Cancer cells have high iron requirements due to their rapid growth and proliferation. Iron depletion using iron chelators has a potential in cancer treatment. Previous studies have demonstrated that ...deferoxamine (DFO) specifically chelates Fe(III) and exhibited antitumor activity in clinical studies. However, its poor pharmacokinetics has limited the therapeutic potential and practical application. Although polymeric iron chelators have been developed to increase the blood retention, none of previous studies has demonstrated their potential in iron chelation cancer therapy. Here, we developed polymeric DFO by the covalent conjugation of DFO to poly(ethylene glycol)‐poly(aspartic acid) (PEG‐PAsp) block copolymers. The polymeric DFO exhibited iron‐chelating ability comparable with free DFO, thereby arresting cell cycle and inducing apoptosis and antiproliferative activity. After intravenous administration, the polymeric DFO showed marked increase in blood retention and tumor accumulation in subcutaneous tumor models. Consequently, polymeric DFO showed significant suppression of the tumor growth compared with free DFO. This study reveals the first success of the design of polymeric DFO for enhancing iron chelation cancer therapy.
Deferoxamine (DFO) is a unique iron chelator that exhibits antiproliferative activity on cancer cells by regulating the amount of iron in cells; however, its poor pharmacokinetics has limited the therapeutic potential and practical application. To realize effective iron chelation cancer therapy, we synthesized a simple biocompatible polymeric DFO (a polymer‐DFO conjugate) offering prolonged retention in blood and augmented tumor accumulation through the enhanced permeability and retention effect. Our polymeric DFO exhibited significant suppression of the tumor growth compared with free DFO, and was consistent with the pharmacokinetics and pharmacodynamics.
In photodynamic therapy (PDT), the inherent physicochemical properties of a photosensitizer (PS) critically affect its biodistribution and therapeutic outcome as well as side effect. Here, we ...developed a PS-polymer conjugate displaying isothermal hydrophilic-to-hydrophobic phase transition in response to tumorous acidic pH. The polymer backbone was poly(N-isopropylacrylamide (NIPAAm)/2-aminoisoprpylacrylamide (AIPAAm)) (P(NIPAAm/AIPAAm)), which shows lower critical solution temperature (LCST) of 30 °C. The amine groups in its side chains were converted to hydrophilic acid-labile 2-propionic-3-methylmaleic (PMM) amides, forming poly(NIPAAm/AIPAAm-PMM). The conjugation of PMM moieties drastically increased the LCST of the polymer to 40 °C and displayed hydrophilic character to minimalize unspecific interaction of PS-P(NIPAAm/AIPAAm-PMM) in bloodstream, diminishing potential photosensitivity. The detachment of PMM at tumorous pH lowered the LCST to that of original P(NIPAAm/AIPAAm), permitting hydrophilic-to-hydrophobic transition at a physiological temperature (37 °C). This pH-responsive isothermal phase transition facilitated interaction with the cultured cancer cells, accomplishing 8.1 times-enhanced cellular uptake and strong phototoxicity in a tumorous pH-selective manner. Even in subcutaneous tumor models, our polymer conjugates exhibited efficient tumor accumulation and significantly augmented PDT effect without inducing unfavorable photochemical toxicity to the skin. This study offers a novel concept of PS delivery systems targeting tumorous pH by the use of isothermal phase transition.
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•pH-responsive isothermal phase transition potentiates photosensitizer delivery.•The polymer could target mild acidic extracellular pH in a tumor.•Hydrophilicity prevented unfavorable interaction with serum components.•Hydrophobicity facilitated cellular uptake and augmented therapeutic effect.
Intravenously injected high-dose vitamin C (VC) induces extracellular H2O2, which can penetrate into the tumor cells and suppress tumor growth. However, extracellular labile iron ions in the tumor ...decompose H2O2 via the Fenton reaction, limiting the therapeutic effect. In this regard, we recently developed a polymeric iron chelator that can inactivate the intratumoral labile iron ions. Here, we examined the effect of our polymeric iron chelator on the high-dose VC therapy in in vitro and in vivo. In the in vitro study, the polymeric iron chelator could inactivate the extracellular labile iron ions and prevent the unfavorable decomposition of VC-induced H2O2, augmenting pro-oxidative damage to DNA and inducing apoptosis in cultured cancer cells. Even in the in vivo study, the polymeric iron chelator significantly improved the antitumor effect of VC in subcutaneous DLD-1 and CT26 tumors in mice, while conventional iron chelators could not. This work indicates the importance of modulating tumor-associated iron ions in the high-dose VC therapy and should contribute to a better understanding of its mechanism.
