The poly(amidoamine)s (PAAs) ISA 1 and ISA 23 display pH-dependent conformational change and pH-dependent membrane perturbation. These properties confer potential for use as endosomolytic polymers for intracytoplasmic delivery of toxins and genes. Both polymers are relatively non-toxic, and moreover ISA 23 has the beneficial property in vivo, of being non hepatotropic when administered intravenously. Although ISA 23 and ISA 1 demonstrate ability to transfect cells, ISA 1 is also able to promote intracellular delivery of non-permeant toxins. The aim of this study was to synthesise random and block copolymers of ISA 1 and ISA 23 and investigate whether these second generation hybrids would allow optimisation of PAA biological characteristics. Random and block copolymers of ISA 1 and ISA 23 were synthesised by hydrogen transfer polyaddition to generate a library of PAAs with an ISA 23:ISA 1 molar ratios of 2:1 to 4:1. The resultant polymers have a pI slightly below 7.4 and a M(w) of 19,900-49,000 g/mol and a M(n) of 13,100-24,100 g/mol. Whereas none of the random or block copolymers were haemolytic at pH 7.4 all demonstrated pH-dependent membrane activity. At pH 5.5 they caused 50-60% haemoglobin (Hb) release over 1 h. This was slightly less than that seen for ISA 23 (80% Hb release). None of the copolymers were cytotoxic against B16F10 cells during a 72 h incubation (IC(50) > 2 mg/ml; MTT assay). The ability of the random and block copolymer PAAs to deliver the toxin gelonin was also examined, but only ISA 1 and the block copolymer B2 (ISA 23:ISA 1 at a 2:1 molar ratio) were able to promote intracellular delivery, as measured by cytotoxic activity. It would be interesting to study the body distribution of B2 and determine whether this toxin-delivering PAA is able to escape liver capture. 相似文献
A new controlled release polymer micelle was designed and synthesized based on the concept of the “AND” logic with two orthogonal molecular triggers, namely pH and reduction, for intracellular drug delivery. Specifically, a hydrazine functionalized PEO‐b‐PMAA block copolymer was used to attach adriamycin (ADR) through the formation of hydrazone, then the as‐prepared ADR‐conjugated block copolymer micelles could be crosslinked by dithiodiethanoic acid. ADR was found to release most efficiently under both the low pH and the reductive conditions. This smart device is therefore equipped with two triggers with the “AND” logic for the releasing action, which is suitable for more complicated physiological conditions because the “ON” state is only realized under the simultaneous presence of the dual signal stimuli.
Although biodegradable amphiphilic block copolymer micelles have been widely applied in the clinical applications as drug delivery nanocarriers, low‐efficiency cellular internalization frequently reduces therapeutic efficacy of the loaded drugs. Here, photothermal effect‐promoted cellular internalization of finely tuned thermo‐responsive amphiphilic biodegradable block copolymer nanocarriers via noninvasive stimuli of near‐infrared (NIR) light irradiation is demonstrated. Amphiphilic block copolymers, poly(ε‐caprolactone)‐block‐poly(N‐isopropylacrylamide‐co‐N,N‐dimethylacrylamide) (PCL‐b‐P(NIPAM‐co‐DMA)), are prepared with finely tuned compositions of P(NIPAM‐co‐DMA) for desirable lower critical solution temperature of the block copolymer micelles in aqueous solution. The block copolymers are then used to co‐encapsulate doxorubicin and indocyanine green, which show high encapsulation efficiency and significant photothermal effect upon exposure to NIR light irradiation. The photothermal effect‐induced collapse and hydrophilic‐to‐hydrophobic transition of P(NIPAM‐co‐DMA) shells significantly enhance the interactions between drug‐loaded micelles and cell membranes, which dramatically promote the cellular internalization of the micelles and therapeutic efficacy of loaded anticancer drugs.
