Cleavable Multifunctional Targeting Mixed Micelles with Sequential pH-Triggered TAT Peptide Activation for Improved Antihepatocellular Carcinoma Efficacy.

Abstract:

:Although tumor-targeting nanovehicles for hepatocellular carcinoma (HCC) chemotherapy have attracted great research and clinic interest, the poor cancer penetration, inefficient cellular uptake, and slow intracellular drug release greatly compromise their therapeutic outcomes. In this work, a multifunctional mixed micellar system, consisting of glycyrrhetinic acid (GA) for specific liver-targeting, trans-activator of transcription (TAT) peptide for potent cell penetration, and pH-sensitive poly(β-amino ester) polymers for acidic-triggered drug release, was developed to provide HCC-targeting delivery and pH-triggered release of doxorubicin (DOX). These micelles were hypothesized to efficaciously accumulate in HCC site by the guide of GA ligands, enter into cancer cells facilitated by the activated TAT peptide on the micellar surface, and finally rapidly release DOX in cytoplasm. To demonstrate this design, DOX was initially loaded in micelles modified with both GA and TAT (DOX/GA@TAT-M) with high drug loading efficiency and pH-sensitive drug release profiles. The HCC-targeting cellular uptake and synergetic anticancer efficacy were tested, indicating DOX/GA@TAT-M could be specifically and effectively internalized into HCC cells by the effect of GA targeting and TAT penetrating with enhanced cytotoxicity. In addition, the prolonged circulation time and enhanced accumulation in tumor facilitated its potent tumor growth inhibition activity in vivo. These results demonstrated that the cleavable multifunctional mixed micelles with tumor targeting, controlled TAT peptide activation, and sequential pH-sensitive drug release could be an efficient strategy for HCC treatment.

journal_name

Mol Pharm

journal_title

Molecular pharmaceutics

authors

Zhang J,Zheng Y,Xie X,Wang L,Su Z,Wang Y,Leong KW,Chen M

doi

10.1021/acs.molpharmaceut.7b00404

subject

Has Abstract

pub_date

2017-11-06 00:00:00

pages

3644-3659

issue

11

eissn

1543-8384

issn

1543-8392

journal_volume

14

pub_type

杂志文章
  • Application of in silico, in vitro and preclinical pharmacokinetic data for the effective and efficient prediction of human pharmacokinetics.

    abstract::In the present age of pharmaceutical research and development, focused delivery of decision making data is more imperative than ever before. Resulting from several years' success, failure and consequential learning, this article also proffers advice and guidance on which in vitro and in vivo experiments to perform to ...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp300476z

    authors: Grime KH,Barton P,McGinnity DF

    更新日期:2013-04-01 00:00:00

  • Delivery of polysaccharides using polymer particles: implications on size-dependent immunogenicity, opsonophagocytosis, and protective immunity.

    abstract::Bacterial capsular polysaccharides are components of many modern vaccines, but they are weakly immunogenic. Herein, we describe the delivery of pneumococcal capsular polysaccharide serotype-1 (PCP-1) in polylactide polymeric particles to enhance its immunogenicity. Immunization with PCP-1-entrapped particles elicited ...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp400589q

    authors: Anish C,Khan N,Upadhyay AK,Sehgal D,Panda AK

    更新日期:2014-03-03 00:00:00

  • Identification of the Uptake Transporter Responsible for Distribution of Acotiamide into Stomach Tissue.

    abstract::The acetylcholinesterase inhibitor, acotiamide, improves gastric motility and is clinically used to treat functional dyspepsia. The present study aimed to identify the transporters involved in the distribution of acotiamide in stomach tissue. Acotiamide uptake by the gastric cancer-derived model cell line, Hs746 T, wa...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.9b00894

    authors: Hirayama M,Hoshino Y,Yoshii K,Toda R,Kawabata Y,Nakanishi T,Tamai I

    更新日期:2020-04-06 00:00:00

  • Protein Delivery by Peptide-Based Stealth Liposomes: A Biomolecular Insight into Enzyme Replacement Therapy.

