Nucleolin-Targeting AS1411 Aptamer-Modified Micelle for the Co-Delivery of Doxorubicin and miR-519c to Improve the Therapeutic Efficacy in Hepatocellular Carcinoma Treatment
Open accessAbstract
BACKGROUND: Multidrug resistance (MDR) has emerged to be a major hindrance in cancer therapy, which contributes to the reduced sensitivity of cancer cells toward chemotherapeutic drugs mainly owing to the over-expression of drug efflux transporters. The combination of gene therapy and chemotherapy has been considered as a potential approach to improve the anti-cancer efficacy by reversing the MDR effect. MATERIALS AND METHODS: The AS1411 aptamer-functionalized micelles were constructed through an emulsion/solvent evaporation strategy for the simultaneous co-delivery of doxorubicin and miR-519c. The therapeutic efficacy and related mechanism of micelles were explored based on the in vitro and in vivo active targeting ability and the suppression of MDR, using hepatocellular carcinoma cell line HepG2 as a model. RESULTS: The micelle was demonstrated to possess favorable cellular uptake and tumor penetration ability by specifically recognizing the nucleolin in an AS1411 aptamer-dependent manner. Further, the intracellular accumulation of doxorubicin was significantly improved due to the suppression of ABCG2-mediated drug efflux by miR-519c, resulting in the efficient inhibition of tumor growth. CONCLUSION: The micelle-mediated co-delivery of doxorubicin and miR-519c provided a promising strategy to obtain ideal anti-cancer efficacy through the active targeting function and the reversion of MDR.
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Written from the paper’s full text.
TL;DR
AS1411 aptamer-modified PEG-PLA micelles co-delivering doxorubicin and miR-519c were developed to target nucleolin-overexpressing hepatocellular carcinoma and reverse ABCG2-mediated multidrug resistance. In HepG2 models, MDPAS micelles improved cellular uptake, intracellular DOX accumulation, apoptosis, and tumor growth inhibition compared with free DOX or non-targeted micelles.
Key findings
- MDPAS micelles had a hydrodynamic diameter of 315 ± 2.15 nm, remained stable over 7 days, and showed pH-dependent DOX release: 49.98% at pH 7.4 versus 88.71% at pH 5.0 after 7 days; miR-519c plasmid encapsulation efficiency was 86.53%.
- AS1411-dependent uptake was observed in HepG2 cells: MDPAS uptake was higher than free DOX or MDP, and pretreatment with free AS1411 aptamer reduced MDPAS internalization; L02 cells showed little effect due to lower nucleolin expression.
- miR-519c delivery decreased ABCG2 mRNA and protein, increased intracellular DOX, and enhanced anti-proliferative effects: MDP and MDPAS reduced HepG2 viability to 47.80% and 36.30%, respectively; MDPAS induced 23.99% apoptosis versus 19.78% for free DOX and increased G2 arrest to 78.35% versus 30.93% for free DOX.
- In 3D HepG2 spheroids, MDPAS increased apoptosis to 18.22% versus 5.54% (control), 9.66% (free DOX), and 10.64% (MDP); in vivo, MDPAS more potently inhibited tumor growth and downregulated ABCG2, with no significant body-weight change or obvious major-organ pathological lesions.
Methods
- MDPAS micelles were prepared by emulsion/solvent evaporation using DC-Chol, Mal-PEG5K-PLA21K, and mPEG5K-PLA10K, with DOX and miR-519c plasmid encapsulated and AS1411 conjugated via Michael addition; characterization included TEM, DLS, zeta potential, agarose gel electrophoresis, and DOX release.
- In vitro studies used HepG2 and L02 cells for FACS/CLSM uptake, lysosomal escape, qPCR/Western blot/LC-MS/MS for ABCG2 and DOX, MTT viability, Annexin V-FITC/PI apoptosis, cell-cycle analysis, and 3D tumor spheroids.
- In vivo studies used HepG2 xenografted BALB/c-nude mice: efficacy groups received free DOX, MDP, or MDPAS intravenously once weekly for 4 times at 3.0 mg/kg DOX (n=6/group); biodistribution used n=3/group at 8.0 mg/kg DOX; analyses included tumor volume, H&E, TUNEL, Ki67, ABCG2 staining/qPCR, and major-organ histology.
Limitations
- The paper does not explicitly state limitations.
- Evident from the text: therapeutic efficacy was tested only in the HepG2 hepatocellular carcinoma cell line and HepG2 xenograft model, without other HCC lines, patient-derived models, or orthotopic models.
- Evident from the text: in vivo efficacy used n=6 per group and biodistribution n=3 per group, with tumor growth monitored for 28 days; no survival endpoint or long-term toxicity assessment beyond body weight and major-organ H&E is reported.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 44 cited sources checked · 0 supported · 0 flagged
- Findingown data
MDPAS micelles possess favorable cellular uptake and tumor penetration ability by specifically recognizing nucleolin in an AS1411 aptamer-dependent manner.
“The micelle was demonstrated to possess favorable cellular uptake and tumor penetration ability by specifically recognizing the nucleolin in an AS1411 aptamer-dependent manner.”
Quote in the paperSubstantial claim - Findingreasoning
The micelle-mediated co-delivery of doxorubicin and miR-519c resulted in efficient inhibition of tumor growth.
“Further, the intracellular accumulation of doxorubicin was significantly improved due to the suppression of ABCG2-mediated drug efflux by miR-519c, resulting in the efficient inhibition of tumor growth.”
Quote in the paperSubstantial claim - Findingown data
The hydrodynamic diameter values of M, MDP and MDPAS micelles were 240 ± 4.99, 280 ± 2.01 and 315 ± 2.15 nm, respectively.
