Real-time SERS monitoring anticancer drug release along with SERS/MR imaging for pH-sensitive chemo-phototherapy

In situ and real-time monitoring of responsive drug release is critical for the assessment of pharmacodynamics in chemotherapy. In this study, a novel pH-responsive nanosystem is proposed for real-time monitoring of drug release and chemo-phototherapy by surface-enhanced Raman spectroscopy (SERS). The Fe3O4@Au@Ag nanoparticles (NPs) deposited graphene oxide (GO) nanocomposites with a high SERS activity and stability are synthesized and labeled with a Raman reporter 4-mercaptophenylboronic acid (4-MPBA) to form SERS probes (GO-Fe3O4@Au@Ag-MPBA). Furthermore, doxorubicin (DOX) is attached to SERS probes through a pH-responsive linker boronic ester (GO-Fe3O4@Au@Ag-MPBA-DOX), accompanying the 4-MPBA signal change in SERS. After the entry into tumor, the breakage of boronic ester in the acidic environment gives rise to the release of DOX and the recovery of 4-MPBA SERS signal. Thus, the DOX dynamic release can be monitored by the real-time changes of 4-MPBA SERS spectra. Additionally, the strong T2 magnetic resonance (MR) signal and NIR photothermal transduction efficiency of the nanocomposites make it available for MR imaging and photothermal therapy (PTT). Altogether, this GO-Fe3O4@Au@Ag-MPBA-DOX can simultaneously fulfill the synergistic combination of cancer cell targeting, pH-sensitive drug release, SERS-traceable detection and MR imaging, endowing it great potential for SERS/MR imaging-guided efficient chemo-phototherapy on cancer treatment.

Mucus-penetrating nonviral gene vaccine processed in the epithelium for inducing advanced vaginal mucosal immune responses

Establishment of vaginal immune defenses at the mucosal interface layer through gene vaccines promise to prevent infectious diseases among females. Mucosal barriers composed of a flowing mucus hydrogel and tightly conjugated epithelial cells (ECs), which represent the main technical difficulties for vaccine development, reside in the harsh, acidic human vaginal environment. Different from frequently employed viral vectors, two types of nonviral nanocarriers were designed to concurrently overcome the barriers and induce immune responses. Differing design concepts include the charge-reversal property (DRLS) to mimic a virus that uses any cells as factories, as well as the addition of a hyaluronic acid coating (HA/RLS) to directly target dendritic cells (DCs). With a suitable size and electrostatic neutrality, these two nanoparticles penetrate a mucus hydrogel with similar diffusivity. The DRLS system expressed a higher level of the carried human papillomavirus type 16 L1 gene compared to HA/RLS in vivo. Therefore it induced more robust mucosal, cellular, and humoral immune responses. Moreover, the DLRS applied to intravaginal immunization induced high IgA levels compared with intramuscularly injected DNA (naked), indicating timely protection against pathogens at the mucus layer. These findings also offer important approaches for the design and fabrication of nonviral gene vaccines in other mucosal systems.

Iron-based and BRD4-downregulated strategy for amplified ferroptosis based on pH-sensitive/NIR-II-boosted nano-matchbox

Ferroptosis (FPT), a novel form of programmed cell death, is characterized by overwhelming iron/reactive oxygen species (ROS)-dependent accumulation of lipid peroxidation (LPO). However, the insufficiency of endogenous iron and ROS level limited the FPT therapeutic efficacy to a large extent. To overcome this obstacle, the bromodomain-containing protein 4 (BRD4)-inhibitor (+)-JQ1 (JQ1) and iron-supplement ferric ammonium citrate (FAC)-loaded gold nanorods (GNRs) are encapsulated into the zeolitic imidazolate framework-8 (ZIF-8) to form matchbox-like GNRs@JF/ZIF-8 for the amplified FPT therapy. The existence of matchbox (ZIF-8) is stable in physiologically neutral conditions but degradable in acidic environment, which could prevent the loaded agents from prematurely reacting. Moreover, GNRs as the drug-carriers induce the photothermal therapy (PTT) effect under the irradiation of near-infrared II (NIR-II) light owing to the absorption by localized surface plasmon resonance (LSPR), while the hyperthermia also boosts the JQ1 and FAC releasing in the tumor microenvironment (TME). On one hand, the FAC-induced Fenton/Fenton-like reactions in TME can simultaneously generate iron (Fe3+/Fe2+) and ROS to initiate the FPT treatment by LPO elevation. On the other hand, JQ1 as a small molecule inhibitor of BRD4 protein can amplify FPT through downregulating the expression of glutathione peroxidase 4 (GPX4), thus inhibiting the ROS elimination and leading to the LPO accumulation. Both in vitro and in vivo studies reveal that this pH-sensitive nano-matchbox achieves obvious suppression of tumor growth with good biosafety and biocompatibility. As a result, our study points out a PTT combined iron-based/BRD4-downregulated strategy for amplified ferrotherapy which also opens the door of future exploitation of ferrotherapy systems.