    abstract::Infantile neural ceroid lipofuscinosis (INCL) is a lysosomal storage disorder characterized by mutations in the CLN1 gene that leads to lack of the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1), which causes the progressive death of cortical neurons. Enzyme replacement therapy (ERT) is one of the most promi...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.0c00615

    authors: Santi M,Finamore F,Cecchettini A,Santorelli FM,Doccini S,Rocchiccioli S,Signore G

    更新日期:2020-12-07 00:00:00

  • Temperature/pH/Enzyme Triple-Responsive Cationic Protein/PAA-b-PNIPAAm Nanogels for Controlled Anticancer Drug and Photosensitizer Delivery against Multidrug Resistant Breast Cancer Cells.

    abstract::The tumor microenvironments are often acidic and overexpress specific enzymes. In this work, we synthesized a poly(AA-b-NIPAAm) copolymer (PAA-b-PNIPAAm) using a reversible addition-fragmentation chain transfer (RAFT) polymerization method. PAA-b-PNIPAAm and a cationic protein (protamine) were self-assembled into nano...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.7b00737

    authors: Don TM,Lu KY,Lin LJ,Hsu CH,Wu JY,Mi FL

    更新日期:2017-12-04 00:00:00

  • Biocompatible Reduction and pH Dual-Responsive Core Cross-Linked Micelles Based on Multifunctional Amphiphilic Linear-Hyperbranched Copolymer for Controlled Anticancer Drug Delivery.

    abstract::Novel strategy has been developed for fabricating the biocompatible reduction and pH dual-responsive core cross-linked (CCL) micelles as drug delivery system (DDS) for the controlled anticancer drug delivery, via the atom transfer radical polymerization (ATRP) of tert-butyl acrylate (tBA) with N,N'-bis(acryloyl)cystam...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.6b01051

    authors: Tian K,Jia X,Zhao X,Liu P

    更新日期:2017-03-06 00:00:00

  • Polyvalent dendrimer-methotrexate as a folate receptor-targeted cancer therapeutic.

    abstract::Our previous studies have demonstrated that a generation 5 dendrimer (G5) conjugated with both folic acid (FA) and methotrexate (MTX) has a higher chemotherapeutic index than MTX alone. Despite this, batch-to-batch inconsistencies in the number of FA and MTX molecules linked to each dendrimer led to conjugate batches ...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp3002232

    authors: Thomas TP,Huang B,Choi SK,Silpe JE,Kotlyar A,Desai AM,Zong H,Gam J,Joice M,Baker JR Jr

    更新日期:2012-09-04 00:00:00

  • Multifunctional Desferrichrome Analogues as Versatile 89Zr(IV) Chelators for ImmunoPET Probe Development.

    abstract::New bifunctional hexa- and octadentate analogues of the hydroxamate-containing siderophore desferrichrome (DFC) have been synthesized and evaluated as 89Zr-chelating agents for immunoPET applications. The in vitro and in vivo inertness of these new ligands, Orn3-hx (hexadentate) and Orn-4hx derivatives (octadentate), ...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.7b00343

    authors: Adams CJ,Wilson JJ,Boros E

    更新日期:2017-08-07 00:00:00

  • Cordycepin Augments the Chemosensitivity of Human Glioma Cells to Temozolomide by Activating AMPK and Inhibiting the AKT Signaling Pathway.

    abstract::Glioblastoma multiforme (GBM) is the most commonly encountered subtype of deadly brain cancer in human adults. It has a high recurrence rate and shows aggressive proliferation. The novel cytotoxic agent temozolomide (TMZ) is now frequently applied as the first-line chemotherapeutic treatment for GBM; however, a consid...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.8b00551

    authors: Bi Y,Li H,Yi D,Sun Y,Bai Y,Zhong S,Song Y,Zhao G,Chen Y

    更新日期:2018-11-05 00:00:00

  • Improved Cancer Immunochemotherapy via Optimal Co-delivery of Chemotherapeutic and Immunomodulatory Agents.

    abstract::It is highly demanded and still a big challenge to develop an effective formulation for immunochemotherapy against advanced tumors. We have previously reported a PEG-NLG-based immunostimulatory nanocarrier (PEG2k-Fmoc-NLG919) for co-delivery of an IDO1 inhibitor (NLG919) and a chemotherapeutic agent (paclitaxel, PTX)....