“The hydrodynamic diameter values of M, MDP and MDPAS micelles were determined to be 240 ± 4.99, 280 ± 2.01 and 315 ± 2.15 nm, respectively.”
Quote in the paperSubstantial claim - Findingown data
AS1411 aptamer was successfully conjugated on the surface of MDPAS micelles.
“Obviously, a clear band could be observed in the free aptamer group, and no bands could be detected for MDPAS micelles, indicating that AS1411 aptamer has been successfully conjugated on the surface of micelles.”
Quote in the paperSubstantial claim - Findingown data
MDPAS micelles exhibited higher cellular uptake in HepG2 cells than free doxorubicin and MDP micelles by FACS analysis.
“In comparison to free DOX and MDP micelles, MDPAS micelles exhibited higher cellular uptake in HepG2 cells by FACS analysis (Figure 2A), indicating that AS1411 aptamer could enhance the cellular uptake efficiency of micelles by the favorable recognition ability towards nucleolin.”
Quote in the paperSubstantial claim
- Findingown data
MDPAS micelles have a core/shell structure.
“Meanwhile, a visible corona observed in micelles suggested that the micelles have been successfully formed with core/shell structure.”
Quote in the paperSubstantial claim - Findingown data
Doxorubicin release from MDPAS micelles showed a faster release pattern at pH 5.0, with a release of 88.71% after 7 days.
“In contrast, the DOX release from micelles showed a faster release pattern at pH of 5.0 (DOX release of 88.71% after 7 days).”
Quote in the paperSubstantial claim - Findingown data
The particle size of M, MDP and MDPAS micelles remained unchanged over 7 days, indicating good stability without formation of large aggregates.
“Notably, the particle size of three micelles remained unchanged in 7 days, indicating that the micelles possessed good stability without the formation of large aggregates.”
Quote in the paperSubstantial claim - Findingown data
Nucleolin was barely expressed in normal cells such as L02 and NIH3T3.
“As shown in Figure S4, nucleolin was barely expressed in normal cells such as L02 and NIH3T3.”
Quote in the paperSubstantial claim - Findingreasoning
The encapsulation efficiency of miR-519c plasmid in MDPAS micelles was 86.53%.
“Particularly, a high EE value of miR-519c plasmid could be realized (86.53%), which was attributed to the presence of hydrophilic core and the positively charged density of DC-Chol confining the diffusion of nucleic acids within MDPAS micelles.”
Quote in the paperSubstantial claim - Findingown data
Red fluorescence intensity was dramatically reduced when HepG2 cells were pre-treated with AS1411 aptamer prior to transfection with MDPAS micelles, indicating that aptamer pre-treatment inhibited intracellular delivery of MDPAS micelles.
“In contrast, the red fluorescence intensity could be dramatically reduced when the cells were pre-treated with AS1411 aptamer prior to the transfection with MDPAS micelles, indicating that the aptamer pre-treatment inhibited the intracellular delivery of MDPAS micelles.”
Quote in the paperSubstantial claim - Findingown data
A sustained drug release from MDPAS micelles was achieved at pH 7.4, with a cumulative doxorubicin release of 49.98% after 7 days.
“A sustained drug release in MDPAS micelles was achieved at pH of 7.4, with a cumulative drug release of 49.98% after 7 days.”
Quote in the paperSubstantial claim - Findingown data
The Tyndall effect was observed for the micelles after storage for 60 days, suggesting the presence of stable micelles in the sample.
“Moreover, the Tyndall effect could be observed for the micelles after the storage for 60 days using a visible optical path, suggesting the presence of stable micelles in the sample (Figure S3).”
Quote in the paperSubstantial claim - Findingown data
MDPAS micelles exhibited a controlled release of drugs in a pH-dependent manner.
“These results indicated that MDPAS micelles exhibited a controlled release of drugs in a pH-dependent manner, which was potential to obtain the rapid drug release and accumulation in the tumor tissue.”
Quote in the paperSubstantial claim - Findingown data
The highest expression of nucleolin was detected in HepG2 cells.
“As the highest expression of nucleolin was detected in HepG2 cells, the cellular uptake studies of MDPAS micelles were conducted using HepG2 and L02 cells through FACS and CLSM.”
Quote in the paperSubstantial claim - Findingown data
Obvious over-expression of nucleolin was achieved in cancer cells.
“In contrast, obvious over-expression of nucleolin was achieved in cancer cells, implying that the abnormal expression of nucleolin was a potential biomarker for the cancer diagnosis.”
Quote in the paperSubstantial claim - Findingreasoning
The cellular uptake efficiency of MDPAS micelles decreased significantly when HepG2 cells were treated with AS1411 aptamer in advance.
“However, the cellular uptake efficiency of MDPAS micelles decreased significantly when the cells were treated with AS1411 aptamer in advance.”
Quote in the paperSubstantial claim - Findingown data
There was no significant change of cellular uptake in HepG2 cells for treatment with MDP micelles regardless of pre-treatment with AS1411 aptamer.
“There was no significant change of cellular uptake in HepG2 cells for the treatment with MDP micelles regardless of the pre-treatment with AS1411 aptamer.”
Quote in the paperNot a substantial claim - Findingreasoning
The loading of hydrophobic doxorubicin and hydrophilic miR-519c plasmid was simultaneously achieved in MDPAS micelles.
“Thus, the loading of hydrophobic DOX and hydrophilic miR-519c plasmid could be simultaneously achieved in MDPAS micelles.”
