All-stage targeted therapy for the brain metastasis from triple-negative breast cancer

Brain metastasis is a common and serious complication of breast cancer, which is commonly associated with poor survival and prognosis. In particular, the treatment of brain metastasis from triple-negative breast cancer (BM-TNBC) has to face the distinct therapeutic challenges from tumor heterogeneity, circulating tumor cells (CTCs), blood-brain barrier (BBB) and blood-tumor barrier (BTB), which is in unmet clinical needs. Herein, combining with the advantages of synthetic and natural targeting moieties, we develop a "Y-shaped" peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC. Inherited from the activated platelet, the hybrid liposomes still retain the native affinity toward CTCs. Further, the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo. The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions, and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug. Overall, this work provides a promising prospect for the comprehensive treatment of BM-TNBC, which could be generalized to other cell types or used in imaging platforms in the future.

A pentapeptide enabled AL3810 liposome-based glioma-targeted therapy with immune opsonic effect attenuated

AL3810, a molecular dual inhibitor of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), has earned the permission of phase II clinical trial for tumor treatment by China FDA. As a reversible ATP-competitive inhibitor, AL3810 targets ATP-binding site on intracellular region of VEGFR and FGFR, whereas, AL3810 lacking interplay with extracellular region of receptors rendered deficient blood-brain tumor barrier (BBTB) recognition, poor brain penetration and unsatisfactory anti-glioma efficacy. Integrin

Liposomes and lipid disks traverse the BBB and BBTB as intact forms as revealed by two-step Förster resonance energy transfer imaging

The blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB) prevent drug and nano-drug delivery systems from entering the brain. However, ligand-mediated nano-drug delivery systems have significantly enhanced the therapeutic treatment of glioma. In this study we investigated the mechanism especially the integrity of liposomes and lipid disks while traversing the BBB and BBTB both and . Fluorophores (DiO, DiI and DiD) were loaded into liposomes and lipid disks to form Förster resonance energy transfer (FRET) nano-drug delivery systems. Using brain capillary endothelial cells as a BBB model, we show that liposomes and disks are present in the cytoplasm as their intact forms and traverse the BBB with a ratio of 0.68‰ and 1.67‰, respectively. Using human umbilical vein endothelial cells as BBTB model, liposomes and disks remained intact and traversed the BBTB with a ratio of 2.31‰ and 8.32‰ at 3 h. imaging and immunohistochemical results revealed that liposomes and disks could traverse the BBB and BBTB as intact forms. In conclusion, these observations explain in part the mechanism by which nano-drug delivery systems increase the therapeutic treatment of glioma.

Efficacy of inverso isomer of CendR peptide on tumor tissue penetration

The dense extracellular matrix and high interstitial fluid pressure of tumor tissues prevent the ability of anti-tumor agents to penetrate deep into the tumor parenchyma for treatment effects. C-end rule (CendR) peptides can enhance the permeability of tumor blood vessels and tumor tissues binding to neuropilin-1 (NRP-1), thus aiding in drug delivery. In this study, we selected one of the CendR peptides (sequence RGERPPR) as the parent l-peptide and substituted d-amino acids for the l-amino acids to synthesize its inverso peptide (RGERPPR). We investigated the NRP-1 binding activity and tumor-penetrating ability of (RGERPPR). We found that the binding affinity of (RGERPPR) with NRP-1 and the cellular uptake was significantly higher than that of RGERPPR. Evans Blue tests revealed that (RGERPPR) exhibited improved tumor-penetrating ability in C6, U87 and A549 tumor-bearing nude mice. Using nude mice bearing A549 xenograft tumors as a model, we found that the rate of tumor growth in the group co-administered with (RGERPPR) and gemcitabine (Gem) was significantly lower than the gemcitabine-treated group with a tumor suppression rate (TSR%) of 55.4%. Together, our results demonstrate that (RGERPPR) is a potential tumor-penetrating peptide.

Enhanced glioma-targeting and stability of GICP peptide coupled with stabilized peptide A7R

Malignant glioma is usually accompanied by vigorous angiogenesis to provide essential nutrients. An effective glioma targeting moiety should include excellent tumor-cell homing ability as well as good neovasculature-targeting efficiency, and should be highly resistant to enzyme degradation in the bloodstream. The phage display-selected heptapeptide, the glioma-initiating cell peptide (GICP), was previously reported as a ligand for the VAV3 protein (a Rho-GTPase guanine nucleotide exchange factor), which is mainly expressed on glioma cells; the stabilized heptapeptide A7R has been shown to be the ligand of both vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1), and has demonstrated good neovasculature-targeting ability. By linking A7R and GICP, a multi-receptor targeting molecule was obtained. The stability of these three peptides was evaluated and their targeting efficiency on tumor-related cells and models was compared. The ability of these peptides to cross the blood--tumor barrier (BTB) was also determined. The results indicate that the coupled Y-shaped peptide A7R-GICP exhibited improved tumor and neovasculature targeting ability and had higher efficiency in crossing the BTB than either individual peptide.

