Preimplantation genetic testing for monogenic disorders (PGT-M) offers an alternative strategy to prevent children from being born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes: a retrospective study.

BACKGROUND: Preimplantation genetic testing for monogenic disorders (PGT-M) is now widely used as an effective strategy to prevent various monogenic or chromosomal diseases. MATERIAL AND METHODS: In this retrospective study, couples with a family history of hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes and/or carrying the pathogenic genes underwent PGT-M to prevent children from inheriting disease-causing gene mutations from their parents and developing known genetic diseases. After PGT-M, unaffected (i.e., normal) embryos after genetic detection were transferred into the uterus of their corresponding mothers. RESULTS: A total of 43 carrier couples with the following hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes underwent PGT-M: Duchenne muscular dystrophy (13 families); methylmalonic acidemia (7 families); spinal muscular atrophy (5 families); infantile neuroaxonal dystrophy and intellectual developmental disorder (3 families each); Cockayne syndrome (2 families); Menkes disease, spinocerebellar ataxia, glycine encephalopathy with epilepsy, Charcot-Marie-Tooth disease, mucopolysaccharidosis, Aicardi-Goutieres syndrome, adrenoleukodystrophy, phenylketonuria, amyotrophic lateral sclerosis, and Dravet syndrome (1 family each). After 53 PGT-M cycles, the final transferable embryo rate was 12.45%, the clinical pregnancy rate was 74.19%, and the live birth rate was 89.47%; a total of 18 unaffected (i.e., healthy) children were born to these families. CONCLUSIONS: This study highlights the importance of PGT-M in preventing children born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes.

Folate Modified Long Circulating Nano-Emulsion as a Promising Approach for Improving the Efficiency of Chemotherapy Drugs in Cancer Treatment.

PURPOSE: In order to improve the therapeutic efficiency of the chemotherapeutic drug paclitaxel in tumors, a folate-based Paclitaxel nanoemulsion (FNEs) was developed for tumor targeted treatment. METHODS: In this study, we designed a folate-targeted nanoemulsion (folate/PEG-DSPE/nanoemulsion, FNEs) based on the traditional nanoemulsion using the principle of long-circulation targeting receptor mediated. The nanoemulsion (folate/PEG-DSPE/nanoemulsion, FNEs) was fabricated using high-pressure homogenization with a microfluidizer. RESULTS: The nanoemulsion (folate/PEG-DSPE/nanoemulsion, FNEs) can improve the delivery efficiency of nanocarriers at the tumor site by virtue of the high expression of folate receptors on the tumor surface. Malvern Nanoseries device and transmission electron microscopy (TEM) analyses showed that the nanoemulsions were spherical with an average diameter of 140 nm. The nanoemulsions can effectively carry paclitaxel (PTX) with an encapsulation rate of about 95%. And in vitro experiments have shown that it can efficiently increase the uptake of PTX in 4 T1 breast cancer cells and FNEs had a targeting capability hundredfold higher than that of PTX-loaded nanoemulsions (PTX-NEs) without folate. In vivo experiments have shown that the pharmacokinetic parameters of FNEs were better than those of other PTX groups and FNEs can significantly enhance circulation time in the body of the subcutaneously implanted 4 T1 breast cancer in mice, increase the accumulation of chemotherapy drugs at tumor sites and effectively inhibit tumor growth with lower system toxicity. CONCLUSIONS: This study can effectively improve the therapeutic efficiency of chemotherapy drugs for tumors, and provide an useful reference for solving the problem of low efficacy of chemotherapy drugs in clinical treatment of tumors. Graphical Abstract Schematic representation of Folic acid/PEG-DSPE/nano-emulsion (FNEs) specifically target tumor cells and enhanced anti-tumor effects.

Tailored Polymers with Complement Activation Ability To Improve Antitumor Immunity.