Quote in the paperSubstantial claim - Findingown data
Cells treated with MDP and MDPAS micelles exhibited larger proportion of cells at G2 phase (65.45% and 78.35%).
“In contrast, the cells treated with MDP and MDPAS micelles exhibited larger proportion of cells at G2 phase (65.45% and 78.35%)”
Quote in the paperSubstantial claim - Findingown data
MDPAS micelles improved apoptotic ratio to 23.99%.
“In contrast, MDPAS micelles could improve the apoptotic ratio to 23.99%”
Quote in the paperSubstantial claim - Findingown data
MDPAS micelles could be successfully taken up by HepG2 cells during the first 2 h.
“Obviously, red fluorescence could be detected during the first 2 h, indicating that MDPAS micelles could be successfully uptake by HepG2 cells.”
Quote in the paperSubstantial claim - Findingown data
No significant change of body weight was achieved during micelles treatment compared to control group.
“As shown in Figure S11, no significant change of body weight was achieved in the period of micelles’ treatment in comparison to the control group”
Quote in the paperSubstantial claim - Findingown data
Compared with free DOX, MDP and MDPAS micelles efficiently suppressed expression of both procaspase-8 and procaspase-9.
“Meanwhile, compared with free DOX, the micelles MDP and MDPAS could efficiently suppress the expression of both procaspase-8 and procaspase-9”
Quote in the paperSubstantial claim - Findingreasoning
MDPAS micelles achieved stronger anti-proliferative effect than MDP group.
“Notably, stronger anti-proliferative effect could be achieved in MDPAS micelles than MDP group”
Quote in the paperSubstantial claim - Findingreasoning
Micelles decreased expression level of ABCG2.
“Nevertheless, the micelles could decrease the expression level of ABCG2”
Quote in the paperSubstantial claim - Findingown data
Relative activity analysis demonstrated activation of caspase-3, -8 and -9 after treatment with MDPAS micelles.
“Consistently, the relative activity analysis of caspase-3, -8 and -9 also demonstrated the activation of these apoptosis-related proteins after the treatment with MDPAS micelles (Figure S7).”
Quote in the paperSubstantial claim - Findingown data
Lower Ki67 expression was detected in tumor tissues treated with MDP and MDPAS micelles.
“Notably, lower Ki67 expression could be detected in tumor tissues treated with MDP and MDPAS micelles”
Quote in the paperSubstantial claim - Findingreasoning
MDPAS micelles achieved higher inhibition of ABCG2 expression than MDP micelles.
“Notably, compared with MDP, MDPAS micelles achieved a higher inhibition of ABCG2 expression”
Quote in the paperSubstantial claim - Findingown data
MDPAS micelles produced higher inhibition of ABCG2 protein expression than MDP micelles.
“and higher inhibition ability was obtained in the cells after the treatment with MDPAS micelles (Figure 3B and C).”
Quote in the paperSubstantial claim - Findingown data
Compared with blank micelle, procaspase-3 expression decreased significantly in MDP and MDPAS micelles, with lowest expression in MDPAS treatment group.
“Compared with blank micelle, the procaspase-3 expression decreased significantly in the case of MDP and MDPAS micelles, with the lowest expression in the MDPAS treatment group.”
Quote in the paperSubstantial claim - Findingown data
Tumor size after MDPAS micelles treatment was smaller than that of MDP group at end of therapy.
“Moreover, the tumor size after the MDPAS micelles’ treatment was smaller than that of MDP group at the end of therapy (Figure 7B).”
Quote in the paperSubstantial claim - Findingown data
After 6 h incubation, MDPAS micelles were mainly entrapped in lysosomes.
“After the incubation for 6 h, red and green fluorescence was obviously overlapped and a large area of yellow fluorescence could be observed, suggesting that MDPAS micelles were mainly entrapped in the lysosomes.”
Quote in the paperSubstantial claim - Findingown data
After 12 h, MDPAS micelles could successfully realize endosomal escape.
“Clearly, stronger red fluorescence could be obtained after 12 h which did not overlap with green fluorescence, demonstrating that MDPAS micelles could successfully realize the endosomal escape.”
Quote in the paperSubstantial claim - Findingreasoning
Compared to micelles without miR-519c plasmid, MDP and MDPAS micelles greatly improved intracellular DOX concentration after 48 h treatment.
“In comparison to the micelles without miR-519c plasmid, MDP and MDPAS micelles could greatly improve the intracellular DOX concentration after the treatment for 48 h”
Quote in the paperSubstantial claim - Findingreasoning
Compared with control and blank micelle M groups, ABCG2 expression was dramatically improved after treatment with free DOX.
“Compared with control and blank micelle M groups, the ABCG2 expression was dramatically improved after the treatment with free DOX.”
Quote in the paperSubstantial claim - Findingown data
MDPAS micelles down-regulated ABCG2 expression more significantly.
“Meanwhile, MDPAS micelles could down-regulate the ABCG2 expression more significantly”
Quote in the paperSubstantial claim - Findingown data
In vivo, free DOX accumulated in tumor tissues during first 1 h and rapidly eliminated by bloodstream.
“As shown in Figure 6 and S9, free DOX was accumulated in tumor tissues during the first 1 h and rapidly eliminated by the bloodstream.”
Quote in the paperSubstantial claim - Findingreasoning
Compared with untreated cells, free DOX induced cell cycle arrest at G2 phase with a ratio of 30.93%.
“Compared with the untreated cells, free DOX could induce the cell cycle arrest at G2 phase with a ratio of 30.93%”
Quote in the paperNot a substantial claim - Findingown data
MDP and MDPAS micelles significantly decreased ABCG2 protein expression in HepG2 cells.