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.8b00717

    authors: Chen Y,Sun J,Huang Y,Lu B,Li S

    更新日期:2018-11-05 00:00:00

  • A cancer-specific variant of the SLCO1B3 gene encodes a novel human organic anion transporting polypeptide 1B3 (OATP1B3) localized mainly in the cytoplasm of colon and pancreatic cancer cells.

    abstract::OATP1B3 is a member of the OATP (organic anion transporting polypeptides) superfamily, responsible for mediating the transport of numerous endogenous and xenobiotic substances. Although initially reported to be exclusively expressed in the liver, several studies reported that OATP1B3 is frequently expressed in multipl...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp3005353

    authors: Thakkar N,Kim K,Jang ER,Han S,Kim K,Kim D,Merchant N,Lockhart AC,Lee W

    更新日期:2013-01-07 00:00:00

  • New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma.

    abstract::In this work, we have developed covalent and low molecular weight docetaxel delivery systems based on conjugation with N-acetyl-d-galactosamine and studied their properties related to hepatocellular carcinoma cells. The resulting glycoconjugates have an excellent affinity to the asialoglycoprotein receptor (ASGPR) in ...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.0c00980

    authors: Petrov RA,Mefedova SR,Yamansarov EY,Maklakova SY,Grishin DA,Lopatukhina EV,Burenina OY,Lopukhov AV,Kovalev SV,Timchenko YV,Ondar EE,Ivanenkov YA,Evteev SA,Vaneev AN,Timoshenko RV,Klyachko NL,Erofeev AS,Gorelkin PV,Bel

    更新日期:2021-01-04 00:00:00

  • Biophysical and Sequence-Based Methods for Identifying Monovalent and Bivalent Antibodies with High Colloidal Stability.

    abstract::In vitro antibody discovery and/or affinity maturation are often performed using antibody fragments (Fabs), but most monovalent Fabs are reformatted as bivalent IgGs (monoclonal antibodies, mAbs) for therapeutic applications. One problem related to reformatting antibodies is that the bivalency of mAbs can lead to incr...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.7b00779

    authors: Alam ME,Geng SB,Bender C,Ludwig SD,Linden L,Hoet R,Tessier PM

    更新日期:2018-01-02 00:00:00

  • Localized hydration in lyophilized myoglobin by hydrogen-deuterium exchange mass spectrometry. 2. Exchange kinetics.

    abstract::Solid-state hydrogen-deuterium exchange with mass spectrometric analysis (ssHDX) is a promising method for characterizing proteins in amorphous solids. Though analysis of HDX kinetics is informative and well-established in solution, application of these methods to solid samples is complicated by possible heterogeneiti...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp2004093

    authors: Sophocleous AM,Topp EM

    更新日期:2012-04-02 00:00:00

  • Fatty acid modulated human serum albumin binding of the β-carboline alkaloids norharmane and harmane.

    abstract::Harmane and norharmane are representative members of the large group of natural β-carboline alkaloids featured with diverse pharmacological activities. In blood, these agents are transported by human serum albumin (HSA) which has a profound impact on the pharmacokinetic and pharmacodynamic properties of many therapeut...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp400531n

    authors: Domonkos C,Fitos I,Visy J,Zsila F

    更新日期:2013-12-02 00:00:00

  • Cannabinoid CB2 receptor as a new phototherapy target for the inhibition of tumor growth.

    abstract::The success of targeted cancer therapy largely relies upon the selection of target and the development of efficient therapeutic agents that specifically bind to the target. In the current study, we chose a cannabinoid CB2 receptor (CB2R) as a new target and used a CB2R-targeted photosensitizer, IR700DX-mbc94, for phot...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp5001923

    authors: Jia N,Zhang S,Shao P,Bagia C,Janjic JM,Ding Y,Bai M

    更新日期:2014-06-02 00:00:00

  • Dry hybrid lipid-silica microcapsules engineered from submicron lipid droplets and nanoparticles as a novel delivery system for poorly soluble drugs.