The complement system plays an important role in host innate immunity, and its activation can be exploited as a potential strategy for vaccine adjuvants. Herein, a pH-responsive micellar vaccine platform (COOH-NPs) was developed using a carboxyl-modified diblock copolymer of poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (COOH-PEOz-PLA). The copolymer self-assembled into micelles with hydroxyl groups shielding on the surface, which activated the complement system for the enhanced immune responses. Compared with the control nanoparticles (OCH3-NPs), COOH-NPs significantly enhanced lymph node-resident dendritic cell maturation, antigen-specific IgG production, antigen-specific CD4+ and CD8+ T-cell activation, and the amount of memory T-cell generation in vivo. Furthermore, immunization with COOH-NPs/OVA in E.G7-OVA tumor-bearing mice not only remarkably inhibited tumor growth but also prolonged the survival of tumor-bearing mice. These results indicated that COOH-NPs with the capability of complement activation efficiently boosted the immune responses for the antitumor effect. The study demonstrated the significance of taking advantage of a complement-activating vaccine platform for cancer immunotherapy.

Rational Design of Multifunctional Polymeric Nanoparticles Based on Poly(l-histidine) and d-α-Vitamin E Succinate for Reversing Tumor Multidrug Resistance.

A multifunctional nanoparticulate system composed of methoxy poly(ethylene glycol)-poly(l-histidine)-d-α-vitamin E succinate (MPEG-PLH-VES) copolymers for encapsulation of doxorubicin (DOX) was elaborated with the aim of circumventing the multidrug resistance (MDR) in breast cancer treatment. The MPEG-PLH-VES nanoparticles (NPs) were subsequently functionalized with biotin motif for targeted drug delivery. The MPEG-PLH-VES copolymer exerts no obvious effect on the P-gp expression level of MCF-7/ADR but exhibited a significant influence on the loss of mitochondrial membrane potential, the reduction of intracellular ATP level, and the inhibition of P-gp ATPase activity of MCF-7/ADR cells. The constructed MPEG-PLH-VES NPs exhibited an acidic pH-induced increase on particle size in aqueous solution. The DOX-encapsulated MPEG-PLH-VES/biotin-PEG-VES (MPEG-PLH-VES/B) NPs were characterized to possess high drug encapsulation efficiency of approximate 90%, an average particle size of approximately 130 nm, and a pH-responsive drug release profile in acidic milieu. Confocal laser scanning microscopy (CLSM) investigations revealed that the DOX-loaded NPs resulted in an effective delivery of DOX into MCF-/ADR cells and a notable carrier-facilitated escape from endolysosomal entrapment. Pertaining to the in vitro cytotoxicity evaluation, the DOX-loaded MPEG-PLH-VES/B NPs resulted in more pronounced cytotoxicity to MCF-/ADR cells compared with DOX-loaded MPEG-PLH-VES NPs and free DOX solution. In vivo imaging study in MCF-7/ADR tumor-engrafted mice exhibited that the MPEG-PLH-VES/B NPs accumulated at the tumor site more effectively than MPEG-PLH-VES NPs due to the biotin-mediated active targeting effect. In accordance with the in vitro results, DOX-loaded MPEG-PLH-VES/B NPs showed the strongest inhibitory effect against the MCF-7/ADR xenografted tumors with negligible systemic toxicity, as evidenced by the histological analysis and change of body weight. The multifunctional MPEG-PLH-VES/B nanoparticulate system has been demonstrated to provide a promising strategy for efficient delivery of DOX into MCF-7/ADR cancerous cells and reversing MDR.

Polyethylene glycol modified PAMAM dendrimer delivery of kartogenin to induce chondrogenic differentiation of mesenchymal stem cells.

Partly PEGylated polyamidoamine (PAMAM) dendrimer was used as the nanocarrier for the cytoplasmic delivery of kartogenin (KGN) to induce chondrogenic differentiation of mesenchymal stem cells (MSCs). Here, KGN was conjugated to the surface of PAMAM and the end group of polyethylene glycol (PEG) to obtain PEG-PAMAM-KGN (PPK) and KGN-PEG-PAMAM (KPP) conjugate, respectively. The effects of PPK and KPP on the in vitro chondrogenic differentiation of MSCs were evaluated. KPP induced higher expression of chondrogenic markers than PPK and free KGN. In particular, after treatment of KPP, CBF ß nuclear localization intensity was significantly increased, indicating enhanced efficacy of chondrogenesis. The fluorescein labeled PEG-PAMAM was capable to persist in the joint cavity for a prolonged time of both healthy and osteoarthritis (OA) rats. Thus, PEG-PAMAM could be a useful nanocarrier for intra-articular (IA) delivery of drug to treat OA.