“Consistently, Western blotting analysis showed that MDP and MDPAS micelles significantly decreased the ABCG2 expression at the protein level”
Quote in the paperSubstantial claim - Findingown data
In vivo, stronger red fluorescence was obtained in tumor tissues for MDPAS micelles compared to free DOX.
“In contrast, stronger red fluorescence could be obtained in tumor tissues for the MDPAS micelles”
Quote in the paperSubstantial claim - Findingown data
In 3D tumor spheroids, apoptotic ratios were: untreated 5.54%, free DOX 9.66%, MDP 10.64%, MDPAS 18.22%.
“As shown in Figure 5C, compared with untreated cells (5.54%), higher apoptotic ratios were obtained in the treatment groups with free DOX and MDP micelles (9.66% and 10.64%). Moreover, the treatment with MDPAS micelles could increase the proportion of apoptotic cells to 18.22% in 3D tumor spheroids”
Quote in the paperSubstantial claim - Findingown data
No obvious pathological lesions of major organs were observed in MDP and MDPAS groups.
“Moreover, there were no obvious pathological lesions of major organs observed in MDP and MDPAS groups”
Quote in the paperSubstantial claim - Premisecitation
Blocking ABCG2-mediated drug efflux by inhibiting ABCG2 expression could efficiently reverse multidrug resistance and enhance the sensitivity of cancer cells to chemotherapeutics.
“Therefore, to block ABCG2-mediated drug efflux by inhibiting the ABCG2 expression could efficiently reverse MDR in the carcinogenesis and enhance the sensitivity of cancer cells to chemotherapeutics.14”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Furedi, 2017, J Control Release source
Not checked in the free run.
- Premisecitation
Multidrug resistance contributes to reduced sensitivity of cancer cells to chemotherapeutic drugs, mainly owing to over-expression of drug efflux transporters.
“Multidrug resistance (MDR) has emerged to be a major hindrance in cancer therapy, which contributes to the reduced sensitivity of cancer cells toward chemotherapeutic drugs mainly owing to the over-expression of drug efflux transporters.”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [6] Cheng, 2020, J Colloid Interface Sci source
Not checked in the free run.
- cites [7] Lee, 2019, Cancer Lett source
Not checked in the free run.
- cites [8] Wang, 2011, ACS Nano source
Not checked in the free run.
- cites [9] Fan, 2018, Cancer Lett source
Not checked in the free run.
- cites [10] Zhang, 2020, Mol Cancer source
Not checked in the free run.
- Premisecitation
miR-519c is highly associated with the reversion of multidrug resistance by targeting ABCG2 mRNA.
“where miR-519c has been demonstrated to be highly associated with the reversion of MDR by targeting the ABCG2 mRNA.19–21”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Differential expression of miRNAs are vital regulators of multidrug resistance acquisition in hepatocellular carcinoma progression.
“Differential expression of miRNAs has emerged to be vital regulators of MDR acquisition in HCC progression,17,18”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
The multidrug resistance phenomenon is mainly attributed to over-expression of the ATP-binding cassette transporter family in cancer cells, including ABCG1, ABCC1 and ABCG2.
“The phenomenon was mainly attributed to the over-expression of ATP-binding cassette (ABC) transporter family in cancer cells, including ABCG1, ABCC1 and ABCG2.8–10”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Intracellular accumulation of doxorubicin was significantly improved due to suppression of ABCG2-mediated drug efflux by miR-519c.
“Further, the intracellular accumulation of doxorubicin was significantly improved due to the suppression of ABCG2-mediated drug efflux by miR-519c, resulting in the efficient inhibition of tumor growth.”
Quote in the paperSubstantial claim - Premisecitation
The combination of gene therapy and chemotherapy is a potential approach to improve anti-cancer efficacy by reversing the MDR effect.
“The combination of gene therapy and chemotherapy has been considered as a potential approach to improve the anti-cancer efficacy by reversing the MDR effect.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Wu, 2016, Mol Pharm source
Not checked in the free run.
- Premisecitation
The combination of chemotherapy and miR-519c delivery exhibits great potential in synergistic hepatocellular carcinoma therapy by overcoming multidrug resistance and enhancing sensitivity to chemotherapeutic drugs.
“Owing to its down-regulated expression in cancer cells, the combination of chemotherapy and miR-519c delivery exhibited great potential in the synergistic HCC therapy by overcoming the MDR and further enhancing the cells’ sensitivity to chemotherapeutic drugs.22”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Wu, 2016, Mol Pharm source
Not checked in the free run.
- Premisecitation
AS1411 possesses a specific interaction with nucleolin, an important biomarker in various cancer cells that promotes tumor growth and metastasis.
“Recently, AS1411 was reported to possess a specific interaction with nucleolin, an important biomarker in various cancer cells to promote the tumor growth and metastasis.48,49”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
The high encapsulation efficiency of miR-519c plasmid was attributed to the hydrophilic core and the positively charged density of DC-Chol confining diffusion of nucleic acids within MDPAS micelles.
“Particularly, a high EE value of miR-519c plasmid could be realized (86.53%), which was attributed to the presence of hydrophilic core and the positively charged density of DC-Chol confining the diffusion of nucleic acids within MDPAS micelles.”
Quote in the paperSubstantial claim - Interpretationown data
AS1411 aptamer could enhance the cellular uptake efficiency of micelles by favorable recognition towards nucleolin.
“In comparison to free DOX and MDP micelles, MDPAS micelles exhibited higher cellular uptake in HepG2 cells by FACS analysis (Figure 2A), indicating that AS1411 aptamer could enhance the cellular uptake efficiency of micelles by the favorable recognition ability towards nucleolin.”
