Intravaginal delivery of siRNA for prevention of sexually transmitted infections faces obstacles such as the acidic environment and vaginal mucus barrier. To achieve effective protection and delivery of siRNA, we developed a polysuccinimide (PSI)-based nanocarrier (PSI-PEG-API-PMA, PPAP) by conjugating methoxy polyethylene glycol amine (Me-PEG-NH2, Mw 5000), 1-(3-aminopropyl)imidazole (API), and 1-pyrenemethylamine hydrochloride (PMA) to PSI. PPAP demonstrated a spherical self-assembled nanostructure before and after encapsulation of a model siRNA. Variable electrostatic interaction between API and siRNA at acidic vs. neutral pH accomplished significantly lower burst release at pH 4.2 (4 ± 1%) than pH 7.0 (26 ± 5%) within 1 h. PEGylation enabled siRNA-PPAP to achieve higher mucus penetration efficiency (64 ± 17%) than free siRNA (27 ± 5%) for 24 h. Moreover, in vitro study showed minimal toxicity, successful internalization of siRNA-PPAP in HeLa cells and improved gene knockdown (97.5 ± 0.4%). Overall, PPAP is promising for developing preventative treatments for battling sexually transmitted infections.

Deep tumor penetration, long blood circulation, rapid drug release, and sufficient stability are the most concerning dilemmas of nano-drug-delivery systems for efficient chemotherapy. Herein, we develop reduction/oxidation-responsive hierarchical nanoparticles co-encapsulating paclitaxel (PTX) and pH-stimulated hyaluronidase (pSH) to surmount the sequential biological barriers for precise cancer therapy. Poly(ethylene glycol) diamine (PEG-dia) is applied to collaboratively cross-link the shell of nanoparticles self-assembled by a hyaluronic acid-stearic acid conjugate linked via a disulfide bond (HA-SS-SA, HSS) to fabricate the hierarchical nanoparticles (PHSS). The PTX and pSH coloaded hierarchical nanoparticles (PTX/pSH-PHSS) enhance the stability in normal physiological conditions and accelerate drug release at tumorous pH, and highly reductive or oxidative environments. Functionalized with PEG and HA, the hierarchical nanoparticles preferentially prolong the circulation time, accumulate at the tumor site, and enter MDA-MB-231 cells via CD44-mediated endocytosis. Within the acidic tumor micro-environment, pSH would be partially reactivated to decompose the dense tumor extracellular matrix for deep tumor penetration. Interestingly, PTX/pSH-PHSS could be degraded apace by the completely activated pSH within endo/lysosomes and the intracellular redox micro-environment to facilitate drug release to produce the highest tumor inhibition (93.71%) in breast cancer models.

Background: The combination of novel starving therapy with chemotherapy is one of the most promising strategies to achieve an effective antitumor activity. Methods: Herein, we developed a multifunctional mesoporous silica nanoparticle (MSNs-GOx/PLL/HA) coated with poly (L-lysine) (PLL) and hyaluronic acid (HA) for co-delivery of glucose oxidase (GOx) and anticancer drug paclitaxel (PTX) for cancer treatment for the first time. Compared to single chemotherapy, introduction of GOx would not only selectively trigger the consumption of intracellular glucose, leading to the interruption of energy supply, but also elevat the endogenous H2O2 level, inducing stronger therapeutic effects. Results: The novel drug delivery system possessed desirable particle diameter of 40 nm and exhibited a pH-sensitive drug release behavior. An in vitro cellular uptake study indicated that MSNs-GOx/PLL/HA nanoparticles effectively enhanced the cellular uptake of drug in an apparently CD44 receptor-dependent manner, and delivered more cargo into cytoplasm via endolysosomal escape effect in presence of PLL. The nanoplatform has also demonstrated amplified synergistic therapeutic effects for remarkable tumor inhibition in a xenograft animal tumor model. Conclusion: Consequently, the developed synergistic starving-like/chemotherapy may provide a potential platform for next generation cancer therapy.

Melittin (Mel), one of the host defense peptides derived from the venom of honeybees, demonstrates substantial anticancer properties, which is attributed to augmenting reactive oxygen species (ROS) generation. However, little has been reported on its pro-oxidation capacity in cancer oxidation therapy. In this study, an ROS amplifying nanodevice was fabricated through direct complexation of two natural pro-oxidants, Mel and condensed epigallocatechin gallate (pEGCG). The obtained nanocomplex (NC) was further covered with phenylboronic acid derivatized hyaluronic acid (pHA) through the ROS-responsive boronate ester coordination bond to produce pHA-NC. Upon undergoing receptor-mediated endocytosis into cancer cells, the inner cores of pHA-NC will be partially uncovered once pHA corona is degraded by hyaluronidase and will then escape from the lysosome by virtue of cytolytic Mel. The elevated ROS level in the tumor cytoplasm can disrupt the boronate ester bond to facilitate drug release. Both Mel and pEGCG could synergistically amplify oxidative stress and prolong ROS retention in cancer cells, leading to enhanced anticancer efficacy. This ROS cascade amplifier based on selective coordination bond and inherent pro-oxidation properties of natural ingredients could detect and elevate intracellular ROS signals, potentiating to move the tumor away from its homeostasis and make the tumor vulnerable. Compared to previously reported chemosynthetic pro-oxidants, the ROS self-sufficient system, fully composed of natural medicine, from this study provides a new insight in developing cancer oxidation therapy.

