Abstract:
:Although novel molecular targeted drugs have been recognized as an effective therapy for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, their efficacy fails to meet the expectation due to the acquired resistance in tumors. Up-regulation of the anti-apoptotic protein Survivin was shown to contribute to the resistance to EGFR tyrosine kinase inhibitors (TKI) in EGFR mutation-positive NSCLC. However, the unorganized tumor blood vessels impeded drug penetration into tumor tissue. The resulting insufficient intracellular drug/gene delivery in drug-resistant cancer cells remarkably weakened the drug efficacy in NSCLC. In this work, a multi-functional drug delivery system AP/ES was developed by using anti-EGFR aptamer (Apt)-modified polyamidoamine to co-deliver erlotinib and Survivin-shRNA. Chloroquine (CQ) was used in combination with AP/ES to normalize tumor vessels for sufficient drug/gene delivery to overcome drug resistance in NSCLC cells. The obtained AP/ES possessed desired physicochemical properties, good biostability, controlled drug release profiles, and strong selectivity to EGFR-mutated NSCLC mediated by Apt. CQ not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation, which further promoted drug delivery and enhanced drug efficacy in erlotinib-resistant NSCLC cells. Our innovative gene/drug co-delivery system in combination with CQ showed a promising outcome in fighting against erlotinib resistance both in vitro and in vivo. This work indicates that normalization of tumor vessels could help intracellular erlotinib/Survivin-shRNA delivery and the down-regulation of Survivin could act synergistically with erlotinib for reversal of erlotinib resistance in EGFR mutation-positive NSCLC. STATEMENT OF SIGNIFICANCE:NSCLC patients who benefited from EGFR-TKIs inevitably developed acquired resistance. Previous research focused on synthesis of new generation of molecular targeted drugs that could irreversibly inhibit EGFR with a particular gene mutation to overcome drug resistance. However, they failed to inhibit EGFR with other gene mutations. Activation of bypass signaling pathway and the changes of tumor microenvironment are identified as two of the mechanisms of acquired resistance to EGFR-TKIs. We therefore constructed multifunctional gene/drug co-delivery nanocomplexes AP/ES co-formulated with chloroquine that could target the both two mechanisms. We found that chloroquine not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation, which further promoted drug delivery into tumor tissue and enhanced drug efficacy in erlotinib-resistant NSCLC.
journal_name
Acta Biomaterjournal_title
Acta biomaterialiaauthors
Lv T,Li Z,Xu L,Zhang Y,Chen H,Gao Ydoi
10.1016/j.actbio.2018.06.034subject
Has Abstractpub_date
2018-08-01 00:00:00pages
257-274eissn
1742-7061issn
1878-7568pii
S1742-7061(18)30380-5journal_volume
76pub_type
杂志文章abstract::The specific aim of this study was to gain insight into the influence of scaffold pore size, pore shape and permeability on the in vitro proliferation and differentiation of three-dimensional (3-D) human periosteum-derived cell (hPDC) cultures. Selective laser melting (SLM) was used to produce six distinct designed ge...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2012.04.001
更新日期:2012-07-01 00:00:00
abstract::Despite of the progress made to engineer structured microtissues such as BioMEMS and 3D bioprinting, little control exists how microtissues transform as they mature, as the misbalance between cell-generated forces and the strength of cell-cell and cell-substrate contacts can result in unintended tissue deformations an...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2016.08.044
更新日期:2016-11-01 00:00:00
abstract::Incorporation of hydroxyapatite (HA) within a degradable polymeric scaffold may provide a favorable synthetic microenvironment that more closely mimics natural bone tissue physiology. Both incorporation of HA nanoparticles and alterations of the paracrine cell-cell signaling distance may affect the intercellular signa...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2010.11.007
更新日期:2011-03-01 00:00:00
abstract:OBJECTIVE:An underlying abnormality in collagen turnover is implied in the occurrence of complications and recurrences after mesh augmented pelvic floor repair surgeries. Ascorbic acid is a potent stimulant of collagen synthesis. The aim of this study is to produce ascorbic acid releasing poly-lactic acid (PLA) scaffol...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.10.019
更新日期:2016-01-01 00:00:00
abstract::The present study focuses on apatite coating on collagen films, with various different densities of carboxyl groups, using an alternate soaking process. Anionic collagen (AC), which has different densities of carboxylic groups compared to native collagen (NC), was obtained by hydrolysis of carboxyamides of asparagine ...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2007.02.008
更新日期:2007-09-01 00:00:00