[Techniques and methods evaluation on pharmaceutical stability of liposomes].

Liposomes as a drug carrier is easy to form aggregation and cause drug leakage in vitro. In addition, the degradation and elimination in vivo happens frequently to reduce its delivery activity. Development and application of liposomes are restricted by the instability. The appropriate techniques and methods are great important in the study of pharmaceutical stability of liposomes. In this paper, the techniques and methods are reviewed on pharmaceutical stability evaluation of liposomes, which was done from physical, chemical and biological stability for the difference in stability of liposomes. The research strategies for establishing the stability evaluation system and improving the value of liposomes have been discussed to make full therapeutic advantage of it.

[Poly(ß-amino esters)-based barriers for tumor targeted delivery system].

Poly(ß-amino esters) (PBAE) are used for drug carrier and have many advantages, such as pH-sensitivity, low toxicity, structural diversity and the synthetic method of PBAE is easy. Therefore they are possessed broad application prospect in tumor-targeted drugs delivery systems. In this paper, the structural features and target drugs delivery property of PBAE are reviewed. The application forms of PBAE and different anti-cancer drugs loaded in the copolymer for tumor-targeted drugs delivery systems are introduced particularly.

Poly(l-histidine) based triblock copolymers: pH induced reassembly of copolymer micelles and mechanism underlying endolysosomal escape for intracellular delivery.

Various poly(l-histidine) based amphiphilic copolymers have been developed for intracellular drug delivery due to the pH responsive properties and the escape from endolysosomal pathway. However, the pH induced reassembly of copolymer micelles and the assumed endolysosome membrane rupture during the copolymer facilitated endolysosomal escape have never been elucidated. To address these issues, a series of poly(ethylene glycol)-poly(d,l-lactide)-poly(l-histidine) (mPEG-PLA-PHis) with different degrees of polymerization of PLA and PHis block were synthesized. The self-assembly and reassembly behaviors of the copolymers were characterized using transmission electron microscopy (TEM), (1)H NMR, fluorescence probe technique, and dynamic light scattering (DLS). The copolymers self-assembled into micelles with PLA and unprotonated PHis blocks as hydrophobic core and PEG as hydrophilic shell at neutral pH. The changes in TEM images, (1)H NMR spectrum of PHis peak, pyrene fluorescene spectrum, and particle size as well as size distribution over the pH range from pH 8.5 to 4.5 suggest that the copolymer micelles reassembled into micelles with PLA as hydrophobic core and protonated PHis and PEG as hydrophilic shell under acidic environment. The pH induced reassembly triggered the incoporated doxorubicin (DOX) release, as indicated by the in vitro accelerated drug release and enhanced cytotoxicity. The integrity of endolysosome membrane during the copolymer facilitated DOX endolysosomal escape was observed by confocal laser scan microscopy (CLSM) and further evaluated by hemolysis test and calculation of the critical size of endolysosomal membrane. The results indicate that the endolysosomal membrane remained intact during the copolymer facilitated endolysosomal escape of DOX. It is more reasonable to ascribe the PHis based copolymer facilitation endolysosomal escape to the "proton sponge" hypothesis without rupturing the endolysosomal membrane.

Folate and TAT peptide co-modified liposomes exhibit receptor-dependent highly efficient intracellular transport of payload in vitro and in vivo.

