classified into two major groups: lipid and polymer vectors. For both, the efficiency is often cell type dependent, with siRNA delivery to primary and stem cells being particularly difficult. Here, we report for the first time an adaptive amphiphilic dendrimer-based Address correspondence to: Ling Peng, Ph.D., ling.peng@univ-amu.fr. [9] which, in the presence of siRNA, spontaneously undergo structural rearrangement into smaller, spherical micelles, thereby maximizing the interactions between the siRNA and AD (Scheme 1B). The peculiar self-assembly of AD into adaptive supramolecular structures alongside its advantageous combination of lipid and dendrimer vector features is evocative of virus-like delivery. Our study hence opens new perspectives in nonviral vector design for siRNA-based gene therapy. HHS Public AccessThe amphiphilic dendrimer AD (Scheme 1A) was synthesized readily via click chemistry (Scheme S1-3). [10] It spontaneously self-assembled in water into spherical nanostructures of ~200 nm in diameter, as revealed by dynamic light scattering (DLS) and transmission electron microscopy (TEM) ( Figure 1A,B). TEM images revealed a corona structure ( Figure 1C), which we inferred to be a bilayer, from the fact that its thickness was 7 nmapproximately twice the theoretical length of AD (~3.5 nm). Accordingly, AD readily selfassembled to form unilamellar vesicles aptly termed dendrimersomes. [9] In addition, AD formed a Langmuir monolayer film at the air/water interface and could be swelled to form stable giant vesicles ( Figure S1), providing further indication of its lipid-like behavior and vesicle-forming properties.Most interestingly, upon interaction with siRNA, the AD-dendrimersomes underwent structural rearrangement to form nanosized siRNA/AD complexes ( Figure 1D) composed of many highly ordered smaller spherical substructures of 6-8 nm diameter ( Figure 1E,F). From this size, which is twice the size of AD, we conclude that these substructures are micelles. This vesicular to micellar structural transition is expected to expose more the positively charged dendrimer surface area, thereby providing stronger stabilizing electrostatic interactions with the negatively charged siRNA. This implies that AD is able to dynamically self-assemble into responsive and adaptive supramolecular assemblies (Scheme 1B) in the presence of external stimuli.In order to verify this hypothesis and ...
The integration of photodynamic therapy (PDT) with photothermal therapy (PTT) offers improved efficacy in cancer phototherapy. Herein, a PDT photosensitizer (IR-808) with cancer-targeting ability and near-infrared (NIR) sensitivity was chemically conjugated to both polyethylene glycol (PEG)- and branched polyethylenimine (BPEI)-functionalized nanographene oxide (NGO). Because the optimal laser wavelength (808 nm) of NGO for PTT is consistent with that of IR-808 for PDT, the IR-808-conjugated NGO sheets (NGO-808, 20-50 nm) generated both large amounts of reactive oxygen species (ROS) and local hyperthermia as a result of 808 nm laser irradiation. With PEG- and BPEI-modified NGO as the carrier, the tumor cellular uptake of NGO-808 exhibited higher efficacy than that of strongly hydrophobic free IR-808. Through evaluation with both human and mouse cancer cells, NGO-808 was demonstrated to provide significantly enhanced PDT and PTT effects compared to individual PDT using IR-808 or PTT using NGO. Furthermore, NGO-808 preferentially accumulated in cancer cells as mediated by organic-anion transporting polypeptides (OATPs) overexpressed in many cancer cells, providing the potential for highly specific cancer phototherapy. Using the targeting ability of NGO-808, in vivo NIR fluorescence imaging enabled tumors and their margins to be clearly visualized at 48 h after intravenous injection, providing a theranostic platform for imaging-guided cancer phototherapy. Remarkably, after a single injection of NGO-808 and 808 nm laser irradiation for 5 min, the tumors in two tumor xenograft models were ablated completely, and no tumor recurrence was observed. After treatment with NGO-808, no obvious toxicity was detected in comparison to control groups. Thus, high-performance cancer phototherapy with minimal side effects was afforded from synergistic PDT/PTT treatment and cancer-targeted accumulation of NGO-808.
Supercritical carbon dioxide was used as a reaction medium to synthesize statistically random (i.e., no specific correlation between the location of the monomers on the polymer) copolymers of tetrafluoroethylene (TFE) and vinyl acetate (VAc) with similar molar mass and 11.6-63.3 mol % TFE content. The solubility of the copolymers at 25°C in CO 2 reduced after reaching a maximum value at a TFE molar concentration of 19.3 mol %. The 46.7 mol % TFE copolymer only dissolved in CO2 at elevated temperatures, whereas the 63.3 mol % TFE copolymer did not dissolve in CO2 even at temperatures in excess of 144°C and pressures of 210 MPa. The molecular modeling results show that the interaction of CO2 with acetate side group was not affected by presence of fluorine in the polymer backbone; therefore, the enhanced solubility of the semifluorinated copolymers is attributable to the enhanced binding between CO2 and the semifluorinated backbone of the copolymer when the CO2 molecule can access both the fluorinated (Lewis base) and hydrogenated (Lewis acid) parts of the backbone simultaneously.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.