A series of dual stimuli responsive synthetic polymer bioconjugate chimeric materials, poly(N-isopropylacrylamide)55-block-poly(L-histidine)n [p(NIPAM)55-b-p(His)n] (n=50, 75, 100, 125), have been synthesized by employing reversible addition-fragmentation chain transfer polymerization of NIPAM, followed by ring-opening polymerization of α-amino acid N-carboxyanhydrides. The dual stimuli responsive properties of the resulting biocompatiable and membrenolytic p(NIPAM)55-b-p(His)n polymers are investigated for their use as a stimuli responsive drug carrier for tumor targeting. Highly uniform self-assembled micelles (∼55 nm) fabricated by p(NIPAM)55-b-p(His)n polymers display sharp thermal and pH responses in aqueous media. An anticancer drug, doxorubicin (Dox), is effectively encapsulated in the micelles and the controlled Dox release is investigated in different temperature and pH conditions. Antitumor effect of the released Dox is also assessed using the HepG2 human hepatocellular carcinoma cell lines. Dox molecules released from the [p(NIPAM)55-b-p(His)n] micelles remain biologically active and have stimuli responsive capability to kill cancer cells. The self-assembling ability of these hybrid materials into uniform micelles and their efficiency to encapsulate Dox makes them a promising drug carrier to cancer cells. The new chimeric materials thus display tunable properties that can make them useful for a molecular switching device and controlled drug delivery applications needing responses to temperature and pH for the improvement of cancer chemotherapy.
A series of synthetic polymer bioconjugate hybrid materials consisting of poly(2‐hydroxyethyl methacrylate) (p(HEMA)) and poly(l‐histidine) (p(His)) are synthesized by combining atom transfer radical polymerization of HEMA with ring opening polymerization of benzyl‐N‐carboxy‐L‐histidine anhydride. The resulting biocompatible and membranolytic p(HEMA)25‐b‐p(His)n (n = 15, 25, 35, and 45) polymers are investigated for their use as pH‐sensitive drug‐carrier for tumor targeting. Doxorubicin (Dox) is encapsulated in nanosized micelles fabricated by a self‐assembly process and delivered under different pH conditions. Micelle size is characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM) observations. Dox release is investigated according to pH, demonstrating the release is sensitive to pH. Antitumor activity of the released Dox is assessed using the HCT 116 human colon carcinoma cell line. Dox released from the p(HEMA)‐b‐p(His) micelles remains biologically active and has the dose‐dependent capability to kill cancer cells at acidic pH. The p(HEMA)‐b‐p(His) hybrid materials are capable of self‐assembling into nanomicelles and effectively encapsulating the chemotherapeutic agent Dox, which allows them to serve as suitable carriers of drug molecules for tumor targeting.
A series of poly(ethylene glycol) methyl ether acrylate-block-poly(L-lysine)-block-poly(L-histidine) [p(PEGA)30-b-p(Lys)25-b-p(His)n] (n = 25, 50, 75, 100) triblock copolypeptides were designed and synthesized for tumoral pH-responsive intracellular release of anticancer drug doxorubicin hydrochloride (Dox). The tumoral acidic pH-responsive hybrid vesicles fabricated were stable at physiological pH 7.4 and could gradually destabilize in acidic pH as a result of pH-induced swelling of the p(His) block. The blank vesicles were nontoxic over a wide concentration range (0.01-100 μg/mL) in normal cell lines. The tumor acidic pH responsiveness of these vesicles was exploited for intracellular delivery of Dox. Vesicles efficiently encapsulated Dox, and pH-induced destabilization resulted in the controlled and sustained release of Dox in CT26 murine cancer cells, and dose-dependent cytotoxicity. The tumor-specific controlled release Dox from vesicles demonstrates this system represents a promising theranostic agent for tumor-targeted delivery.
Smart delivery system of photosensitizer chlorin e6 (Ce6) has been developed for targeted photodynamic therapy (PDT). Simple self-assemblies of the mixtures comprising soybean lecithin derived phosphatidylcholine (PC), phosphatidylethanolamine-poly(L-histidine)40 (PE-p(His)40), and folic acid (FA) conjugated phosphatidylethanolamine-poly(N-isopropylacrylamide)40 (PE-p(NIPAM)40-FA) in different ratios yield smart nanospheres characterized by (i) stable and uniform particle size (∼100 nm), (ii) positive surface charge, (iii) high hydrophobic drug (Ce6) loading efficiency up to 45%, (iv) covalently linked targeting moiety, (v) low cytotoxicity, and (vi) smartness showing p(His) block oriented pH and p(NIPAM) oriented temperature responsiveness. The Ce6-encapsulated vesicular nanospheres (Ce6@VNS) were used to confirm the efficiency of cellular uptake, intracellular distribution, and phototoxicity against KB tumor cells compared to free Ce6 at different temperature and pH conditions. The Ce6@VNS system showed significant photodynamic therapeutic efficiency on KB cells than free Ce6. A receptor-mediated inhibition study proved the site-specific delivery of Ce6 in targeted tumor cells.
Stimuli-responsive nanocarriers are a class of soft materials that includes natural polymers, synthetic polymers, and polypeptides. Recently, modern synthesis tools such as atom transfer radical polymerization, reversible addition-fragmentation chain transfer polymerization, nitroxide-mediated radical polymerization, ring-opening polymerization of α-amino acid N-carboxyanhydrides, and various "click" chemistry strategies were simultaneously employed for the design and synthesis of nanosized drug delivery vehicles. Importantly, the research focused on the improvement of the nanocarrier targetability and the site-specific, triggered release of therapeutics with high drug loading efficiency and minimal drug leakage during the delivery to specific targets. In this context, nanocarriers responsive to common stimuli such as pH, temperature, redox potential, light, etc. have been widely used for the controlled delivery of therapeutics to pathological sites. Currently, different synthesis and self-assembly strategies improved the drug loading efficacy and targeted delivery of therapeutic agents to the desired site. In particular, polypeptide-containing hybrid materials have been developed for the controlled delivery of therapeutic agents. Therefore, stimuli-sensitive synthetic polypeptide-based materials have been extensively investigated in recent years. This review focuses on recent advances in the development of polymer-block-polypeptides and polymer-conjugated hybrid materials that have been designed and evaluated for various stimuli-responsive drug and gene delivery applications.
For decades, researchers have aspired to develop materials for noninvasive treatment and monitoring of pathological conditions. Various organs, tissues, subcellular compartments, and their pathophysiological states can be characterized by their pH values. pH-dependent intracellular tumor targeting has received particular attention due to the unique acidic environment of the solid tumors created by physiological and metabolical abnormalities. Responsive nanocarriers, when exposed to these pH stimuli, respond quickly to the physicochemical changes by undergoing structural deformations, such as swelling and phase transition, which favors the drug release specifically at the diseased site. Recently, researchers have developed several new poly(L-histidine) (p(His))-based pH responsive systems for sustained drug release and molecular targeting. This review focuses on the p(His)-based pH responsive nanocarriers, which are utilized in biomedical applications such as anti-cancer drug delivery and nucleic acid delivery. V C 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40796.
Injectable, drug-releasing hydrogel scaffolds with multifunctional properties including haemostasis and anti-bacterial activity are essential for successful wound healing, however, the design of an ideal material is still challenging. Herein, we...
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