Quote in the paperSubstantial claim - Premisecitation
Polyethylene glycol-polylactic acid can self-assemble into micelles with a core/shell structure in aqueous phase.
“Polyethylene glycol-polylactic acid (PEG-PLA), one of the most prominent amphiphilic block copolymers, can self-assemble into micelles with core/shell structure in aqueous phase.38”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] Daman, 2015, Pharm Res source
Not checked in the free run.
- Interpretationown data
Abnormal expression of nucleolin is a potential biomarker for cancer diagnosis.
“In contrast, obvious over-expression of nucleolin was achieved in cancer cells, implying that the abnormal expression of nucleolin was a potential biomarker for the cancer diagnosis.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Faster drug release from MDPAS micelles at pH 5.0 is due to pH-sensitive ester bonds in the carriers Mal-PEG5K-PLA21K and mPEG5K-PLA10K.
“As ester bonds in the carriers Mal-PEG5K-PLA21K and mPEG5K-PLA10K were pH-sensitive, faster drug release could be achieved in MDPAS micelles at pH of 5.0.”
Quote in the paperSubstantial claim - Interpretationreasoning
Modification of micelles with AS1411 will facilitate drug delivery by recognizing tumor cells via active targeting.
“Thus, the modification of micelles with AS1411 will dramatically facilitate the drug delivery by recognizing the tumor cells via active targeting.”
Quote in the paperSubstantial claim- Rests on an assumption: Micelles are unsatisfactory for clinical applications due to their limited cellular uptake efficiency and lack of tumor-targeting ability.
- Premisecitation
The nanosized structure of micelles contributes to diffusion through leaky blood vessels to accumulate drugs in tumor tissues, known as the enhanced permeability and retention effect.
“The nanosized structure of micelles contributes to the diffusion of micelles through the leaky blood vessels to accumulate drugs in the tumor tissues, also known as enhanced permeability and retention (EPR) effect.40,41”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
MDPAS micelles were capable of diffusing and penetrating across multilayer cells due to targeting ability.
“Particularly, MDPAS micelles were capable of diffusing and penetrating across multilayer cells due to the targeting ability”
Quote in the paperSubstantial claim- Rests on an assumption: Nucleolin is over-expressed on cancer cells (including HepG2) and the AS1411 aptamer specifically recognizes it, enabling tumor targeting.
- Interpretationown data
The improved apoptotic ratio by MDPAS micelles relied on enhanced intracellular DOX concentration through suppression of MDR effect by miR-519c.
“which was relied on the enhanced intracellular DOX concentration through the suppression of MDR effect by miR-519c.”
Quote in the paperSubstantial claim- Rests on an assumption: Delivery of the miR-519c plasmid leads to functional miR-519c that inhibits ABCG2 expression and drug efflux.
- Interpretationown data
The improvement in intracellular DOX concentration by MDP and MDPAS micelles relied on blockade of ABCG2-dependent drug efflux by miR-519c.
“which was relied on the blockade of ABCG2-dependent drug efflux by miR-519c.”
Quote in the paperSubstantial claim- Rests on an assumption: Delivery of the miR-519c plasmid leads to functional miR-519c that inhibits ABCG2 expression and drug efflux.
- Interpretationown data
Co-delivery of DOX and miR-519c by MDPAS micelles could achieve better therapeutic efficacy through enhanced cellular uptake and deep penetration in tumor tissues.
“suggesting that the co-delivery of DOX and miR-519c by MDPAS micelles could achieve better therapeutic efficacy through the enhanced cellular uptake and deep penetration in tumor tissues.”
Quote in the paperSubstantial claim - Interpretationown data
The micelles could facilitate penetration by overcoming inner pressure of spheroids.
“indicating that the micelles could facilitate the penetration by overcoming the inner pressure of spheroids.”
Quote in the paperSubstantial claim - Interpretationown data
Micelles-mediated co-delivery of DOX and miR-519c could improve therapeutic efficacy by reversion of MDR effect.
“Our findings confirmed that the micelles-mediated co-delivery of DOX and miR-519c could improve the therapeutic efficacy by the reversion of MDR effect.”
Quote in the paperSubstantial claim- Rests on an assumption: Delivery of the miR-519c plasmid leads to functional miR-519c that inhibits ABCG2 expression and drug efflux.
- Interpretationreasoning
The improvement of ABCG2 expression by free DOX was probably caused by sustained administration of DOX inducing MDR effect via ABCG2 over-expression.
“This phenomenon was probably caused by the fact that the sustained administration of DOX could induce the MDR effect to resist the therapeutic efficacy via the induction of ABCG2 over-expression.”
Quote in the paperSubstantial claim - Interpretationreasoning
The inhibition of cell proliferation by MDP and MDPAS micelles was mainly caused by improved DOX accumulation in tumor cells due to inhibition of ABCG2 drug efflux transporter by miR-519c.
“This phenomenon was mainly caused by the improved DOX accumulation in tumor cells due to the inhibition of ABCG2 drug efflux transporter by miR-519c.”
Quote in the paperSubstantial claim- Rests on an assumption: Delivery of the miR-519c plasmid leads to functional miR-519c that inhibits ABCG2 expression and drug efflux.
- Interpretationown data
Co-delivery of DOX and miR-519c could realize a synergistic anti-cancer response.
“indicating that the co-delivery of DOX and miR-519c could realize a synergistic anti-cancer response.”
Quote in the paperSubstantial claim - Interpretationreasoning
The higher inhibition of ABCG2 expression by MDPAS micelles was mainly caused by enhanced delivery efficiency from AS1411 aptamer-targeting ability.