Stimuli-responsive nanocarriers have demonstrated their potentials in optimizing chemotherapeutics and anticancer efficacy. In this study, a mixed micelle system (THSP) was prepared by combining reduction-sensitive hyaluronic acid-poly(lactide) (HA-ss-PLA) conjugates and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), with objective to achieve multiple functionalities of selective intracellular rapid release, active targeting capability and multidrug resistance reversal. The mixed micelle possessed desirable particle diameter of 124.32 nm and high entrapment efficiency at 87.97%. Importantly, the THSP mixed micelles demonstrated good stability in systemic circulation and rapidly released PTX in intracellular reductive environment. In vitro cellular uptake study and cytotoxicity assay indicated that the mixed micelles effectively increased drug accumulation in A549 cells and Taxol resistant A549/Taxol cells, and inhibited growth of tumor cells. In addition, the redox-responsive THSP micelles preferentially accumulated to the tumor site and improved anticancer drug activity in vivo, with a TIR of 69.08%. It was concluded that redox-sensitive mixed micelles THSP provided a potential vehicle for efficient anticancer drug delivery and enhancement in treating MDR tumor in the future.

The quest for an ideal cancer treatment has led to the exploration of a variety of platforms to facilitate highly desirable and efficient drug delivery. As most anticancer drugs possess therapeutic potency to destroy tumor cells, there is a need to steer the compounds to their required sites using site-specific drug delivery vehicles. This has inspired the investigation of various natural particulates and biomaterials for the purpose. Bio-inspired platforms that directly mimic natural components in the body have demonstrated their ability to serve as one of the most versatile and innovative drug delivery systems in cancer therapy and diagnosis. The primary advantage of this innovation lies in the fundamental changes in systemic biodistribution that non-native drug delivery does not possess. This review will try to provide a comprehensive understanding and a succinct evaluation of various intelligent bio-inspired delivery platforms, which have become prominent in recent studies. Recent innovative examples and their advantages and limitations as well as future clinical potential will also be thoroughly discussed.

Biocompatible, pH-sensitive and charge-conversion micelles derived from hyaluronic acid (HA), poly(lactide) (PLA) and half-generation of sectorial poly(amidoamine) dendrimers (sPA G4.5) were designed and fabricated to target delivery of docetaxel (DTX) to cancer cells. The novel micelles (HA-PALA-DTX) possessed stability against rat plasma and were capable of reversing surface zeta potential under acidic conditions in the presence of HAase. Moreover, the blank micelles demonstrated satisfactory biocompatibility and viability for biomedical applications. A cellular internalization experiment indicated that HA played an important role in increasing intracellular accumulation of DTX delivered by the micelles. Compared to Taxotere (R) and PALA-DTX, HA-PALA-DTX showed an enhanced anticancer activity in vivo, with a tumor growth inhibition rate of 72.32 +/- 5.22%. Overall, the functionalized micelles could be utilized as an alternative carrier for effective targeted delivery of anticancer agents to improve therapeutic efficacy and minimize adverse effects.

An ideal wound dressing ensures a moist environment around the wound area and absorbs exudates from the wound surface. Topical application of bromelain to incised wounds has been shown to reprogram the wound microenvironment to promote effective tissue repair. Combining the characteristics of hydrogels and bromelain is therefore of great interest. Herein, we describe the development of a hydrogel, formulated using alginate and Arabic gum, for bromelain loading and release. The hydrogel formulation was evaluated using response surface methodology, considering the pH value and the concentration of alginate and Arabic gum. Bromelain loading and release were evaluated based on passive diffusion. Differential scanning calorimetry and Fourier transform infrared spectroscopy were performed to confirm bromelain immobilization in the hydrogel. The final hydrogel formulation had a swelling ratio of 227% and incorporated 19% of bromelain from a bromelain solution. Bromelain immobilization in the hydrogel was the result of hydrogen bond formation and was optimal at 4 degrees C after 4 h of contact. This evidence suggests that bromelain entrapment into a hydrogel is a promising strategy for the development of wound dressings that support the debridement of burns and wounds.