The polymerization of N-isopropylacrylamide (NIPAAm) with ionizable monomers results in pH-responsive lower critical solution temperature (LCST) polymer which works in an ionization-dependent manner. ...However, gradual ionization of the comonomer occurs at a broad pH range due to the electrostatic field generated by the polymers, limiting the extent of LCST shift in response to pH change. Furthermore, excess introduction of comonomer may dull phase transition behavior. Here, we report the development of an ionization-independent LCST polymer that exerts a sharp isothermal hydrophilic-to-hydrophobic phase transition in response to slight pH change. Our polymer has a poly(NIPAAm/2-aminoisoprpylacrylamide (AIPAAm)) (P(NIPAAm/AIPAAm)) backbone that retains the continuous structural similarity of N-alkyl groups for preserving phase transition sensitivity, and primary amine for forming hydrophilic acid-labile 2-propionic-3-methylmaleic (PMM) amide linkage. The PMM moiety improves the polymer’s hydrophilicity and drastically increases the LCST. Detachment of the PMM moiety in response to mild acidic condition (pH < 6.8) lowers the LCST to that of original P(NIPAAm/AIPAAm), permitting isothermal pH-responsive phase transition. Utilizing this mechanism, P(NIPAAm/AIPAAm) modified with PMM amide linkage exhibits a sharp hydrophilic-to-hydrophobic transition at a physiological temperature (37 °C) and, strikingly, facilitates interaction with cultured cells. Most importantly, our polymer showed significantly higher accumulation within a solid tumor after systemic injection compared to conventional PNIPAAm, which may be due to its phase transition responding to slightly acidic tumor microenvironment. Thus, this study provides a novel polymer that offers delicate control of LCST and pH-responsiveness suitable for use in even fuzzy biological environments.
Nanomaterials have been explored in the sensing research field in the last decades. Mainly, 3D nanomaterials have played a vital role in advancing biomedical applications, and less attention was ...given to their application in the field of biosensors for pathogenic virus detection. The versatility and tunability of a wide range of nanomaterials contributed to the development of a rapid, portable biosensor platform. In this review, we discuss 3D nanospheres, one of the classes of nanostructured materials with a homogeneous and dense matrix wherein a guest substance is carried within the matrix or on its surface. This review is segmented based on the type of nanosphere and their elaborative application in various sensing techniques. We emphasize the concept of signal amplification strategies using different nanosphere structures constructed from a polymer, carbon, silica, and metal-organic framework (MOF) for rendering high-level sensitivity of virus detection. We also briefly elaborate on some challenges related to the further development of nanosphere-based biosensors, including the toxicity issue of the used nanomaterial and the commercialization hurdle.
Tocotrienol is a subfamily of natural vitamin E with multiple biological activities, including antioxidants, antiproliferative, proapoptotic, antiangiogenic, and anti-inflammatory properties. Despite ...numerous biological activities, the application of tocotrienol is hampered by its poor solubility, resulting in low bioavailability, and in turn, limits its therapeutic effectivity. To address these limitations, the present study focuses on the development of tocotrienol nanoemulsion, followed by an in vitro anticancer evaluation of the formula. The tocotrienol nanoemulsion was prepared by a combination of high-speed homogenization with ultrasonication, using food-grade canola oil and Tween 80 as oil phases and surfactants, respectively. The formulated nanoemulsion observed an encapsulation efficiency of 90.26% with particle size and zeta potential of 145 ± 0.06 nm and −25.27 ± 0.01 mV, respectively. The FTIR spectra show no interference between the active compounds and the excipients, indicating that tocotrienol was successfully loaded into the nanoemulsion. Besides, the tocotrienol nanoemulsions demonstrated higher antioxidant ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging activity than the free form of tocotrienol at the same concentration (
p
< 0.05). In the in vitro cytotoxicity studies, there was a decrease in cell viability observed against MCF-7 breast and A549 lung cancer cell lines for tocotrienol nanoemulsion. Overall, it suggests that nanoemulsion-based natural component delivery systems have substantial implications in developing and designing encapsulated biologically active systems. The potent cytotoxicity of tocotrienol-loaded nanoemulsion under aqueous phases provides insight into the development of nanoemulsion systems for enhancing the bioavailability and activity of tocotrienol as well as other lipophilic compounds in water systems, particularly for anticancer therapeutic.