Anti-tumor activity of yeast vesicle biomimetic nanomedicine with the ability of active tumor penetration / 药学学报

The dense extracellular matrix (ECM) of the tumor severely limits the deep penetration of nanomedicine and weakens its anti-tumor effect. Based on this, the yeast vesicle biomimetic nanomedicine with active deep penetration ability of tumor tissue was designed and developed for enhanced tumor therapy. Results of characterization showed that the yeast cell vesicles (YCV) displayed a spherical morphology with diameter of around 100 nm and was well dispersed. Then the chemotherapeutic drug doxorubicin (DOX) was selected as a model drug, and DOX was loaded into YCV to obtain YCV/DOX through electrostatic interaction, the encapsulation efficiencies of DOX were calculated as 82.5%. The drug release profile of YCV/DOX implied that DOX release showed a manner of pH-dependent, it may be that pH has affected the electrostatic effect of YCV and DOX. Compared with liposomes (Lipo), in vitro cell experiments showed that YCV from natural sources had stronger permeability in three-dimensional multicellular spheres. It is speculated that the mechanism may be good deformation capacity of YCV. A 4T1 xenograft tumor model was established to evaluate the therapeutic efficacy of YCV/DOX. The results suggested that YCV/DOX has stronger tumor tissue penetration ability and could effectively inhibit the tumor growth. All animal experiments were performed in line with national regulations and approved by the Animal Experiments Ethical Committee of Zhengzhou University. This study brings new ideas for the development of biomimetic nanomedicine to overcome the ECM of solid tumors.

The effect of pH transition points of ultra-pH sensitive fluorescent nanoprobes on tumor imaging efficiency / 药学学报

During fluorescence-guided cancer surgery, ultra-pH sensitive (UPS) fluorescent nanoprobes has multiple advantages such as real-time imaging procedures, ultra-high imaging sensitivity as well as broad tumor detection specificity. UPS nanoprobes stay at "OFF" state at higher pH and turn into "ON" state at lower pH with emission of strong fluorescence. Moreover, the transition pH points (transition pH point, pHt) can be precisely controlled by structural-based strategy. One of the previously-reported UPS nanoprobes showed good imaging effect. However, it is still not clear about the effect of pHt on cancer imaging efficiency of UPS nanoprobes and to further identify the optimal UPS. In this study, we synthesized a series of UPS nanoprobes with pHt at 4.5, 6.2, 6.6, 7.8 by adjusting the hydrophobic blocks of UPS polymers. Each nanoprobe showed excellent stability in "OFF" state by dynamic light scattering and uniform morphology observed by transmission electron microscopy. In vitro imaging characterized the ultra-pH sensitive fluorescence transition of each probe. In vivo imaging results identified two UPS nanoprobes (NP-6.2 and NP-6.6) with superior tumor imaging effect. All animal experiments in this study were approved by the Animal Ethics Committee of Peking University Health Science Center and were strictly followed by the welfare regulations of laboratory animals of Peking University Health Science Center. Therefore, this study has explored the effect of pHt on the cancer imaging efficiency of UPS nanoprobes and provides a new idea for design of the other cancer microenvironment-responsive polymers.