The occurrence of bisphenol A (BPA) raised significant concerns about potential adverse impacts on environmental health, and its removal has become a hot research topic. We conducted batch adsorption and photo-degradation experiments to determine the removal performance of BPA by beta-cyclodextrin (beta-CD) modified pine sawdust (CD-PS) in an aquatic environment for the first time. Pine sawdust (B-PS) was treated by NaOH firstly and then modified by beta-CD. The adsorption behaviour of BPA on the B-PS and CD PS were observed to follow Langmuir and pseudo-second-order kinetic models, and that CD-PS had a 1.2 times higher adsorption capacity than B-PS. At 25 degrees C and pH = 7.0, the maximum adsorption capacity of CD-PS reached 0.0319 mmol/g. Moreover, the effects of beta-CD, CD-PS and B-PS on the photo-degradation of BPA were compared under UV irradiation, indicating that CD-PS significantly enhanced the removal efficiency. Additionally, the "saturated" CD-PS could be regenerated several times using UV irradiation without loss during BPA adsorption process. Results of this work demonstrate that,beta-CD immobilized on the surface of CD-PS could be acted as an excellent catalyst for BPA removal, and a possible reactive mechanism was further proposed in this regards. These observations indicate that the CD-PS system can remediate BPA-polluted aquatic environment very well. (C) 2017 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.

The effects of clay type, microbial quantity, and inoculation time on the microbial degradation of 0# diesel oil and 180# heavy oil were studied. The results showed that the surfactant-modified clay had a significant promotion effect on the degradation of oil. The removal efficiencies of diesel oil and heavy oil after 7 days were up to 87% and 95%. The optimum conditions were determined and the oil biodegradation was in accordance with the first-order kinetics. All the results obtained can provide experimental basis for oil microbial degradation.

A liquid chromatography-tandem mass spectroscopy (LC–MS/MS) assay was developed and validated to simultaneously quantify anticancer drugs reparixin and paclitaxel in this study. The compounds were extracted from plasma and urine samples by protein precipitation with acetone (supplemented with 0.1% formic acid). Chromatographic separation was achieved using a C18 column, and drug molecules were ionized using dual ion source electrospray and atmospheric pressure chemical ionization (DUIS: ESI-APCI). Reparixin and paclitaxel were quantified using negative and positive multiple reaction monitoring (MRM) mode, respectively. Stable isotope palcitaxel-D5 was used as the internal standard (IS). The assay was validated for specificity, recovery, carryover and sample stability under various storage conditions; it was also successfully applied to measure drug concentrations collected from a pharmacokinetic study in rats. The results confirmed that the assay was accurate and simple in quantifying both reparixin and paclitaxel in plasma and urine with minimal sample pretreatment.

Novel pH-sensitive hybrid micelles with high entrapment efficiency were constructed to realize rapid intracellular drug release without premature release.

In this study, a simple and green approach ‘bioinspired disassembly-reassembly strategy’ was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein-decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20μg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy.

Introduction: Cancer stem cells (CSCs) play an important role in the development of drug resistance, metastasis and recurrence. Current conventional therapies do not commonly target CSCs. Nanocarrier-based delivery systems targeting cancer cells have entered a new era of treatment, where specific targeting to CSCs may offer superior outcomes to efficient cancer therapies.Areas covered: This review discusses the involvement of CSCs in tumor progression and relevant mechanisms associated with CSCs resistance to conventional chemo- and radio-therapies. It highlights CSCs-targeted strategies that are either under evaluation or could be explored in the near future, with a focus on various nanocarrier-based delivery systems of drugs and nucleic acids to CSCs. Novel nanocarriers targeting CSCs are presented in a cancer-specific way to provide a current perspective on anti-CSCs therapeutics.Expert opinion: The field of CSCs-targeted therapeutics is still emerging with a few small molecules and macromolecules currently proving efficacy in clinical trials. However considering the complexities of CSCs and existing delivery difficulties in conventional anticancer therapies, CSC-specific delivery systems would face tremendous technical and clinical challenges. Nanocarrier-based approaches have demonstrated significant potential in specific drug delivery and targeting; their success in CSCs-targeted drug delivery would not only significantly enhance anticancer treatment but also address current difficulties associated with cancer resistance, metastasis and recurrence.

Recently, the removal of phenolic compounds has attracted great attention in wastewater treatment. In this work, the influences of various cyclodextrins (CDs) on the photodegradations of phenol and bisphenol A (BPA) under UV light were investigated systematically. The results show that the photodegradation of phenol displays no obvious differences in the presence or absence of CDs. In contrast, BPA photodegradation increases considerably in the presence of β-CD and its derivatives. Moreover, the catalytic effects of BPA differed among α-CD, β-CD, carboxymethyl-β-CD (CM-β-CD), and hydroxypropyl-β-CD (HP-β-CD), following the order β-CD ≈ HP-β-CD > CM-β-CD > α-CD. Specifically, over 99% of the BPA was degraded in the HP-β-CD and β-CD systems within 120 min. Additionally, six main intermediates of BPA in the presence of β-CD were confirmed, and the probable degradation pathway was proposed, which provides a useful platform for the application of CDs in the photodegradation of BPA.

