ABSTRACT
Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.
ABSTRACT
In order to prepare angiopep-2 modified fluorescein isothiocyanate-labeled neurotoxin nanoparticles( ANG-NPs/FITCNT),emulsion/solvent evaporation method was used with m PEG-PLA and ANG-PEG-PLA( in proper proportions) as carriers and with FITC-NT as drug. With particle size and encapsulation efficiency as comprehensive indexes,the effects of different ultrasound power and ultrasound time combinations on the process were investigated. The in vitro release characteristics of nanoparticles in PBS buffer at p H 7. 4 and p H 6. 5 were investigated by dialysis method. The results indicated that the optimum process for preparing ANG-NPs/FITC-NT was as follows: ultrasonic power 90 W,ultrasonic time 30 s. In such optimal process,ANG-NPs/FITC-NT were well-shaped under the transmission electron microscope,with an average particle size of( 123. 9±0. 5) nm,Zeta potential of(-10. 5±0. 5) m V,encapsulation efficiency of( 68. 1±0. 4) %,and the drug loading of( 0. 82±0. 01) %. The in vitro drug release profiles of the nanoparticles in PBS buffer at p H 7. 4 and p H 6. 5 were both consistent with Ritger-Peppas equation,ln Q = 0. 508 8 lnt-2. 285 0,r = 0. 961 5( p H 7. 4) and ln Q= 0. 449 9 lnt-1. 855 3,r = 0. 970 3( p H 6. 5),respectively. The experiment results proved that the nanoparticles prepared by emulsion/solvent evaporation method had uniform particle size,high encapsulation efficiency and in vitro sustained release characteristic,which might be a potential carrier for NT intracerebral drug delivery.
Subject(s)
Drug Carriers , Fluorescein-5-isothiocyanate , Nanoparticles , Particle Size , Peptides , Polyethylene GlycolsABSTRACT
Objective To prepare an angiopep-2 modified disulfide cross-linked lipoic acid-polyarginine polypeptide and histidine nanomicelle loading anticancer agent doxorubicin (DOX) brain-targeting drug delivery system for glioma (LHRss-An/DOX). Methods LHRss-An/DOX was prepared by ultrasonic emulsification method, and the particle size, zeta potential and appearance were detected. The loading content (LC) and encapsulation efficiency (EE) of DOX in the polymeric micelles and the in vitro release profiles were determined. Transmembrane transport efficiency of LHRss-An/DOX was evaluated using in vitro blood-brain barrier (BBB) model. The intracellular distribution of DOX and glioma targeting ability were observed by laser scanning confocal microscopy. Results Spherical micelles LHRss-An/DOX were successfully obtained. The mean particle size of the LHRss-An/DOX was (100.9±8.7) nm, polymer dispersity index was 0.232, zeta potential was (28.8±3.3) mV, optimal drug loading ratio was 40%, LC was 15.8% and EE was 55.3%. Cumulative DOX release within 72 h reached (60.3±2.6)%, (84.1±3.9)% and (96.6±2.7)% in the solutions of pH 7.4, pH 5.5 and pH 5.5 with 10 mmol/L DL-dithiothreitol (DTT), respectively. The transporting BBB efficiency of LHRss-An/DOX was 2.04 and 4.27 times of that of LHRss/DOX and free DOX, respectively (both P0.05). The fluorescence intensity of LHRss-An/DOX uptake by of glioma cells U251 was stronger than that of LHRss/DOX and free DOX. Conclusion Angiopep-2-modified loading drug nanomicelles have good penertrating capacity of BBB and gliomatargeting, and it can be a potential drug delivery system for brain-targeting.
ABSTRACT
Objective: To enhance the blood-brain barrier (BBB) penetration and glioma targeting ability of arsenic trioxide (As2O3), the lipid-coated mesoporous silica nanoparticles (MSN) modified with Angiopep-2 and polyacrylic acid (ANG-PAA-LP-MSN) is prepared by thin-film hydration method. This complex is specifically recognized and bound between ANG and low-density lipoprotein receptor-related protein-1 (LRP-1) which is highly expressed on BBB and glioma cells. Methods: The drug delivery system characterization were analysed by transmission electron microscopy (TEM) and thermogravimetric analysis (TGA). Dialysis bag method was used to analyse the drug release characteristics at different pH conditions (pH 6.0 and 7.4, respectively). Cytotoxicity of nanocarriers and the antitumor activity in vitro of this drug delivery system were measured on human brain micro-capillary endothelial cells (HBMEC) and glioma cells (C6) by MTT assay. Moreover, in vitro cells model of BBB was established to study the effect of vehicle on the transmembrane transport of As2O3. Results: The drug delivery system (ANG-PAA-LP-MSN@As2O3) was constructed successfully, it showed a rounded "core-shell" structure with good dispersibility and stability. The drug loading efficency was 6.32%. After PAA modification, this drug delivery system showed higher pH responsiveness to release medium, and the burst release of As2O3 was significantly reduced compared with that of unmodified group. Lipid coating could significantly improve the biosafety and penetration ability of BBB. The antitumor activity study showed that ANG-PAA-LP-MSN@As2O3 exhibited an ideal glioma inhibition effect in vitro. Conclusion: This smart targeting drug delivery system enhance the BBB penetration ability of As2O3, and the special pH responsiveness demonstrated antitumor ability through increasing its accumulation in the tumor site.