abstract::The preparation of scaffolds to facilitate the replacement of damaged tissues and organs by means of tissue engineering has been much investigated. The key properties of the biomaterials used to prepare such scaffolds include biodegradability, biocompatibility and a well-defined three-dimensional 3-Dpore network struc...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2012.12.004
更新日期:2013-04-01 00:00:00
abstract::Differentiation of stem and progenitor cells routinely relies on the application of soluble growth factors, an approach that enables temporal control of cell fate but enables no spatial control of the differentiation process. Angiogenic progenitor cells derived from mouse embryonic stem cells (ESCs) were differentiate...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2009.12.005
更新日期:2010-06-01 00:00:00
abstract::Damages in pelvic floor muscles often cause dysfunction of the entire pelvic urogenital system, which is clinically challenging. A bioengineered skeletal muscle construct that mimics structural and functional characteristics of native skeletal muscle could provide a therapeutic option to restore normal muscle function...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2020.12.012
更新日期:2021-02-01 00:00:00
abstract::Synthetic three-dimensional scaffolds for cell and tissue engineering routinely utilize peptide ligands to provide sites for cell adhesion and to promote cellular activity. Given the fact that recent studies have dedicated great attention to the mechanisms by which cell behavior is influenced by various ligands and sc...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2010.03.040
更新日期:2010-09-01 00:00:00
abstract::We previously reported that PTH(1-34) inhibits the terminal differentiation of articular chondrocytes and, in turn, suppresses the progression of osteoarthritis (OA). However, this treatment requires an injection of PTH(1-34) once every 3 days over the treatment period. In this study, we studied the effect of sustaine...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2012.03.015
更新日期:2012-07-01 00:00:00
abstract::Postoperative adhesion is a serious complication that can further lead to morbidity and/or mortality. Polymer anti-adhesion barrier material provides an effective precaution to reduce the probability of postoperative adhesion. Clinical application requires these materials to be easily handled, biocompatible, biodegrad...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2017.08.047
更新日期:2017-10-15 00:00:00
abstract::Multicomponent formulations coupled with complex processing conditions govern the final properties of photopolymerizable dental composites. In this study, a single test substrate was fabricated to support multiple formulations with a gradient in degree of conversion (DC), allowing the evaluation of multiple processing...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2009.01.043
更新日期:2009-07-01 00:00:00
abstract::Despite the rapid progress which has been made in hepatocellular carcinoma (HCC) chemotherapeutics, recurrence of liver cancer still remains a barrier to achieve satisfying prognosis. Herein, we aimed to decipher the role of berberine (BER) in chemotherapy-exacerbated HCC repopulation via developing a nanocarrier co-d...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2019.09.034
更新日期:2019-12-01 00:00:00
abstract::The effects of a biphasic mineralized collagen scaffold (BCS) containing intrafibrillar silica and apatite on osteogenesis of mouse mesenchymal stem cells (mMSCs) and inhibition of receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclastogenesis were investigated in the present study. mMSCs were cult...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.03.012
更新日期:2015-06-01 00:00:00
abstract::Substrate stiffness is emerging as an effective tool for the regulation of cell behaviours such as locomotion, proliferation and differentiation. In order to explore the potential application of this biophysical tool, material platforms displaying lateral and continuously graded stiffness are advantageous since they a...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2011.09.030
更新日期:2012-02-01 00:00:00
abstract::Dengue results in substantial human morbidity and significant socio-economic impacts, but a specific dengue therapeutic is not available. The currently available dengue vaccine has low efficacy and high rate of adverse effects, necessitating different strategies for the development of a safer and more efficient vaccin...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2018.08.011
更新日期:2018-09-15 00:00:00
abstract::β-Cyclodextrin can form inclusion complex with a series of guest molecules including phenyl moieties, and has gained considerable popularity in the study of supramolecular nanostructure. In this study, a biodegradable nanocomplex (HA(CD)-4Phe4 nanocomplex) was developed from β-cyclodextrin grafted hyaluronic acid (HA)...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2017.08.036
更新日期:2017-10-15 00:00:00
abstract:UNLABELLED:A synergistic effect of biochemical and mechanical cues emanating from the extracellular matrix (ECM) on inducing malignant transformation of epithelial cells has been observed recently. However, the effect of quantitative changes in biochemical stimuli on cell phenotype, without changes in ECM component and...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2016.05.006