Preparation and immune-enhancing effects of monophosphoryl lipid A pH-sensitive liposome / 中华微生物学和免疫学杂志

Objective:To prepare pH-sensitive liposomes to avoid the degradation of monophosphoryl lipid A (MPLA) by lysosomes.Methods:Using DOPE and CHEMS as carrier materials, pH-sensitive liposomes were prepared by thin-film dispersion method. Particle sizes and Zeta potential of the liposomes were detected by dynamic light scattering. The morphological features of pH-sensitive liposomes under different pH conditions were observed by transmission electron microscopy. Flow cytometry was performed to detect the phagocytosis of liposomes by THP-1 and DC2.4 cells. Confocal laser microscopy was used to observed the colocalization of liposomes and lysosomes. BALB/c mice were immunized with hepatitis B surface antigen (HBsAg) using MPLA pH-sensitive liposome as an adjuvant. The levels of serum anti-HBs were quantitatively detected by ELISA. IFN-γ and IL-2 spot forming cells (SFCs) in mouse splenic lymphocytes were detected by ELISPOT.Results:The pH-sensitive liposomes were constructed with an average particle size of (90.90±1.13) nm, polydispersity index (PDI) of 0.076±0.013 and Zeta potential of (-27.900±0.666) mV. As the pH value of the solution decreased, the particle size increased significantly and the liposomes presented irregular shapes, indicating the pH-sensitive features. The phagocytosis rates by THP-1 cells and DC2.4 cells were 10.40% and 12.40% for pH-sensitive fluorescent liposomes, and 1.09% and 0.28% for fluorescent liposomes. Confocal laser microscopy revealed that pH-sensitive fluorescent liposomes were phagocytosed by THP-1 cells and existed in the cytoplasm, while fluorescent liposomes existed in lysosomes. Compared with MPLA liposomes, MPLA pH-sensitive liposomes could significantly improve the cellular immune response in mice. The levels of IFN-γ and IL-2 SFCs in the MPLA pH-sensitive liposome group were significantly higher than those in the MPLA liposome group ( P<0.01) and the non-adjuvant group ( P<0.001). Conclusions:The pH-sensitive liposome delivery system could improve the utilization of MPLA as an adjuvant.

Design and evaluation of ocular hydrogel containing combination of ofloxacin and dexamethasone for the treatment of conjunctivitis

Abstract Conjunctivitis is an inflammation of the conjunctiva, which covers the white part of the eyeball. It can be caused by allergies, bacterial or viral infection. In situ hydrogels are three-dimensional hydrophilic cross-linked network of polymers. In situ hydrogel provided better therapeutic index when compared to conventional treatment. The present work describes the formulation and evaluation of ofloxacin and dexamethasone based on the concept of pH triggered in situ gelation. Carbopol 934p was used as the gelling agent in combination with HPMC, as a viscosity-enhancing agent, benzalkonium chloride as preservative, sodium chloride as tonicity adjusting agent. The prepared formulations were liquid at the low pH and underwent rapid transition into viscous gel at the pH of the tear fluid. Formulations were evaluated for various rheological, in vitro and in vivo release characteristics. Infrared spectroscopy studies showed that there were no interactions between the drug and polymers. Viscosity of the prepared hydrogels lies in the optimum range and drug was released up to 85 % as the end of 13 h. The prepared in situ hydrogel was sterile, non-irritant to the eye. The present study indicated that it is possible to develop safe and physiologically effective in situ hydrogel which is patient compliant.

Amplification of urea detection based on pH-sensitive liposomes

BACKGROUND: This study aimed to develop an amplification method of urea detection based on pHsensitive liposomes. RESULTS: The urease covalently immobilized on the magnetic particles and the pH-sensitive liposomes encapsulating ferricyanide were added to the cyclic-voltammeter cell solution where urea was distributed. The conversion of urea into carbonic acid seemed to induce a pH decrease that caused a reduction in the electrostatic repulsion between the headgroups of weakly acidic 1,2-dipalmitoyl-sn-glycero3-succinate. The reduction induced the liposomes to release potassium ferricyanide that was encapsulated inside. The effects of urea concentration and pH value were investigated. A specific concentration (0.5 mg/mL) of the urea solution was set to observe the response. The activity of urease was reversible with respect to the pH change between 7 and 5. The sensitivity of this detection was almost identical to the comparable techniques such as an enzyme-linked immunosorbent assay and a field-effect transistor. CONCLUSIONS: In summary, the methodology developed in this study was feasible as a portable, rapid, and sensitive method.