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Early diagnosis of dengue infection by detecting the dengue virus non-structural protein 1 (DENV-NS1) is important to the patients to initiate speedy treatment. Enzyme-linked immunosorbent assay ...(ELISA)-based NS1 detection and RT-PCR are time-consuming and too complex to be employed in remote areas of dengue-endemic countries. Meanwhile, those of NS1 rapid test by lateral flow assay suffer from low detection limit. Electrochemical-based biosensors using screen-printed gold electrodes (SPGEs) have become a reliable detection method to convey both ELISA’s high sensitivity and rapid test portability. In this research, we developed an electrochemical biosensor for DENV-NS1 detection by employing polydopamine (PDA)-modified SPGE. The electrodeposition of PDA on the surface of SPGE serves as a bioconjugation avenue for anti-NS1 antibody through a simple and low-cost immobilization procedure. The biosensor performance was evaluated to detect DENV-NS1 protein in PBS and human serum through a differential pulse voltammetric (DPV) technique. The developed sensing platform displayed a low limit of detection (LOD) of 1.63 pg mL
–1
and a wide linear range of 10 pg mL
–1
to 1 ng mL
–1
(
R
2
∼ 0.969). The sensing platform also detected DEV-NS1 from four different serotypes in the clinical samples collected from dengue patients in India and Indonesia, with acceptable sensitivity, specificity, and accuracy values of 90.00%, 80.95%, and 87.65%, respectively. This result showcased the facile and versatile method of PDA coating onto the surface of screen-printed gold electrodes for a miniaturized point-of-care (PoC) detection device.
Graphical Abstract
Curcuma xanthorrhiza Roxb, Phyllanthus niruri L., and Morinda citrifolia L. are Indonesian medicinal herbs used empirically as traditional therapeutics for maintaining health. The cocktail extract of ...these three plants (CECPM) had been developed and demonstrated immunostimulant activity in rats. This study aimed to evaluate the acute and subchronic toxicity of CECPM in vivo. The acute toxicity assay was conducted by orally administering a range dose of CECPM (313, 625, 1250, 2500, or 5000 mg/kg body weight (bw) on female mice once and then evaluating the toxic symptom every day for 14 days later. The chronic toxicity test was carried out by giving various doses of CECPM (600, 800, and 1000 mg/kg·bw) to female and male rats orally continuously for 90 consecutive days. The signs of toxicities were evaluated at the 90- and 28 days postadministration. The acute oral toxicity assays showed that there was no toxic syndrome and mortality found during the period of the experiment. The lethal dose level (LD50) of CECPM was more than 5000 g/kg, which was categorized as practically non-toxic. Meanwhile, in the sub-chronic toxicity study, some parameters tested at 90 days postadministration and after 28 days of withdrawal, such as the body weight, relative organ weight, food intake, hematological and biochemical blood parameters, and also histopathological examination of five primary tissues (heart, liver, kidney, spleen, and lung) revealed no abnormalities. There was no-observed adverse effect level (NOAEL) for the present study of CECPM 1000 mg/kg·bw of the rat. Therefore, it is concluded that the orally administered CECPM was relatively nontoxic during acute and subchronic toxicology studies.
Photosensitizer delivery is prerequisite for successful photodynamic therapy (PDT), and many photosensitizers have been developed and investigated in in vitro and in vivo studies 1. In general, ...hydrophobic photosensitizers can efficiently interact with biological components including cell membrane via hydrophobic interaction and exhibit high cellular uptake, inducing strong PDT effects in in vitro conditions.
However, in in vivo conditions, such hydrophobic photosensitizers also interact with normal cells and tissues as well as target tumours, which causes unfavourable photochemical damage. On the other hand, hydrophilic photosensitizers avoid unfavourable interaction with biological components and their retention in the skin, reducing photosensitivity which is one of the side effects in PDT. However, the compromised interaction leads to low cellular uptake and PDT effects. Thus, it is difficult to develop photosensitizers that can induce strong PDT effects without showing severe photochemical damage to normal tissues.
In this study, to integrate these conflicting properties of hydrophobic/hydrophilic photosensitizers, we developed a functional polymer exerting isothermal hydrophilic-to-hydrophobic phase transition in response to mildly acidic pH in tumours 2. The backbone of the polymer was a poly(N-isopropylacrylamide) derivative, which is well known to show lower critical solution temperature, and its side chain was modified with hydrophilic pH-cleavable moieties. The polymer termed P(NIPAAm/AIPAAm-PMM) showed hydrophilicity in a physiological condition (37°C, pH 7.4); however, in a tumour microenvironment-like condition (37°C, pH ≤ 6.9), P(NIPAAm/AIPAAm-PMM) exhibited hydrophobicity by detaching the hydrophilic moieties from the side chain. Owing to this pH-responsive hydrophilic-to-hydrophobic phase transition, the polymer exerted efficient cellular uptake in a pH-responsive manner. We then conjugated a phthalocyanine-based photosensitizer (IRDye 700DX) with the polymer and examined the potential of the polymer for PDT. In in vitro study, The photosensitizer-polymer conjugate exhibited strong PDT effects at acidic pH because of the aforementioned pH-responsive cellular uptake. In in vivo study, the photosensitizerpolymer conjugate efficiently accumulated within tumours in mice after intravenous injection and accomplished significantly enhanced PDT effects. Our results indicate that the control of hydrophilicity and hydrophobicity may be a promising approach to develop new photosensitizers for successful PDT.
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