“which was mainly caused by the enhanced delivery efficiency from AS1411 aptamer-targeting ability.”
Quote in the paperSubstantial claim- Rests on an assumption: Nucleolin is over-expressed on cancer cells (including HepG2) and the AS1411 aptamer specifically recognizes it, enabling tumor targeting.
- Interpretationown data
MDPAS micelles did not induce obvious systemic toxicity.
“indicating that MDPAS micelles did not induce obvious systemic toxicity.”
Quote in the paperSubstantial claim - Interpretationown data
MDPAS micelles could extend retention time of DOX in tumors owing to inhibition of MDR effect by miR-519c.
“indicating that MDPAS micelles could extend the retention time of DOX in tumors owing to the inhibition of MDR effect by miR-519c.”
Quote in the paperSubstantial claim- Rests on an assumption: Delivery of the miR-519c plasmid leads to functional miR-519c that inhibits ABCG2 expression and drug efflux.
- Interpretationown data
MDPAS micelles could initiate apoptosis by activation of caspase-3.
“These results showed that MDPAS micelles could initiate the apoptosis by the activation of caspase-3.”
Quote in the paperSubstantial claim - Interpretationown data
Conjugation of AS1411 aptamer on the micelles could improve the intracellular delivery efficiency of nanoparticles in cancer cells in an AS1411 aptamer-dependent internalization pathway.
“These results revealed that the conjugation of AS1411 aptamer on the micelles could improve the intracellular delivery efficiency of nanoparticles in cancer cells in an AS1411 aptamer-dependent internalization pathway.”
Quote in the paperSubstantial claim - Interpretationown data
Co-delivery of DOX and miR-519c could induce cell cycle arrest at G2 phase leading to inhibition of cell proliferation in a synergistic mode.
“indicating that the co-delivery of DOX and miR-519c could induce the cell cycle arrest at G2 phase leading to the inhibition of cell proliferation in a synergistic mode.”
Quote in the paperSubstantial claim - Interpretationown data
The suppression of procaspase-8 and procaspase-9 by MDP and MDPAS implies activation of caspase-8 and caspase-9.
“implying the activation of caspase-8 and caspase-9 by these two micelles.”
Quote in the paperSubstantial claim - Interpretationown data
Delivery of miR-519c plasmid could efficiently achieve knockdown of ABCG2.
“All these results elucidated that the delivery of miR-519c plasmid could efficiently achieve the knockdown of ABCG2.”
Quote in the paperSubstantial claim- Rests on an assumption: Delivery of the miR-519c plasmid leads to functional miR-519c that inhibits ABCG2 expression and drug efflux.
- Interpretationreasoning
The stronger anti-proliferative effect of MDPAS micelles was attributed to efficient cellular uptake mediated by targeting ability of AS1411 aptamer.
“attributing to their efficient cellular uptake mediated by the targeting ability of AS1411 aptamer.”
Quote in the paperSubstantial claim- Rests on an assumption: Nucleolin is over-expressed on cancer cells (including HepG2) and the AS1411 aptamer specifically recognizes it, enabling tumor targeting.
- Interpretationown data
MDPAS micelles provided a favorably biocompatible delivery system for chemotherapeutics and oligonucleotides.
“Overall, the MDPAS micelles provided a favorably biocompatible delivery system for chemotherapeutics and oligonucleotides”
Quote in the paperSubstantial claim - Interpretationown data
Encapsulation of DOX by micelles could reduce its systemic toxicity especially cardiotoxicity.
“suggesting that the encapsulation of DOX by micelles could reduce its systemic toxicity especially the cardiotoxicity.”
Quote in the paperSubstantial claim
- May combine two claims. 41
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 10
May combine two claims.
FindingreasoningIn L02 cells, similar red fluorescence intensity was achieved in MDP and MDPAS groups, and pre-treatment of AS1411 aptamer did not influence doxorubicin fluorescence in cytosol.
“In L02 cells, similar red fluorescence intensity could be achieved in MDP and MDPAS groups, and the pre-treatment of AS1411 aptamer did not influence the DOX fluorescence in cytosol.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAll micelles exhibited a negatively charged state, and no substantial change of zeta potential was detected.
“In addition, all these micelles exhibited negatively charged state, and no substantial change of zeta potential was detected.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPre-treatment with AS1411 aptamer had almost no influence on the endocytosis of MDPAS micelles in L02 cells, owing to the lower expression of nucleolin on L02 cells.
“Conversely, the pre-treatment with AS1411 aptamer had almost no influence on the endocytosis of MDPAS micelles in L02 cells, owing to the lower expression of nucleolin on L02 cells (Figure 2B).”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataM, MDP and MDPAS micelles exhibited a uniform and spherical nanostructure with hydrodynamic diameter ranging from 240 to 300 nm.
“Three micelles exhibited a uniform and spherical nanostructure with hydrodynamic diameter ranging from 240 to 300 nm.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataCompared with free DOX, MDP and MDPAS micelles exhibited evident inhibition of cell proliferation, with cell viability of 47.80% and 36.30%, respectively.
“Compared with free DOX, MDP and MDPAS micelles exhibited evident inhibition of cell proliferation, with cell viability of 47.80% and 36.30%, respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn vivo, rapid tumor growth was obtained in control group, and blank micelle M showed no inhibitory effects on tumor growth.
“Rapid tumor growth was obtained in the control group, and blank micelle M showed no inhibitory effects on the tumor growth.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn HepG2 cells, blank micelle M induced no apparent apoptosis, while free DOX induced obvious cell apoptosis with apoptotic ratio of 19.78%.