The reversed intra- and extracellular pH in tumors as a unified strategy to chemotherapeutic delivery using targeted nanocarriers

Solid tumors are complex entities, comprising a wide variety of malignancies with very different molecular alterations. Despite this, they share a set of characteristics known as "hallmarks of cancer" that can be used as common therapeutic targets. Thus, every tumor needs to change its metabolism in order to obtain the energy levels required for its high proliferative rates, and these adaptations lead to alterations in extra- and intracellular pH. These changes in pH are common to all solid tumors, and can be used either as therapeutic targets, blocking the cell proton transporters and reversing the pH changes, or as means to specifically deliver anticancer drugs. In this review we will describe how proton transport inhibitors in association with nanocarriers have been designed to block the pH changes that are needed for cancer cells to survive after their metabolic adaptations. We will also describe studies aiming to decrease intracellular pH in cancer using nanoparticles as molecular cages for protons which will be released upon UV or IR light exposure. Finally, we will comment on several studies that have used the extracellular pH in cancer for an enhanced cell internalization and tumor penetration of nanocarriers and a controlled drug delivery, describing how nanocarriers are being used to increase drug stability and specificity.

Application of environmentally sensitive hydrogels in drug delivery / 药学学报

Environmentally sensitive hydrogels are a novel formulation that has developed rapidly in recent years. It could form semi-solid with good adhesion in the topical sites based on different physiological environments. Its long local retention time is conducive for sustained drug release, and the preparation process is relatively simple and easy to realize industrialization. This review summarized the categories, commonly used polymer, and different administration routes based on the recently published literatures. According to different response factors, it can be divided into temperature, pH, ion, light, and multiple sensitive hydrogels, among which temperature-sensitive hydrogels are the most common. The most commonly used polymers include chitosan, poly N-isopropyl acrylamide, and poloxamer. There are different administration routes for environmentally sensitive hydrogels, such as transdermal, ophthalmic, nasal, oral, vaginal, rectal, injection, etc. Environmentally sensitive hydrogels have broad prospects in clinical application.

pH-sensitive and bubble-generating mesoporous silica-based nanoparticles for enhanced tumor combination therapy

Chemotherapy has been a major option in clinic treatment of malignant tumors. However, single chemotherapy faces some drawbacks, such as multidrug resistance, severe side effects, which hinder its clinic application in tumor treatment. Multifunctional nanoparticles loading with chemotherapeutic agent and photosensitizer could be a promising way to efficiently conduct tumor combination therapy. In the current study, a novel pH-sensitive and bubble-generating mesoporous silica-based drug delivery system (denoted as M(a)D@PI-PEG-RGD) was constructed. Ammonium bicarbonate (NH

Preparation and in vitro evaluation of pH-sensitive drug releasing As2O3-loaded liposome / 中草药

Objective: To prepare pH-sensitive drug releasing As2O3 loaded liposome (CaAs-LP) and evaluate it in vitro. Methods: CaAs-LP was prepared by thin film dispersion and ion precipitation method. The particle size, PDI, and Zeta potential of CaAs-LP were measured by Malvern particle size analyzer; The morphology of the liposome was investigated by transmission electron microscopy; The drug loading and entrapment efficiency of CaAs-LP by inductively coupled plasma emission spectrum. In vitro release characteristics of CaAs-LP under different pH conditions were investigated by dialysis bag method. MTT assay was used to investigate the toxicity of carrier and CaAs-LP to MCF-7, U87 and HepG2 cells. Results: The prepared CaAs-LP were spherical and well-dispersed with particle size of (117.16 ± 1.94) nm. The encapsulation efficiency and the drug loading rate of CaAs-LP were (74.31 ± 2.11)% and (8.31 ± 0.13)%, respectively. In vitro release studies showed that CaAs-LP had the characteristics of sustained release and pH sensitive drug release, which can achieve specific drug release in the tumor environment. The carrier displayed remarkable biocompatibility in MCF-7, U87, HepG2 and L02 cells. MTT assay showed that the median lethal concentrations (IC50 values) of MCF-7, U87 and HepG2 cells were 11.91, 4.90 and 19.41 μmol/L, while L02 was 27.59 μmol/L, respectively, which showed strong inhibiting effect on tumor cells. Conclusion: CaAs-LP reveals significantly sustained and pH sensitive release characteristics. CaAs-LP is a potential drug delivery system against solid tumor with tumor micro-environment responsive.

pH responsive docetaxel micelles with improved therapeutic efficacy on mice xenograft tumor / 药学学报