Polymer-drug conjugates have demonstrated application potentials in optimizing chemotherapeutics. In this study a new bioconjugate, HA-ss-PTX, was designed and synthesized with cooperative dual characteristics of active tumor targeting and selective intracellular drug release. Paclitaxel (PTX) was covalently attached to hyaluronic acid (HA) with various sizes (MW 9.5, 35, 770 kDa); a cross-linker containing disulfide bond was also used to shield drug leakage in blood circulation and to achieve rapid drug release in tumor cells in response to glutathione. Incorporation of HA to the conjugate enhanced the capabilities of drug loading, intracellular endocytosis and tumor targeting of micelles in comparison to mPEG. HA molecular weight showed significant effect on properties and antitumor efficacy of the synthesized conjugates. Intracellular uptake of HA-ss-PTX toward MCF-7 cells was mediated by CD44-caveolae-mediated endocytosis. Compared to Taxol and mPEG-ss-PTX, HA9.5-ss-PTX demonstrated improved tumor growth inhibition in vivo with a TIR of 83.27 ± 5.20%. It was concluded that HA9.5-ss-PTX achieved rapid intracellular release of PTX and enhanced its therapeutic efficacy, thus providing a platform for specific drug targeting and controlled intracellular release in chemotherapeutics.STATEMENT OF SIGNIFICANCE:Polymer-drug conjugates, promising nanomedicines, still face some technical challenges including a lack of specific targeting and rapid intracellular drug release at the target site. In this manuscript we designed and constructed a novel bioconjugate HA-ss-PTX, which possessed coordinated dual characteristics of active tumor targeting and selective intracellular drug release. Redox-responsive disulfide bond was introduced to the conjugate to shield drug leakage in blood circulation and to achieve rapid drug release at tumor site in response to reductant like glutathione. Paclitaxel was selected as a model drug to be covalently attached to hyaluronic acid (HA) with various sizes to elucidate the structure-activity relationship and to address whether HA could substitute PEG as a carrier for polymeric conjugates. Based on a series of in vitro and in vivo experiments, HA-ss-PTX performed well in drug loading, cellular internalization, tumor targeting by entering tumor cells via CD44-caveolae-mediated endocytosis and rapidly release drug at target in the presence of GSH. One of the key issues in clinical oncology is to enhance drug delivery efficacy while minimizing side effects. The study indicated that this new polymeric conjugate system would be useful in delivering anticancer agents to improve therapeutic efficacy and to minimize adverse effects, thus providing a platform for specific drug targeting and controlled intracellular release in chemotherapeutics.

Pine sawdust modified with citric acid (CA-PS) is used as an adsorbent for the removal of Cu 2+ and methylene blue (MB) from the single and binary compound systems. The initial pH has a significant effect on Cu 2+ adsorption, but a relatively little effect on MB adsorption. The kinetic and isotherm studies indicate that the pseudo-second-order model and the generalized model provide the best correlation of the experimental data in the single systems as well as in the binary systems. The adsorption capacities of CA-PS from Generalized isotherm model are 0.23 mmol/g for Cu 2+ and 0.25 mmol/g for MB, which are higher than that of B-PS. In the binary systems, Cu 2+ and MB exhibit competitive adsorption behaviors. The adsorption capacity of Cu 2+ or MB is considerably reduced with an increase in the concentration of the other, and Cu 2+ exhibits better competiveness than MB. However, the total adsorption capacity is higher compared with that in the single systems, which increases with an increase in the initial concentration of Cu 2+ or MB and reaches a plateau value of 0.301 mmol/g.

Recently, the removal of phenolic compounds has attracted great attention in wastewater treatment. In this work, the influences of various cyclodextrins (CDs) on the photodegradations of phenol and bisphenol A (BPA) under UV light were investigated systematically. The results show that the photodegradation of phenol displays no obvious differences in the presence or absence of CDs. In contrast, BPA photodegradation increases considerably in the presence of beta-CD and its derivatives. Moreover, the catalytic effects of BPA differed among a-CD, beta-CD, carboxymethyl-beta-CD (CM-beta-CD), and hydroxypropyl-beta-CD (HP-beta-CD), following the order beta-CD approximate to HP-beta-CD > CM-beta-CD > a-CD. Specifically, over 99% of the BPA was degraded in the HP-beta-CD and beta-CD systems within 120 min. Additionally, six main intermediates of BPA in the presence of beta-CD were confirmed, and the probable degradation pathway was proposed, which provides a useful platform for the application of CDs in the photodegradation of BPA.