“As shown in Figure 4C, no apparent apoptosis was obtained in HepG2 cells after the treatment with blank micelle M, while free DOX induced obvious cell apoptosis with apoptotic ratio of 19.78%.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRed fluorescence of MDPAS micelles remained in tumor after 24 h post-injection, while no visible fluorescence was shown in free DOX.
“In addition, red fluorescence of MDPAS micelles still remained in the tumor after 24 h post-injection, while no visible fluorescence was shown in free DOX”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFree DOX and MDP micelles reduced tumor volume, but MDPAS micelles exhibited more potent inhibition of tumor growth.
“Though free DOX and MDP micelles could reduce the tumor volume, MDPAS micelles exhibited more potent inhibition of tumor growth”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn 3D tumor spheroids, free DOX was distributed on the surface, whereas more red fluorescence of MDP and MDPAS micelles was observed in the inner portion.
“The 3D reconstruction and serial Z-stacks demonstrated that free DOX were distributed on the surface of tumor spheroids. In contrast, more red fluorescence of MDP and MDPAS micelles was observed in the inner portion of spheroids”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataH&E staining showed intact cellular structure in control group, whereas tumor tissues of mice treated with free DOX, MDP and MDPAS micelles exhibited obvious cell apoptosis evidenced by pyknotic nuclei and incompact cytoplasm.
“As shown in H&E staining images, an intact cellular structure could be observed in the control group, whereas the tumor tissues of mice treated with free DOX, MDP and MDPAS micelles exhibited obvious cell apoptosis evidenced by the pyknotic nuclei and incompact cytoplasm in the cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTUNEL staining demonstrated apoptosis of tumor cells could be triggered by free DOX, MDP and MDPAS micelles, while micelles containing DOX and miR-519c induced more apoptotic cells than other two groups.
“The results demonstrated that the apoptosis of tumor cells could be triggered by the treatment with free DOX, MDP and MDPAS micelles, while the micelles containing DOX and miR-519c could induce more apoptotic cells than other two groups.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn HepG2 cells, blank micelle M and free DOX did not inhibit ABCG2 mRNA expression, whereas MDP and MDPAS micelles decreased ABCG2 mRNA expression.
“As shown in Figure 3A, blank micelle M and free DOX could not inhibit the expression of ABCG2 by qPCR analysis, whereas the micelles harboring miR-519c plasmid (MDP and MDPAS) dramatically decreased the expression of ABCG2 at the mRNA level.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationChemotherapy is the primary strategy in the treatment of hepatocellular carcinoma and exhibits significant therapeutic efficacy in the clinic.
“Chemotherapy has been widely accepted to be the primary strategy in the treatment of hepatocellular carcinoma (HCC), exhibiting significant therapeutic efficacy in the clinic.1,2”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim. May combine two claims.
PremisecitationNon-coding microRNAs post-transcriptionally regulate mRNA expression by targeting the 3ʹ-UTR region and play a significant role in cellular functions such as differentiation, proliferation and apoptosis.
“Non-coding microRNAs (miRNAs) can post-transcriptionally regulate the mRNA expression by targeting the 3ʹ-UTR region, and thus play a significant role in various cellular functions such as differentiation, proliferation and apoptosis.15,16”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationThe occurrence of multidrug resistance of cancer cells reduces the efficacy of chemotherapeutic drugs and has become the most crucial reason for the failure of hepatocellular carcinoma treatment.
“Especially, the occurrence of multidrug resistance (MDR) of cancer cells can reduce the efficacy of chemotherapeutic drugs,6,7 which has become the most crucial reason for the failure of HCC treatment.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationABCG2 plays an important role in ABC-dependent drug efflux, is capable of transporting chemotherapeutic agents such as paclitaxel and doxorubicin, and confers drug resistance leading to high recurrence and poor survival in hepatocellular carcinoma patients.
“Among them, ABCG2, one of the initially discovered transporters, plays an important role in the ABC-dependent drug efflux, and is capable of transporting a broad range of chemotherapeutic agents such as paclitaxel and doxorubicin (DOX), thus conferring the drug resistance and further leading to high recurrence and poor survival of patients bearing HCC.11–13”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Interpretationown dataPretreatment with AS1411 aptamer inhibits endocytosis of MDPAS micelles by blocking nucleolin expressed on the surface of HepG2 cells, revealing that internalization of MDPAS micelles in HepG2 cells is performed in an AS1411 aptamer-mediated endocytic pathway.
“This phenomenon suggested that the pretreatment with aptamer could inhibit the endocytosis of MDPAS micelles by blocking the nucleolin expressed on the surface of HepG2 cells, therefore revealing that the internalization of MDPAS micelles in HepG2 cells was performed in an AS1411 aptamer-mediated endocytic pathway.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAS1411 has been systemically evaluated in a Phase II clinical trial for leukemia treatment.
“AS1411, a 26-mer DNA oligonucleotide, has been systemically evaluated in Phase II clinical trial for leukemia treatment.47”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Deng, 2018, Biomaterials source
Not checked in the free run.
May combine two claims.
InterpretationreasoningMDPAS micelles have the potential to obtain rapid drug release and accumulation in tumor tissue.
“These results indicated that MDPAS micelles exhibited a controlled release of drugs in a pH-dependent manner, which was potential to obtain the rapid drug release and accumulation in the tumor tissue.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationAptamers can specifically recognize various targets.