retention of poloxamer-basedhydrogels for vaginal application in mouse and rat models

The purpose of this study is to evaluate theretention capabilities of poloxamer-basedhydrogels for vaginal application with nonoxinol-9 as the model drug. Twohydrogel formulations, which contained 18% poloxamer 407 plus 1% poloxamer 188 (GEL1, relative hydrophobic) or 6% poloxamer 188 (GEL2, relative hydrophilic), were compared with respect to the rheological properties,hydrogel erosion and drug release. The vaginal retention capabilities of these hydrogel formulations were further determined in two small animal models, including drug quantitation of vaginal rinsing fluid in mice and isotope tracing withTc in rats. The two formulations exhibited similar phase transition temperatures ranging from 27 to 32 °C. Increasing the content of poloxamer 188 resulted in higher rheological moduli under body temperature, but slightly accelerated hydrogel erosion and drug release. When compared, GEL1 was eliminated significantly slower in rat vagina than GEL2, while the vaginal retention of these two hydrogel formulations behaved similarly in mice. In conclusion, increases in the hydrophilic content of formulations led to faster hydrogel erosion, drug release and intravaginal elimination. Rats appear to be a better animal model than mice to evaluate thehydrogel for vaginal application.

Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: preparation, characterization and application in a vaginal drug delivery system

Lack of mucoadhesive properties is the major drawback to poloxamer 407 (F127)-basedhydrogels for mucosal administration. The objective of the present study was to construct a novel mucoadhesive and thermosensitivehydrogel drug delivery system based on an amino-functionalized poloxamer for vaginal administration. First, amino-functionalized poloxamer 407 (F127-NH) was synthesized and characterized with respect to its micellization behavior and interaction with mucin. Then using acetate gossypol (AG) as model drug, AG-loaded F127-NH-basedhydrogels (NFGs) were evaluated with respect to rheology, drug release,vaginal mucosal adhesion,intravaginal retention and local irritation after vaginal administration to healthy female mice. The results show that F127-NHis capable of forming a thermosensitivehydrogel with sustained drug release properties. An interaction between positively charged F127-NHand negatively charged mucin was revealed by changes in the particle size and zeta potential of mucin particles as well as an increase in the complex modulus of NFG caused by mucin.andfluorescence imaging and quantitative analysis of the amount of AG remaining in mouse vaginal lavage all demonstrated greater intravaginal retention of NFG than that of an unmodified F127-basedhydrogel. In conclusion, amino group functionalization confers valuable mucoadhesive properties on poloxamer 407.

Preliminary investigations into surface molecularly imprinted nanoparticles for Helicobacter pylori eradication

This paper reports investigations into the preparation and characterization of surface molecularly imprinted nanoparticles (SMINs) designed to adhere to Helicobacter pylori (H. pylori). Imprinted nanoparticles were prepared by the inverse microemulsion polymerization method. A fraction of Lpp20, an outer membrane protein of H. pylori known as NQA, was chosen as template and modified with myristic acid to facilitate its localization on the surface of the nanoparticles. The interaction between these SMINs with the template NQA were evaluated using surface plasmon resonance (SPR), change in zeta potential and fluorescence polarization (FP). The results were highly consistent in demonstrating a preferential recognition of the template NQA for SMINs compared with the control nanoparticles. In vitro experiments also indicate that such SMINs are able to adhere to H. pylori and may be useful for H. pylori eradication.

Brain tumor-targeted drug delivery strategies

Despite the application of aggressive surgery, radiotherapy and chemotherapy in clinics, brain tumors are still a difficult health challenge due to their fast development and poor prognosis. Brain tumor-targeted drug delivery systems, which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue, are a promising new approach to brain tumor treatments. Since brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues, potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug delivery. In this review, we briefly describe the physiological characteristics of brain tumors, including blood-brain/brain tumor barriers, the tumor microenvironment, and tumor stem cells. We also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges.

Modification by wheat germ agglutinin delays the ocular elimination of liposome / 药学学报

The purpose of this study is to explore the feasibility of wheat germ agglutinin (WGA) modified liposome as a vehicle for ophthalmic administration. Liposome loaded with 5-carboxyfluorescein (FAM) was prepared by lipid film hydration method. WGA was thiolated and then conjugated to the surface of the liposome via polyethylene glycol linker to constitute the WGA-modified and FAM-loaded liposome (WGA-LS/FAM). The amount of thiol groups on each WGA molecule was determined, and the bioactivity of WGA was estimated after it was modified to the surface of liposome. The physical and chemical features of the WGA-modified liposome were characterized and the ocular bioadhesive performance was evaluated in rats. The result showed that each thiolated WGA molecule was conjugated with 1.32 thiol groups. WGA-LS/FAM had a mean size of (97.40 +/- 1.39) nm, with a polydispersity index of 0.23 +/- 0.01. The entrapment efficacy of FAM was about (2.95 +/- 0.21)%, and only 4% of FAM leaked out of the liposome in 24 h. Erythrocyte agglutination test indicated that after modification WGA preserved the binding activity to glycoprotein. The in vivo ocular elimination of WGA-LS/FAM fitted first-order kinetics, and the elimination rate was significantly slower than that of the unmodified liposome, demonstrating WGA-modified liposome is bioadhesive and suitable for ophthalmic administration.