    abstract::We report on the fabrication and characterization of dry hybrid lipid-silica nanoparticle based microcapsules with an internal porous matrix structure for encapsulation of poorly soluble drugs, and their delivery properties (in vitro release and lipolysis and in vivo pharmacokinetics demonstrated for indomethacin as a...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp900063t

    authors: Simovic S,Heard P,Hui H,Song Y,Peddie F,Davey AK,Lewis A,Rades T,Prestidge CA

    更新日期:2009-05-01 00:00:00

  • PXR/CYP3A4-humanized mice for studying drug-drug interactions involving intestinal P-glycoprotein.

    abstract::Rodent models are less suitable for predicting drug-drug interactions at the level of the human intestinal mucosa, especially when nuclear receptors such as pregnane X receptor (PXR) are involved. Recently, a transgenic mouse model, expressing both human PXR and CYP3A4, was developed and shown to be a better predictor...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp300512r

    authors: Holmstock N,Gonzalez FJ,Baes M,Annaert P,Augustijns P

    更新日期:2013-03-04 00:00:00

  • Real time, noninvasive imaging and quantitation of the accumulation of ligand-targeted drugs into receptor-expressing solid tumors.

    abstract::Targeted therapies are emerging as a preferred strategy for treatment of cancer and other diseases. To evaluate the effect of high affinity receptors on the rate and extent of tumor penetration of receptor-targeted drugs, we have characterized the kinetics of folate-rhodamine uptake by folate receptor (FR)-expressing ...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp900158d

    authors: Vlashi E,Sturgis JE,Thomas M,Low PS

    更新日期:2009-11-01 00:00:00

  • Highly viscous antibody solutions are a consequence of network formation caused by domain-domain electrostatic complementarities: insights from coarse-grained simulations.

    abstract::Therapeutic monoclonal antibody (mAb) candidates that form highly viscous solutions at concentrations above 100 mg/mL can lead to challenges in bioprocessing, formulation development, and subcutaneous drug delivery. Earlier studies of mAbs with concentration-dependent high viscosity have indicated that mAbs with negat...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp500485w

    authors: Buck PM,Chaudhri A,Kumar S,Singh SK

    更新日期:2015-01-05 00:00:00

  • Capsid-Incorporation Strategy To Display Antigens for an Alternative Adenoviral Vector Vaccine Approach.

    abstract::The adenovirus (Ad) is widely used as a vaccine because of its ability to induce a cellular and humoral immune response. In addition, human clinical trials have validated the safety and efficacy of Ad as a vaccine vector. The traditional approach for employing the adenovirus as vaccine is to configure the antigen gene...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章,评审

    doi:10.1021/acs.molpharmaceut.8b00591

    authors: van Winkel CAJ,Moreno A,Curiel DT

    更新日期:2018-12-03 00:00:00

  • Engineered Nanoparticle Applications for Recombinant Influenza Vaccines.

    abstract::Influenza viruses cause seasonal epidemics and represent a pandemic risk. With current vaccine methods struggling to protect populations against emerging strains, there is a demand for a next-generation flu vaccine capable of providing broad protection. Recombinant biotechnology, combined with nanomedicine techniques,...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.0c00383

    authors: Sia ZR,Miller MS,Lovell JF

    更新日期:2021-02-01 00:00:00

  • Validation of Thiosemicarbazone Compounds as P-Glycoprotein Inhibitors in Human Primary Brain-Blood Barrier and Glioblastoma Stem Cells.

    abstract::P-glycoprotein (Pgp) is highly expressed on blood-brain barrier (BBB) and glioblastoma (GB) cells, particularly on cancer stem cells (SC). Pgp recognizes a broad spectrum of substrates, limiting the therapeutic efficacy of several chemotherapeutic drugs in eradicating GB SC. Finding effective and safe inhibitors of Pg...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.9b00018

    authors: Salaroglio IC,Abate C,Rolando B,Battaglia L,Gazzano E,Colombino E,Costamagna C,Annovazzi L,Mellai M,Berardi F,Capucchio MT,Schiffer D,Riganti C