PURPOSE: Using different chain lengths of PEG as linkers to develop a novel folate (FA) and TAT peptide co-modified doxorubicin (DOX)-loaded liposome (FA/TAT-LP-DOX) and evaluate its potential for tumor targeted intracellular drug delivery. METHODS: FA/TAT-LP-DOX was prepared by pH gradient method and post-insertion method and the optimal ligand density was screened by MTT assay. In vitro evaluation was systematically performed through cytotoxicity assay, cellular uptake studies, subcellular localization and cellular uptake mechanism in folate receptor (FR) over-expressing KB tumor cells. In vivo tumor targeted delivery of FA/TAT-LP-DOX was also studied by in vivo fluorescence imaging in a murine KB xenograft model. RESULTS: The particle size and zeta potential determination indicated that FA and TAT were successfully inserted into the liposome and cationic TAT peptide was completely shielded. With the optimal ligand density (5% of FA and 2.5% TAT), the FA/TAT-LP-DOX exhibited improved cytotoxity and cellular uptake efficiency compared with its single-ligand counterparts (FA-LP-DOX and PEG/TAT-LP-DOX). Competitive inhibition and uptake mechanism experiments revealed that FA and TAT peptide played a synergistic effect in facilitating intracellular transport of the liposome, and association between FA and FA receptors activated this transport process. In vivo imaging further demonstrated the superiority of FA/TAT-LP in tumor targeting and accumulation. CONCLUSIONS: Folate and TAT peptide co-modified liposome using different chain lengths of PEG as linkers may provide a useful strategy for specific and efficient intracellular drug delivery.

Preparation, characterization, cellular uptake and evaluation in vivo of solid lipid nanoparticles loaded with cucurbitacin B.

In this work, solid lipid nanoparticles loaded with cucurbitacin B (Cu B-SLNs) were prepared. It was found that the concentration of poloxamer 188 and soybean lecithin had effects on the mean particle size and size distribution. The zeta potentials were around -33 mV. In vitro release studies showed a sustained release after a burst release. Internalization of Cu B into HepG2 cells could be enhanced by the encapsulation of SLN matrix. The IC50 values of Cu B-SLNs were lower than that of Cu B solution. Both free Cu B and Cu B-SLNs had effectively inhibited the tumor growth and displayed a dose-dependent anti-tumor efficacy. Cu B-SLNs at a dose of 0.11 mg/kg produced the greatest anti-tumor effects (53.3%), which was significant higher than Cu B solution (31.5%, p < 0.05). Cu B-SLNs showed a longer MRT in vivo. The AUC of Cu B-SLNs for tumor increased 3.5 -fold when compared to Cu B solution. The targeting efficiency of Cu B-SLNs was 1.94 times higher in liver as compared to that of Cu B solution. These results indicated that Cu-B SLNs could passively target the tumor with EPR effect, improve the therapeutic efficacy of Cu B, and reduce the doses.

Poly(D, L-lactide-co-glycolide)/montmorillonite nanoparticles for improved oral delivery of exemestane.

The aim of this study was to develop poly(D,L-lactide-co-glycolide)/montmorillonite (PLGA/MMT) nanoparticles formulations for improved oral delivery of exemestane. Exemestane-loaded PLGA nanoparticles and PLGA/MMT nanoparticles were prepared by a modified solvent extraction/evaporation technology with vitamin E succinated polyethylene glycol 1000 (TPGS) as emulsifier. The content of MMT was estimated by thermal gravimetric analysis. The drug encapsulation efficiency and in vitro drug release kinetics were measured by high-performance liquid chromatography. The size, size distribution, surface charge and morphology of the exemestane-loaded nanoparticles were characterized using a Zetasizer Nano ZS and field emission scanning electron microscopy. The physical status of exemestane in the nanoparticles was characterized by differential scanning calorimetry. In vitro cellular uptake of coumarin-6-loaded nanoparticles was investigated by confocal laser scanning microscope, demonstrating that the fluorescence nanoparticles were internalized by Caco-2 cells (as an in vitro gastrointestinal model). The results of in vitro cytotoxicity experiment on MCF-7 cells (as a model of breast cancer cells) showed the exemestane-loaded nanoparticles resulted in lower cell viability versus the pure exemestane solution. The cytotoxicity against MCF-7 cells for exemestane-loaded nanoparticles and pure exemestane solution was dependent on the drug concentration and incubation time. In conclusion, this study indicates the capability of PLGA nanoparticles and PLGA/MMT nanoparticles in enhancing the oral delivery of exemestane.

Preparation and characterization of stable pH-sensitive vesicles composed of α-tocopherol hemisuccinate.