The non-specific administration of antitumor drugs is the main cause for the side effects of chemotherapy drugs on normal tissues. The application of nanotechnology in the delivery of anti-tumor drugs is one of the important ways to improve the therapeutic effect and to reduce the side effects. The current study aimed to synthesize pH responsive poly (methoxy-ethylene glycol)-poly(lactic acid)-poly-(β-amino ester) (PBAE) triblock copolymers to deliver docetaxel (DTX) and improve the anti-tumor activity of DTX. PBAE was synthesized by ring opening polymerization and Michael addition reaction, its structure and molecular weight was characterized by 1H NMR, the dissociation constant of base (pKb) were determined by acid-base titration method. The critical micelles concentration (CMC) of copolymers was measured by pyrene fluorescence spectroscopy. DTX loaded copolymer micelles were prepared by membrane hydration method. The size and its distribution as well as the stability of micelles were determined by laser light scattering analysis. The drug loading content (DL), entrapment efficiency (EE) and cumulative drug release from micelles were evaluated by high-performance liquid chromatography (HPLC). The sizes of DTX drug-loaded micelles were in the range of 10 to 100 nm with narrow distribution. DL of DTX in PBAE1 and PBAE2 micelles was (5.3 ± 0.10) % and (4.9 ± 0.05) %, respectively, with EE was (93.8 ± 1.70) % and (87.2 ± 4.10) %, respectively. The drug-loaded micelles showed pH sensitive drug release properties under weak acidic conditions, which showed potential drug release of DTX under mild acidic tumor environment. A mouse Lewis lung carcinoma model was established to evaluate the therapeutic efficacy of micellar DTX formulations. Significant inhibitory effect of the nanodrugs was observed with DTX dosages of 10 and 20 mg·kg-1, respectively. Moreover, the pH responsive PBAE1-DTX micellar drug exhibited stronger therapeutic efficacy on mice xenograft tumor, as compared with the non pH sensitive micellar drug (PELA-DTX) and free DTX. All animal experiments were performed according to the animal ethical standards and approved by the Animal Experiments and Ethical Committee of China Academy of Chinese Medical Sciences (No. 2017090110). The in vivo anti-tumor activity studies showed that the tumor volume growth rates of mice in different drug-administered groups were: PBAE1-DTX 20 mg·kg-1 < PBAE1-DTX 10 mg·kg-1 < PELA-DTX 10 mg·kg-1 < DTX 10 mg·kg-1 < normal saline, with the PBAE1-DTX group as the most potent group for tumor inhibition. The current pH sensitive DTX nano-micelles showed high potential in further studies to promote the application of nano DTX formulations for tumor treatment.

Research progress on the effect of pH-sensitive drug delivery systems on oral microorganisms / 口腔疾病防治

@#Microorganisms are closely related to the occurrence and development of common oral diseases. Due to the unique physiological and anatomical characteristics of the oral cavity, locally introduced antibacterial drugs cannot be maintained in the effective concentration range under the effect of saliva erosion. Therefore, to enhance the retention and bioavailability of antibacterial drugs in biofilms, some scholars designed pH sensitive drug delivery systems with the fact that the pH value of oral biofilm is lower than the physiological pH value. This article reviews the research reports of a pH-sensitive drug delivery system in the oral cavity and elaborates its application in oral diseases such as dental caries, endodontic disease, periapical disease, peri-implant diseases, and oral candidiasis. Literature review Results show that the pH-sensitive drug delivery system loaded with antibacterial drugs could be used for the control of oral microorganisms with excellent pH sensitivity and antibacterial properties, especially in the application of acid-producing bacteria such as Streptococcus mutans for the prevention and treatment of dental caries. However, the research of pH-sensitive drug delivery systems in the oral cavity is still limited to basic research,and in clinical applications, it still faces many challenges, such as a complex design and synthesis, difficulties with lasting effects and eliminating drug-resistance and persistent bacteria. Further optimization of pH sensitive systems, as well as animal experiments and in vivo studies will be the focus of future research.