    更新日期:2019-08-05 00:00:00

  • Using glycosaminoglycan/chemokine interactions for the long-term delivery of 5P12-RANTES in HIV prevention.

    abstract::5P12-RANTES is a recently developed chemokine analogue that has shown high level protection from SHIV infection in macaques. However, the feasibility of using 5P12-RANTES as a long-term HIV prevention agent has not been explored partially due to the lack of available delivery devices that can easily be modified for lo...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp3007242

    authors: Wang NX,Sieg SF,Lederman MM,Offord RE,Hartley O,von Recum HA

    更新日期:2013-10-07 00:00:00

  • Superparamagnetic iron oxide nanotheranostics for targeted cancer cell imaging and pH-dependent intracellular drug release.

    abstract::Studies were conducted to develop antibody- and fluorescence-labeled superparamagnetic iron oxide nanoparticle (SPIO) nanotheranostics for magnetic resonance imaging (MRI) and fluorescence imaging of cancer cells and pH-dependent intracellular drug release. SPIO nanoparticles (10 nm) were coated with amphiphilic polym...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp100273t

    authors: Zou P,Yu Y,Wang YA,Zhong Y,Welton A,Galbán C,Wang S,Sun D

    更新日期:2010-12-06 00:00:00

  • Transdermal Drug Delivery for Hair Regrowth.

    abstract::Today, about 50% of men and 15-30% of women suffer from hair loss as well as the associated psychological impact. Drug therapy, especially through topical administration, is the main treatment strategy for stimulating hair regrowth. However, challenges exist due to the skin barrier that hinders drug penetration. To th...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.0c00041

    authors: Yang G,Chen G,Gu Z

    更新日期:2021-02-01 00:00:00

  • Challenges and Opportunities of Deferoxamine Delivery for Treatment of Alzheimer's Disease, Parkinson's Disease, and Intracerebral Hemorrhage.

    abstract::Deferoxamine mesylate (DFO) is an FDA-approved, hexadentate iron chelator routinely used to alleviate systemic iron burden in thalassemia major and sickle cell patients. Iron accumulation in these disease states results from the repeated blood transfusions required to manage these conditions. Iron accumulation has als...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/acs.molpharmaceut.0c00474

    authors: Farr AC,Xiong MP

    更新日期:2021-02-01 00:00:00

  • Cationic shell-cross-linked knedel-like (cSCK) nanoparticles for highly efficient PNA delivery.

    abstract::Peptide nucleic acids have a number of features that make them an ideal platform for the development of in vitro biological probes and tools. Unfortunately, their inability to pass through membranes has limited their in vivo application as diagnostic and therapeutic agents. Herein, we describe the development of catio...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp800199w

    authors: Fang H,Zhang K,Shen G,Wooley KL,Taylor JS

    更新日期:2009-03-01 00:00:00

  • Chemical and enzymatic stability of amino acid prodrugs containing methoxy, ethoxy and propylene glycol linkers.

    abstract::We evaluated the chemical and enzymatic stabilities of prodrugs containing methoxy, ethoxy and propylene glycol linkers in order to find a suitable linker for prodrugs of carboxylic acids with amino acids. l-Valine and l-phenylalanine prodrugs of model compounds (benzoic acid and phenyl acetic acid) containing methoxy...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章

    doi:10.1021/mp900084v

    authors: Gupta D,Gupta SV,Lee KD,Amidon GL

    更新日期:2009-09-01 00:00:00

  • The art of engineering viral nanoparticles.

    abstract::Viral nanotechnology is an emerging and highly interdisciplinary field in which viral nanoparticles (VNPs) are applied in diverse areas such as electronics, energy and next-generation medical devices. VNPs have been developed as candidates for novel materials, and are often described as "programmable" because they can...

    journal_title:Molecular pharmaceutics

    pub_type: 杂志文章,评审

    doi:10.1021/mp100225y

    authors: Pokorski JK,Steinmetz NF

    更新日期:2011-02-07 00:00:00