The current study aims to develop a stable pH-sensitive drug delivery system. First, cleavable polyethylene glycol-α-tocopherol hemisuccinate (PEG-THS) was synthesized. Conventional pH-sensitive vesicles composed of the Tris salt of α-tocopherol hemisuccinate (THST) were then prepared using the detergent removal technique. The vesicles had a mean particle size of (163.8 ± 5.5) nm and a zeta potential of -74.5 ± 6.4 mV. The THST vesicles were then modified using PEG-THS or uncleavable PEG-cholesterol (PEG-CHOL) (THST/PEG-lipids, 100:6 molar ratio). The mean vesicle particle size and absolute zeta potential decreased with increasing PEG-THS proportion. When the pH was decreased, the vesicle particle size and calcein release rate increased. The THST vesicles were initially Ca(2+)-unstable but exhibited significantly improved stability after modification with PEG-THS, especially at PEG-lipid ratios above 6%. Incubation in an acid serum increased the calcein release rate of conventional THST vesicles to 45 ± 1.98% at 10 min. However, the release rate of the PEG-CHOL vesicles remained low. The calcein release rate of PEG-THS vesicles was between those of conventional and PEG-CHOL-V. Therefore, PEG-THS can protect vesicles in serum and reconstitute their pH sensitivity in acidic conditions. Cleavable PEG-THS can be used in stable pH-sensitive preparations without loss of pH sensitivity. Free calcein and conventional vesicles eliminated from the plasma soon after injection, as well as the half-life (t(1/2)) and area under the curve of PEG-THS-V encapsulating calcein, were dramatically increased. This phenomenon indicates that the use of PEG-lipid derivatives has gained a favorably long circulation effect in mice.

Watson-Crick Base Pairing-Inspired Laser/GSH Activatable miRNA-Coordination Polymer Nanoplexes for Combined Cancer Chemo-Immuno-Photothermal Therapy.

The tumor immunosuppressive microenvironment (TIM) greatly hindered the efficacy of cancer immunotherapy. Overexpressed indoleamine 2,3-dioxygenase-1 (IDO1) in tumor tissues plays a vital role in TIM generation, and downregulation of IDO1 expression may reverse TIM. Inspired by the Watson-Crick base-pairing rule, a versatile noncationic miRNA vector (miDAC@PDA) is developed for cancer immunotherapy. Doxorubicin (DOX), adenosine triphosphate (ATP), and copper ions (Cu2+) are coassembled into coordination polymer nanoparticles (DAC) and bind miRNA via the hydrogen bond interaction (miDAC) between adenine residues (ATP) and uracil residues (miRNA). Polydopamine (PDA) is deposited onto the surface of miDAC for photothermal therapy. miDAC@PDA can efficiently accumulate into tumor tissues for cellular uptake. Under laser irradiation and high intracellular GSH levels, the PDA shell of miDAC@PDA can dissociate from miDAC for miRNA release due to local hyperthermia. Cu2+-mediated GSH consumption and intracellular ATP release can amplify the DOX-based immunogenic cell death (ICD) cascade, together with miR-448-mediated IDO1 inhibition, and these versatile nanoplexes will not only restrain primary tumor growth but also display a remarkable abscopal effect on distant tumors. Collectively, our study provides a unique strategy for intracellular gene delivery and an inspirational approach for multimechanism cancer management.

Drug pH-sensitive release in vitro and targeting ability of polyamidoamine dendrimer complexes for tumor cells.

Recently, dendrimers have been widely used in medical applications such as drug delivery and gene transfection. In this study, a pH-sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and polyethylene glycol (PEG) modified by lactose (LA-PEG-b-PSD) was synthesized. The pK(a) value of the LA-PEG-b-PSD was also measured. Then, polyamidoamine (PAMAM) complexes were prepared with PAMAM (G4.0) and LA-PEG-b-PSD by electrostatic interaction. To investigate drug pH-sensitive release in vitro, doxorubicin (DOX) was loaded in PAMAM. A higher drug cumulative release from LA-PEG-b-PSD/PAMAM complexes in phosphate buffered saline (PBS) was found at pH 6.5 than at pH 7.4. The cytotoxicity and cellular uptake of PAMAM complexes were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and confocal microscopy. LA-PEG-b-PSD/PAMAM/DOX complexes were able to enhance the cytotoxicity of DOX against HepG2 cells at pH 7.4. Confocal microscopy showed a higher cellular uptake of PEG-b-PSD/PAMAM complexes at pH 6.5. PAMAM complexes modified by lactose showed a higher affinity for hepatic cancer cells than those without lactose at pH 7.4. These results suggest that LA-PEG-b-PSD/PAMAM complexes exhibit selective targeting and cytotoxicity against HepG2 cells. In vivo antitumor studies showed that the LA-PEG-b-PSD/PAMAM/DOX complexes displayed higher antitumor efficacy compared with non-targeted PAMAM/DOX and DOX solution. These results indicate that this strategy should be applicable to the treatment of liver cancers.