Pharmacokinetics and Tumor Tissue Distribution of Docetaxel Nanomicelles in Mice / 中国实验方剂学杂志

Objective: To investigate the pharmacokinetics and the distribution in tumor tissues of docetaxel nanomicelles. Method: The docetaxel nanomicelles was prepared by filming-rehydration method.HPLC was employed to determine the content of docetaxel in biological samples and the corresponding methodological evaluation was carried out.The mouse Lewis lung carcinoma model was established,when dosage of administration in tail vein was 20 mg·kg-1,and then the effect of free drug(DTX),non-pH-sensitive drug-loaded micelles(PELA-DTX) and pH-sensitive drug-loaded micelles(PBAE-DTX) on the pharmacokinetics and tissue distribution of tumor-bearing mice were investigated. Result: The docetaxel nanomicelles(PELA-DTX and PBAE-DTX) were successfully prepared.The method for the determination of docetaxel in mice was established by HPLC,the linearity,precision of the method and the recovery rate of samples all met the requirements.In the pharmacokinetic study,the plasma concentration of PBAE-DTX was always at a high level within 24 h.Compared with PELA-DTX and DTX,the areas under the curve(AUC0-∞) of PBAE-DTX were increased by 3.63% and 8.96%,the mean residence times(MRT) were extended by 2.86% and 6.43%,the half-life and the drug blood circulation time were prolonged.In the tissue distribution study,it was found that three docetaxel preparations were distributed in the heart,liver,spleen,lung,kidney and tumor tissue within 1 h after administration,but the distribution of these drugs in the tissues was reduced along with the extension of time,the accumulation of PBAE-DTX in tumor tissue was significantly higher than that in DTX and PELA-DTX at 24 h. Conclusion: PBAE-DTX can prolong the circulation time of docetaxel in the blood,increase its bioavailability,and significantly increase its distribution in tumor tissue.

Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy

Hyaluronic acid (HA) is a natural ligand of tumor-targeted drug delivery systems (DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors (HARE and LYVE-1) are also overexpressing in the reticuloendothelial system (RES). Therefore, polyethylene glycol (PEG) modification of HA-based DDS is necessary to reduce RES capture. Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement, significantly compromising the antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform (Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage. The and investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and nonspecific biodistribution.

Preparation and in vitro evaluation of pH-sensitive charge-reversal nanoparticles loaded with curcumin / 中草药

Objective: To prepare charge-reversal pH-sensitive nanoparticles loaded with curcumin (PCE/Cur NPs), and investigate the optimizing technology, physicochemical characterizations, and inhibitory effect on B16 cell. Methods: The β-carboxyl amidized cationic MPEG-PCL-PEI polymers (PCE) were negatively charged, which were prepared into the negative PCE/Cur NPs with pH dependence. When pH > 7, there was no charge-reversal. When pH < 6, the β-carboxyl amides were hydrolyzed rapidly into corresponding amines. As a result, PCE/Cur NPs became positively charged again. The obtained PCE/Cur NPs were characterized by detection of particle size, morphology study, drug loading, encapsulation efficiency, and release study. The effect of anti-migratory and anti-invasive actions of PCE/Cur NPs on B16 cell was investigated using MTT assays and wound healing test. Results: PCE/Cur NPs dependent on pH charge inversion were successfully prepared. The obtained PCE/Cur NPs were round, and the size was uniform, the adhesion was not found. The Results: showed that the prepared PCE/Cur NPs had the highest DL (8.0 ± 1.0)%, EE (90.0 ± 2.0)%, mean particle size of (80 ± 5) nm, and zeta potential of (-35 ± 5) mV. Within 48 h, the accumulative release rate was (69.2 ± 5.2)% (pH 7.4) and (71.2 ± 4.3)% (pH 5), respectively, and then PCE/Cur NPs released slowly. These Results: by MTT assay and wound healing assay indicated that PCE/Cur NPs not only inhibited the proliferation of B16 cells in a concentration- and time-dependent manner, but also can induce apoptosis. Conclusion: PCE/Cur NPs were prepared successfully, which might have great potential application in drug delivery system.