更新日期:2016-07-15 00:00:00
abstract::First-principles calculations were carried out to reveal local atomic arrangements and thermodynamic stability of substitutional divalent cations of Mg(2+), Zn(2+), Sr(2+) and Ba(2+) in tricalcium phosphates (TCPs). There are two modifications of α-TCP and β-TCP, and a number of inequivalent Ca sites are present in th...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.05.014
更新日期:2015-09-01 00:00:00
abstract::For spinal-fixation applications, implants should have a high Young's modulus to reduce springback during operations, though a low Young's modulus is required to prevent stress shielding for patients after surgeries. In the present study, Ti-29Nb-13Ta-4.6Zr alloy (TNTZ) with a low Young's modulus was modified by addin...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2013.04.032
更新日期:2013-08-01 00:00:00
abstract::Sickle cell disease (SCD) is characterized by the abnormal deformation of red blood cells (RBCs) in the deoxygenated condition, as their elongated shape leads to compromised circulation. The pathophysiology of SCD is influenced by both the biomechanical properties of RBCs and their hemodynamic properties in the microv...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2012.07.011
更新日期:2012-11-01 00:00:00
abstract::The aim of this work was to study the phase transformation during the setting reaction of two calcium phosphate bone cements based on either alpha tricalcium phosphate (alpha-TCP) or tetracalcium phosphate (TetCP) initial solid phase, and a magnesium carbonate-phosphoric acid solution as the hardening liquid. Low mole...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2008.01.006
更新日期:2008-07-01 00:00:00
abstract::Chemically cross-linked poly(aspartic acid) (PASP) gels were prepared by the hydrolysis of poly(succinimide) (PSI). The latter was prepared by thermal polycondensation of aspartic acid. The PSI chains were cross-linked by natural amines and amino acid derivatives such as putrescin, spermine, spermidine, lysine and cys...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2007.12.004
更新日期:2008-05-01 00:00:00
abstract::Our objective was to compare the polymerization stress (sigma(pol)) of a series of composites obtained using poly(methyl methacrylate) (PMMA) or glass as bonding substrates, and to compare the results with those from in vitro microleakage of composite restorations. The tested hypothesis was that stress values obtained...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2009.07.003
更新日期:2010-02-01 00:00:00
abstract::CRISPR gene editing technology is strategically foreseen to control diseases by correcting underlying aberrant genetic sequences. In order to overcome drawbacks associated with viral vectors, the establishment of an effective non-viral CRISPR delivery vehicle has become an important goal for nanomaterial scientists. H...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2020.07.027
更新日期:2020-09-15 00:00:00
abstract::Chitosan-poly(ethylene glycol)-tyramine (CPT) hydrogels were rapidly formed in situ using horseradish peroxidase and hydrogen peroxide to explore their performance as efficient tissue adhesives. A poly(ethylene glycol) modified with tyramine was grafted onto a chitosan backbone to enhance the solubility of the chitosa...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2012.05.001
更新日期:2012-09-01 00:00:00
abstract::High porosity and pore interconnectivity are important features of a successful tissue engineering scaffold. The objective of this work was to optimize the pore interconnectivity and to increase the porosity of an elastomeric degradable/polar/hydrophobic/ionic (D-PHI) polyurethane porous scaffold while maintaining its...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2010.06.018
更新日期:2010-11-01 00:00:00
abstract::This paper presents the preparation and absorption performance of iodixanol-imprinted polymers in aqueous and blood plasma media in vitro for biomedical applications. The imprinted polymers were prepared by non-covalent imprinting of iodixanol in a matrix of poly(4-vinylpyridine) crosslinked by ethylene glycol dimetha...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2009.11.007
更新日期:2010-06-01 00:00:00
abstract::Light curable methacrylate dental monomers containing reactive calcium phosphate filler (monocalcium phosphate monohydrate (MCPM) with particle diameter of 29 or 90microm) and beta-tricalcium phosphate (beta-TCP) at 1:1 weight ratio in a powder:liquid ratio (PLR) of 1:1 or 3:1 and chlorhexidine diacetate (0 or 5 wt.%)...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2009.03.030
更新日期:2009-09-01 00:00:00
abstract::Titanium (Ti) has been widely used as an implant material due to the excellent biocompatibility and corrosion resistance of its oxide surface. Biomaterials must be sterile before implantation, but the effects of sterilization on their surface properties have been less well studied. The effects of cleaning and steriliz...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2011.11.026
更新日期:2012-05-01 00:00:00