Application of Ulex europaeus agglutinin I-modified liposomes for oral vaccine: Ex Vivo bioadhesion and in Vivo immunity.

The conjugation of Ulex europaeus agglutinin I (UEAI) onto surface of liposomes has been demonstrated to effectively improve the intestinal absorption of antigen, subsequently induced strong mucosal and systemic immune responses. In this context, we prepared bovine serum albumin (BSA)-encapsulating UEAI-modified liposomes (UEAI-LIP) and unmodified ones (LIP). The specific bioadhesion on mice gastro-intestinal mucosa was studied ex vivo. An important increase of interaction between UEAI-conjugated liposomes and the intestinal segments with Peyer's Patches (PPs) was observed compared with the unconjugated one (p<0.01). However, under the presence of α-L-fucose, which is the reported specific sugar for UEAI, specifically inhibited the activity of these conjugates. The immune-stimulating activity in vivo was studied by measuring immunoglobulin G (IgG) levels in serum and immunoglobulin A (IgA) levels in intestinal mucosal secretions following oral administration of BSA solution, LIP and UEAI-LIP in mice. Results indicate that antigen encapsulated in liposomes, especially the UEAI-modified ones, was favorable for inducing immune response. At 42 d after the first immunization, the highest IgG and IgA antibody levels produced by UEAI-LIP occurred, respectively showing 4.4-fold and 5-fold higher levels compared to those of the groups receiving BSA alone. This data demonstrated high potential of UEAI-modified liposomes for their use as carrier for oral vaccines.

[Rheological properties of poloxamer 407 aqueous solutions].

Rheological properties of poloxamer 407 (brand named Pluronic F127) were examined by changing shear rate, temperature and the recovery properties of apparent viscosity after heating for several times. The results indicated that poloxamer 407 aqueous solution showed a Newtonian behavior at a low concentration while it might be a pseudoplastic fluid when the concentration reached a certain point. The thixotropy and the sol-gel transition temperature decreased with increasing the concentration (it could be an in situ gel at body temperature when the concentration of poloxamer 407 up to 15.25%). The results that obtained from the theological data would be useful in the application of poloxamer 407 such as in situ gel preparation.

[The characterisitics of temperature/pH sensitive block copolymer micelles in vitro].

The dialysis method was employed to prepare blank and doxorubicin (DOX) loaded micelles formed by temperature- and pH- sensitive polyhistidine-co-polyDL-lactide-co-glycolide-co-polyethyleneglycol-co-polyDL-lactide-co-glycolide-co-polyhistidine (PHis-b-PLGA-b-PEG-b-PLGA-b-PHis). The critical micelle concentrations (CMC) of the copolymers were measured with Pyrene Fluorescent Probe Technique. The temperature- and pH- sensitive properties of the blank micelles solution were investigated by optical transmittance measurement. The morphology and diameter of DOX micelles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The entrapment rate and drug-loading rate were determined with dialysis method. The in vitro release study was further performed to examine the temperature- and pH-responsive drug release behavior from DOX-loaded micelles. The results indicated that the CMC, entrapment efficiency and drug-loaded amount of the micelles were 7.5 x 10(-3) g x L(-1), 85.2 +/- 3.1% and 10.4 +/- 4.5%, respectively. The DOX micelle was globular-shaped with a mean diameter of 91.1 +/- 15.8 nm. The transmittance of micelle solution consistently increased with the increasing temperature or decreasing pH. In comparison to the drug release profile at physiological conditions (37 degrees C, pH 7.4), the DOX-loaded micelles showed faster drug release rate at higher temperature (41 degrees C), lower pH (pH 7.0, pH 6.5, pH 5.0) or higher temperature and lower pH (41 degrees C, pH 5.0). This indicated that the micelles showed a temperature and pH-triggered drug release pattern. Base on the above results, it can be concluded that PHis-b-PLGA-b-PEG-b-PLGA-b-PHis block copolymer micelles which respond to temperature and pH stimuli are promising smart carriers for anti-tumor drugs with the advantages of temperature- and pH- triggered drug release.