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The key factor of chemotherapy for brain disorders is to penetrate brain blood barrier(BBB). Receptor mediated en-docytosis is one of the mechanisms for drug carriers to cross the BBB. Angiopep-2(ANG)can specifically bind to low density lipopro-tein receptor-related proteins 1(LRP-1)overexpressed on BBB and glioma cells,thus exhibits a higher LRP-mediated BBB penetra-tion capability. Its targeting efficiency is higher than that of other targeting molecules such as transferrin and(TF)lactoferrin(LF). This paper introduces the structure and function of ANG,and its application in brain targeting delivery systems,in order to provide references for research and development of brain targeting preparations and guidance for therapy of brain diseases.
ABSTRACT
OBJECTIVE: To prepare and evaluate the novel core-shell structural phospholipid-functionalized mesoporous silica nanoparticles (MSN-LP) modified with angiopep-2 (ANG-MSN-LP). METHODS: Mesoporous silica nanoparticles (MSN) was synthesized by the modified Stober method. MSN-PTX was prepared by saturated solution adsorption method. ANG-MSN-LP was developed by selfassembly and film hydration method. By using dialysis bag method to investigate the in vitro drug release characteristics and MTT method to investigate the cytotoxicity on HBMEC and C6 cells. The transport ability and effects on cell cycle of the carrier was investigated by the BBB monolayer model. RESULTS: MSN was synthesized with high specific surface area (SBET, 425 m · g-1), cumulative pore volume (Vp, 0.37 cm · g-1) and pore size(3.5 nm). PTX was highly encapsulated (drug loading efficiency up to 11.1%) into MSN. Results of in vitro release showed that about 75.5% of PTX released from ANG-MSN-LP-PTX after 48 h and burst release was effectively reduced compared with MSN-PTX or PTX solution, indicating pronounced sustained-release characteristics. The good biocompatibility and low toxicity of ANG-MSN-LP were evaluated by HBMEC and C6 cells. The transport ratio was 2.49% for PTX, 2.72% for MSN-PTX, 4.45% for MSN-LP-PTX and 10.74% for ANG-MSN-LP-PTX respectively. In addition, ANG-MSN-LP-PTX showed a higher cell number of G2-M phase of 40.92 ± 6.20%. CONCLUSION: ANG-MSN-LP is a prospective targeting drug delivery system for therapy of brain glioma. Meanwhile, saturated solution adsorption method can increase the drug loading efficiency highly.
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The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells, which is usually caused by abnormal gene expression. RNA interference mediated by siRNA and miRNA can selectively knock down the carcinogenic genes by targeting specific mRNAs. Therefore, combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy. Due to poor stability and solubility associated with gene agents and drugs, suitable protective carriers are needed and have been widely researched for the co-delivery. In this review, we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents, as well as the advances in co-delivery systems.
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Objective To prepare angiopep-2 and transferrin co-modified liposomes (ANG/TF-LPs) and to observe their propertyof passing the blood-brain barrier (BBB). Methods ANG/TF-LPs were prepared by film-ultrasonic method. The particle size, Zeta potential and stability in fetal bovine serum (FBS) of ANG/TF-LPs were evaluated. The cellular uptake of ANG/TF-LPs by bEnd. 3 cells in vitro was observed to evaluate the targeting efficiency. The in vitro BBB model was used to evaluate the ability of liposomes passing the BBB. Results The diameter of the prepared ANG/TF-LPs was (93.2 ± 13.5) nm, the Zeta potential was (7.55 ± 1.85) mV, and they were stable in FBS within 24 h. tt was found that the uptake of ANG/TF-LPs by bEnd. 3 cells was 2.9, 2.4 and 4.8 folds those of transferrin modified liposomes (TF-LPs), angiopep-2 modified liposomes (ANG-LPs) and liposomes (LPs), respectively (P < 0.01). The efficiency of ANG/TF-LPs passing the BBB was 3.1, 2.9 and 5.4 folds those of TF-LPs, ANG-LPs and LPs, respectively (P < 0.01). Conclusion The angiopep-2 and transferrin co-modified liposomes are easy to prepare, and the modification can enhance the BBB passing ability, making the prepared liposomes a promising brain drug delivery system.