Application of activatable cell-penetrating peptide in the field of tumor therapy / 药学学报

Cell-penetrating peptide (CPP) is a kind of small molecular peptide which can pass through a variety of cell membranes. It can carry bioactive macromolecules into cells. Due to lacking of tissue-selecting and targeting behavior, the application of CPP in the field of tumor treatment is limited. Activatable cell- penetrating peptide (ACPP) has brought the dawn to the application of CPP. This review mainly introduces the applications of ACPP in the targeting antitumor drug delivery which was designed based on the differences between tumor microenvironment and normal tissues as well as the exogenous physical stimulation.

Preparation of bovine serum albumin nanoparticles loaded with gemcitabine and the cytotoxic effect on pancreatic cancer cells in vitro / 中华胰腺病杂志

Objectives To investigate preparation of gemcitabine albumin nanoparticles, and its property of slow-release, the cytotoxic effect on pancreatic cancer cells (PANC1) in vitro, for improving the effect of regional intra-arterial infusion chemotherapy in pancreatic cancer with new medicament in the future. Methods The gemcitabine albumin nanoparticles were prepared with bovine serum albumin and gemcitabine with the desolvation-crosslink method, the concentration of gemcitabine was detected by high performance liquid chromatography (HPLC). The cytotoxic effect on pancreatic cancer cells in vitro were detected with MTT colorimetric assay. Results The mean diameter of gemcitabine albumin nanoparticles was (156.2±2.2) nm, and Zeta potential was (-20.4±1.41)mV, drug loading was 10.8%, drug release time in virto was 3 hours respectively. Gemcitabine albumin nanoparticles (0.01～50 μg/ml) had a 31%～44% inhibitory rate on PANC1 cell, which was similar to the inhibitory rate of same concentration of gemcitabine (26%～47%). Conclusions The new preparation of gemcitabine albumin nanoparticles had obvious drug slow-release effect, which may help improve the effect of regional intra-arterial infusion chemotherapy for pancreatic cancer.

Preparation and in vitro targeting of sterically stabilized liposomes modified with chimeric TNT-3 monoclonal antibody / 药学学报

Aim To prepare sterically stabilized liposomes modified with chimeric TNT-3 monoclonal antibody (chTNT-3) and investigate their immunoreactivity and in vitro targeting. Methods An endgroup functionalized polyethylene glycol-lipid derivative (pyridylthiopropionoylamino-polyethylene glycolhydrogenated soy phosphatidylethanolamine, PDP-PEG-HSPE ) was synthesized and incorporated to sterically stabilized liposomes. After mild thiolysis of the PDP groups by dithiothreitol, liposomes were covalently linked with maleimide-derivatized chTNT-3 and formed sterically stabilized immunoliposomes.Coupling efficiency, antibody density, size distribution, immunoreactivity of chTNT-3-modified sterically stabilized liposomes (chTNT-3-SLs) and specific binding properties of the chTNT-3-SLs to fixed Raji cells were determined, separately. Results Higher initial Ab/PDP-PEG-HSPE molar ratios resulted in higher antibody density on the surface of liposomes but lower coupling efficiency. The optimal coupling efficiency of 71% was obtained while antibody density in liposome was 106 μg antibody/μmol phospholipids (as initial antibody/PDP-PEG-HSPE = 1: 10). The chTNT-3-SLs had a narrow size distribution after extrusion and the mean size of this immunoliposomes was (115 ± 33) nm. The immunoreactivity of chTNT-3 can be preserved after efficient attachment of maleimide-derivatized chTNT-3 to the surface of liposomes. But calculated per antibody concentration, the immunoreactivity of chTNT-3-SLs would obviously decrease compared to that of chTNT-3 or chTNT-3 derivatives. Significantly higher binding of chTNT-3-SLs to fixed Raji cells directed by chTNT-3 was obtained compared to other preparations in serial dilutions (P＜0.01). Conclusion chTNT-3-SLs prepared by PDP-PEG-HSPE method remained most immunoreactivity of chTNT-3 and was able to bind nuclear antigens in vitro.

Targeting therapy of magnetic doxorubicin stealth liposome on human gastric cancer xenografts in nude mice / 中国普通外科杂志

Objective To study the effect of magnetic doxorubicin stealth liposome on human gastric cancer xenografts in nude mice.Methods Human gastric cancer cell line MKN-45 was implanted into 36 nude mice.Different kinds of drug were injected through the caudal vein of tumor bearing nude mice divided into 6 groups .Permanent magnet was put into tumor in targeting group.Results The growth speed of tumor in the group of MDL (+) significantaly slowed down than other groups.The rate of tumor restrain in tumor weight and tumor volume of MDL (+) group were 71% and 70%, which were remarkably higher than those of the DOX and MDL (-) group (all P