Diabetes coexistent with Charcot-Marie-Tooth disease presenting as a recurrent foot ulcer misdiagnosed as diabetic foot: A case report.

Both diabetes mellitus and Charcot-Marie-Tooth disease (CMT) can lead to severe peripheral neuropathy. The differential diagnosis of peripheral neuropathy is difficult due to the similar clinical features. There are still some clues, such as unusual muscle atrophy, unmatched severity of peripheral neurogenic damage with nephropathy or retinopathy, which could alert clinicians to make differential diagnosis. Although diabetes mellitus is rarely concurrent with CMT, it will exacerbate clinical disorders in patients with CMT. To date, there is no specific medicine for CMT treatment. Offloading devices and desirable comprehensive management of diabetes mellitus might be beneficial to avoid plantar ulcer recurrence and anti-progression of CMT.

Laser/GSH-Activatable Oxaliplatin/Phthalocyanine-Based Coordination Polymer Nanoparticles Combining Chemophotodynamic Therapy to Improve Cancer Immunotherapy.

There are two severe obstacles in cancer immunotherapy. The first is that the low response rate challenges the immune response owing to the immunosuppressive tumor microenvironment (ITM) and poor immunogenicity of the tumor. The second obstacle is that the dense and intricate pathophysiology barrier seriously restricts deep drug delivery in solid tumors. A laser/glutathione (GSH)-activatable nanosystem with tumor penetration for achieving highly efficient immunotherapy is reported. The core of the nanosystem was synthesized by coordinating zinc ions with GSH-activatable oxaliplatin (OXA) prodrugs and carboxylated phthalocyanine. Such an OXA/phthalocyanine-based coordination polymer nanoparticle (OPCPN) was wrapped by a phospholipid bilayer and NTKPEG. NTKPEG is a PEGylated indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor prodrug containing a thioketal (TK) linker, which was modified on the OPCPN (OPCPN@NTKPEG). Upon the laser irradiation tumor site, ROS production of the OPCPN@NTKPEG triggers cleavage of NTKPEG by degradation of TK for promoted tumor penetration and uptake. OXA, phthalocyanine, and IDO1 inhibitor were released by the intracellular high-level GSH. OXA inhibits cell growth and is combined with photodynamic therapy (PDT) to induce immunogenic cell death (ICD). The IDO1 inhibitor reversed the ITM by suppressing IDO1-mediated Trp degradation and exhaustion of cytotoxic T cells. Laser/GSH-activatable drug delivery was more conducive to enhancing ICD and reversing ITM in deep tumors. Chemo-PDT with OPCPN@NTKPEG significantly regressed tumor growth and reduced metastasis by improved cancer immunotherapy.

DOX-loaded PEG-PLGA and Pluronic copolymer composite micelles enhances cytotoxicity and the intracellular accumulation of drug in DOX-resistant tumor cells.

In the present study, doxorubicin (DOX) loaded polyethyleneglycol-poly (DL-lactic-co-glycolic acid) micelle as well as composite micelles composed polyethyleneglycol- poly(DL-lactic-co-glycolic acid) (PEG-PLGA) and Pluronic 105 (P105) were constructed. The micelles, with diameter around 106 nm and 85 nm respectively, were prepared by solvent evaporation method. The results showed that the encapsulation of DOX in micelles could significantly enhance its cytotoxicity in a DOX resistant tumor cell line, K562/DOX. The combination of PEG-PLGA and Pluronic further improved both the tumor-suppressive activity and the intracellular accumulation of DOX, indicating that the composite micelles would be potential to reverse the multidrug resistance in tumor cells.