Preparation and evaluation of 2-methoxyestradiol-loaded pH-sensitive liposomes

The development and clinical application of 2-methoxyestradiol (2-ME) as a new type of antitumor drug are limited due to its poor solubility, rapid metabolism in vivo, and large oral dosage. 2-ME-loaded pH-sensitive liposomes (2-ME-PSLs) was prepared containing the lipids, Lipoid E-80 (E-80), cholesteryl hemisuccinate (CHEMS), and cholesterol (CHOL) via thin-film ultrasonic dispersion. First, preparation conditions of 2-ME-PSLs were optimized by orthogonal test. Then 2-ME-PSL was characterized, and the release behavior and stability of 2-ME-PSL in vitro were evaluated. The optimal preparation conditions for 2-ME-PSLs were as follows: 2-ME : E-80+CHEMS 1:15; CHOL : E-80+CHEMS 1:5; ultrasonication time 20 minutes. The mean particle size, PDI, zeta potential, and entrapment efficiency (EE) of 2-ME-PSLs were 116 ± 9 nm, 0.161 ± 0.025, −22.4 ± 1.7 mV, and 98.6 ± 0.5%, respectively. As viewed under a transmission electron microscope, 2-ME-PSLs were well dispersed and almost spherical. They exhibited significant pH-sensitive properties and were fairly stable when diluted with a physiological solution. In conclusion, 2-ME-PSLs were successfully prepared and possessed a favorable pH sensitivity and good dissolution stability with a normal solution

Preparation of docetaxel-loaded nanomicelles and their anti-Lewis lung cancer effect in vitro / 中国中药杂志

Docetaxel-loaded nanomicelles were prepared in this study to improve the solubility and tumor targeting effect of docetaxel(DTX),and further evaluate their anticancer effects in vitro. PBAE-DTX nanomicelles were prepared by film-hydration method with amphiphilic block copolymer polyethyleneglycol methoxy-polylactide(PELA) and pH sensitive triblock copolymer polyethyleneglycol methoxy-polylactide-poly-β-aminoester(PBAE) were used respectively to prepare PELA-DTX nanomicelles and PBAE-DTX nanomicelles. The nanomicelles were characterized by physicochemical properties and the activity of mice Lewis lung cancer cells was studied. The results of particle size measurement showed that the blank micelles and drug-loaded micelles had similar particle sizes, ranging from 10 to 100 nm. The particle size of PBAE micelles was changed under weak acidic conditions, with good pH response. The encapsulation efficiency of the above two types of DTX-loaded nanomicelles determined by HPLC was(93.8±1.70)% and(87.2±4.10)%, and the drug loading amount was(5.3±0.10)% and(4.9±0.05)%,respectively. Furthermore,the DTX micelles also showed significant inhibitory effects on Lewis lung cancer cells by MTT assay, and pH-sensitive PBAE-DTX showed better cytotoxicity. The results of flow cytometry indicated that,the apoptosis rate of lung cancer Lewis cells was(20.72±1.47)%,(29.71±2.38)%,and(40.91±1.90)%(P<0.05) at 48 h after treatment in DTX,PELA-DTX,and PBAE-DTX groups. The results showed that different docetaxel preparations could promote the apoptosis of Lewis cells, and PBAE-DTX had stronger apoptotic-promoting effect. The pH-sensitive DTX-loaded micelles are promising candidates in developing stimuli triggered drug delivery systems in acidic tumor micro-environments with improved inhibitory effects of tumor growth on Lewis lung cancer.

Impacts of particle shape on cellular uptake and tumor imaging application of ultra-pH sensitive micelles / 药学学报

This study was designed to investigate the impacts of particle shape of micelles on cell uptake and tumor imaging applications. We designed and synthesized an ultra-pH sensitive PEG-iPDPA diblock polymer, and prepared it into wormlike micelles and spherical micelles by thin-film dispersion method and modified solvent evaporation method, respectively. Firstly, the pH responsiveness of two kinds of micelles was investigated in vitro. Both forms of micelles responded to pH sensitively, and each of them could reach 100 times of ON/OFF fold after conjugated with BDP fluorescent probe. Moreover, the cellular uptake of two forms of micelles depended on the concentration and incubation time. However, the amount of cellular uptake of spherical micelles was much higher than that of the wormlike micelles, which proved that the shape of nanoparticles had a great influence on the cellular uptake. The results of in vivo imaging revealed that the spherical micelles had a better tumor accumulation as well as tumor imaging outcomes. Finally, the biosafety of micelles was tested by MTT assay and H&E staining, which indicated that none of the two kinds of micelles had obvious toxicity. Collectively, these results suggest that the spherical micelles could be a better carrier compared with wormlike micelles in terms of cellular uptake, tumor accumulation and tumor detection.