A novel type of drug carrier capable of controlled drug release is proposed. It consists of an acid-sensitive doubly hydrophilic multiarm hyperbranched copolymer with a hyperbranched polyamidoamine core and many linear poly(ethylene glycol) arms. Using pH-sensitive acylhydrazone linkages, the polymer forms unimolecular micelles that can encapsulate hydrophobic drugs. Due to their amphiphilicity, the drug-loaded unimolecular micelles can self-assemble into multimolecular micelles that show acid-triggered intracellular delivery of the hydrophobic drugs. 相似文献
A biodegradable amphiphilic pentablock copolymer PAE‐PCL‐PEG‐PCL‐PAE with a pH‐sensitive unit was synthesized for use as a nontoxic, biodegradable carrier for gene delivery by forming nanocapsules entrapping nucleic acid drugs. The PAE block can interact with plasmid DNA to form polyelectrolyte complexes in an acidic environment. At physiological pH, the PAE blocks are deprotonated and form an insoluble skin, resulting in the formation of nanocapsules that encapsulate plasmid DNA. The surface charges of the nanocapsules became almost neutral at pH = 7.4, and their size ranged from 210 to 280 nm. The nanocapsule maintained most of its transfection efficiency even in the presence of serum. These nanocapsules are therefore potential carriers for systemic gene therapy.
Summary: A new method has been developed to prepare smart polymeric microgels that consist of well‐defined temperature‐sensitive cores with pH‐sensitive shells. The microgels were obtained directly from aqueous graft copolymerizations of N‐isopropylacrylamide and N,N‐methylenebisacrylamide from water‐soluble polymers containing amino groups such as poly(ethyleneimine) and chitosan. The gel diameters ranged from 300 to 400 nm. The unique core‐shell nanostructures, which had narrow size distributions, exhibited tuneable responses to pH and temperature.
Transmission electron micrograph of the poly(N‐isopropylacrylamide)/chitosan core‐shell microgels. 相似文献
A temperature‐responsive polymer poly{2‐(dimethylamino)ethyl methacrylate‐co‐[cis‐butenedioic anhydride‐poly[(N‐isopropylacrylamide)‐co‐(butyl methacrylate)]]} (PDMNIB) was synthesized by free radical polymerization. The polymer had a significant temperature‐responsive behavior with a lower critical solution temperature (LCST) at 20 °C. Gel retardation assay showed that PDMNIB could efficiently interact with DNA. Dynamic light scattering (DLS) and zeta potential measurement indicated that the average sizes and the surface electric charges of the PDMNIB/DNA complexes could be changed by temperature. Due to the thermosensitive interaction between PDMNIB and DNA, the gene transfection efficiency of PDMNIB could be improved by temperature.
α‐Methoxy‐ω‐alkyne poly(ethylene glycol) (PEG) was tagged with pendent N‐hydroxy‐succinimidyl activated esters by photografting of a molecular clip. This easily synthesized heterofunctional PEG was found to be a versatile building block for (i) conjugation with an amino derivative and (ii) grafting to azido functional aliphatic polyesters backbone by Huisgen's 1,3‐dipolar cycloaddition. This original combination of “clip” and “click” reactions provides a versatile and straightforward pathway for the synthesis of functional amphiphilic and degradable copolymers valuable for biomedical applications such as in drug‐delivery.
Near‐infrared light (NIR) possesses great advantages for light‐responsive controllable drug release, such as deep tissue penetration and low damage to healthy tissues. Herein, a NIR‐responsive drug delivery system is developed based on a NIR dye, indocyanine green (ICG), and anticancer drug, doxorubicin (DOX)‐loaded thermoresponsive block copolymer micelles, in which the drug release can be controlled via NIR irradiation. First, block copolymers, poly(oligo(ethylene glycol) methacrylate)‐block‐poly(furfuryl methacrylate) (POEGMA‐b‐PFMA), are synthesized by sequential reversible addition‐fragmentation chain‐transfer (RAFT) polymerization, followed by modification with N‐octyl maleimide through Diels–Alder (DA) reaction to produce POEGMA‐b‐POMFMA. The self‐assembly of POEGMA‐b‐POMFMA by nanoprecipitation in aqueous solution affords the polymeric micelles which are used to simultaneously encapsulate ICG and DOX. Upon irradiation by NIR light (805 nm), the loaded DOX is released rapidly from the micelles due to partial retro DA reaction and local temperature increase‐induced faster drug diffusion by the photothermal effect. Cytotoxicity evaluation and intracellular distribution observation demonstrate significant synergistic effects of NIR‐triggered drug release, photothermal, and chemotherapy toward cancer cells under NIR irradiation.
Synthesis and characterization of a pH‐ and redox‐sensitive hydrogel of poly(aspartic acid) are reported. Reversible gelation and dissolution are achieved both in dimethylformamide and in aqueous medium via a thiol‐disulphide interconversion in the side chain of the polymers. Structural changes are confirmed by Raman microscopy and rheological measurements. Injectable aqueous solutions of thiolated poly(aspartic acid) can be converted into mechanically stable gels by oxidation, which can be useful for drug encapsulation and targeted delivery. Reduction‐facilitated release of an entrapped drug from disulphide cross‐linked hydrogels is studied.
Well‐defined amphiphilic linear‐dendritic prodrugs (MPEG‐b‐PAMAM‐DOX) are synthesized by conjugating doxorubicin (DOX), to MPEG‐b‐PAMAM through the acid‐labile hydrazone bond. The amphiphilic prodrugs form self‐assembled nanoparticles in deionized water and encapsulate the hydrophobic anticancer drug 10‐hydroxycamptothecin (HCPT) with a high drug loading efficiency. Studies on drug release and cellular uptake of the co‐delivery system reveal that both drugs are released in a pH‐dependent manner and effectively taken up by MCF‐7 cells. In vitro methyl thiazolyl tetrazolium (MTT) assays and drug‐induced apoptosis tests demonstrate the HCPT‐loaded nanoparticles suppress cancer cell growth more efficiently than the MPEG‐b‐PAMAM‐DOX prodrugs, free HCPT, and physical mixtures of MPEG‐b‐PAMAM‐DOX and HCPT at equivalent DOX or HCPT doses.
Poly(amidoamine)s with amino pendant groups were prepared by hydrogen‐transfer polyaddition of primary and secondary amines to bis‐acrylamines. Dansyl cadaverine (DC) doxorubicin (Dox) were bound to the polymers via a cis‐aconityl spacer to give conjugates containing 3 µg of DC per mg of polymer and 28 to 35 µg of Dox per mg of polymer. Release of DC and Dox at physiological and acidic pH varied from 0 to 35% over 48 h and was pH dependent. Although the ISA1Dox conjugate (IC50 = 6 µg Dox · mL?1) presented similar toxicity as the parent polymer without Dox, ISA23Dox showed increased toxicity (IC50 = 10 µg Dox · mL?1). These results suggest that ISA23Dox is able to release biologically active Dox in vitro and that this conjugate might be suitable for further development.
Summary: Specific temperature‐responsive biodegradable hydrogels were synthesized and characterized in terms of their regulation of enzymatic accessibility based on the physical properties of the temperature‐responsive polymers. The hydrogels consist of glycidyl methacrylate‐modified dextran grafted with the poly(N‐isopropylacrylamide) (PNIPAAm) homopolymer, and cross‐linked by co‐polymerization with NIPAAm and N,N‐dimethylacrylamide (DMAAm). The coil‐globule change in the grafted poly(NIPAAm) chains and only a slight dehydration of the poly(NIPAAm‐co‐DMAAm) cross‐linkers are effective in controlling the enzymatic degradation over a specific temperature range.
The thermo‐responses of the graft chains (steric hindrance) and the crosslinkers (slight deswelling of the hydrogel networks) control the enzymatic degradation of the hydrogel. 相似文献
The design and development of multifunctional polymer capsules with controlled chemical composition and physical properties has been the focus of academic and industrial research in recent years. Especially in the biomedical field, the formulation of novel polymer‐based encapsulation systems for the early‐stage disease diagnostic and effective delivery of bioactive agents represent one of the most rapidly advancing areas of science. The stimuli‐responsive release of cargo molecules from the carrier gains remarkable attention for in vitro and in vivo delivery of contrast agents, genes, and pharmaceutics. In this Review, the current status and the challenges of different polymer‐based micro‐ and nanocapsule formulations are considered, emphasizing on their potential biological application as carriers for specific drug targeting and controlled release upon applying of external stimulus. 相似文献