“Aptamers, also called “chemical antibodies”, are short DNA/RNA oligonucleotides and selected by SELEX technology based on nucleic acid libraries, which can specifically recognize various targets.45,46”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationPolymeric micelles formed by amphiphilic block copolymers have gained attention due to their core/shell structure, excellent stability, and ideal encapsulation and delivery efficiency of hydrophobic drugs.
“Among them, polymeric micelles formed by amphiphilic block copolymers have gained more attention due to their unique properties such as the core/shell structure, excellent stability, and ideal encapsulation and delivery efficiency of hydrophobic drugs.34–37”
Quote in the paperSubstantial claim0 of 4 sources checkedMay combine two claims.
Interpretationown dataMDPAS micelles possess favorable stability, which is beneficial for long-term storage and in vivo therapeutic applications.
“Hence, MDPAS micelles was identified to possess favorable stability, which was beneficial to achieve the long-term storage and in vivo therapeutic applications.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe hydrophilic shell on the surface of PEG-PLA micelles hinders the adsorption of plasma proteins and avoids elimination by the reticuloendothelial system, resulting in prolonged residence time in the circulation system.
“Also, the hydrophilic shell on the surface of PEG-PLA micelles is capable of hindering the adsorption of plasma proteins and avoiding the elimination by reticuloendothelial system, resulting in prolonged residence time in circulation system.39”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Dou, 2014, Adv Healthcare Mater source
Not checked in the free run.
May combine two claims.
PremisecitationPEG-PLA micelles have excellent biodegradability and low toxicity.
“Besides, the characteristics of excellent biodegradability and low toxicity will facilitate their wide applications in drug or gene delivery.42”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Phan, 2016, Int J Pharm source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll animal studies were conducted according to the Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Ethics Committee of Jilin University.
“All the animal studies were conducted according to the “Guide for the Care and Use of Laboratory Animals” (eighth edition, International Publication No: 978-0-309-15400-0) and approved by the Institutional Animal Ethics Committee of Jilin University (license No. SCXK-(JI) 2014–0012).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationDOX is a cytotoxic drug which suffers from severe side effects such as cardiotoxicity.
“Previous studies have confirmed that DOX is a cytotoxic drug which suffered from severe side effects such as cardiotoxicity.58–60”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Interpretationown dataBoth apoptotic routes could be activated by MDPAS micelles, thereby leading to anti-proliferative effect in cancer cells.
“The data implied that both apoptotic routes could be activated by MDPAS micelles, thereby leading to the anti-proliferative effect in cancer cells.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataHepG2 tumor-bearing mice were randomly separated into different groups with n=6 in each group.
“Once the tumor tissue was developed with an average volume of 100 mm3, the HepG2 tumor-bearing mice were randomly separated into different groups (n=6 in each group) and intravenously injected with free DOX, MDP micelles and MPDAS micelles once a week for 4 times, with an equal DOX dose of 3.0 mg/kg per mouse.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMDPAS micelles possess favorable cellular internalization and lysosomal escape ability, further enhancing the co-delivery efficiency of doxorubicin and miR-519c plasmid.
“In conclusion, these results revealed that MDPAS micelles possessed favorable cellular internalization and lysosomal escape ability, further enhancing the co-delivery efficiency of DOX and miR-519c plasmid.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMDPAS micelles possessed excellent tumor-targeting ability and facilitated tissue penetration of DOX and miR-519c in tumor sites.
“implying that they possessed an excellent tumor-targeting ability and facilitated the tissue penetration of DOX and miR-519c in tumor sites.”
Quote in the paperSubstantial claim- Rests on an assumption: Nucleolin is over-expressed on cancer cells (including HepG2) and the AS1411 aptamer specifically recognizes it, enabling tumor targeting.
Classified as probably not a substantial claim. May combine two claims.
Premisecitation3D tumor spheroids mimic solid tumors more closely by sharing similar features such as spatial distribution of cells, extracellular matrix, cell adhesion, hypoxia and acidic microenvironment, and have been widely used in evaluation of anti-tumor drug delivery systems.
“In contrast to 2D cell culture, the employment of 3D tumor spheroids could mimic the solid tumors more closely by sharing similar features such as the spatial distribution of cells, extracellular matrix, cell adhesion, hypoxia and acidic microenvironment, which has been widely used in the evaluation of anti-tumor drug delivery systems.57”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [57] Huang, 2018, J Control Release source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenExperiments were conducted three times, and data were presented as mean ± standard deviation.
“Experiments were conducted for three times, and the data were presented as mean ± standard deviation (SD).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningIncreased therapeutic efficacy mediated by MDPAS micelles was mainly caused by high delivery efficiency and efficient suppression of MDR effect by miR-519c.
“The increased therapeutic efficacy mediated by MDPAS micelles was mainly caused by the high delivery efficiency as well as the efficient suppression of MDR effect by miR-519c.”
Quote in the paperSubstantial claim- Rests on an assumption: Delivery of the miR-519c plasmid leads to functional miR-519c that inhibits ABCG2 expression and drug efflux.
May combine two claims.
Interpretationown dataMDPAS micelles harboring DOX and miR-519c could be successfully taken up by HepG2 cells through AS1411 aptamer-dependent manner and induce apoptosis and cell cycle arrest to achieve anti-proliferative effect.
“Taken together, our results suggested that MDPAS micelles harboring DOX and miR-519c could be successfully uptake by HepG2 cells through the AS1411 aptamer-dependent manner and induce the apoptosis and cell cycle arrest to achieve the anti-proliferative effect”
Quote in the paperSubstantial claim- Rests on an assumption: Nucleolin is over-expressed on cancer cells (including HepG2) and the AS1411 aptamer specifically recognizes it, enabling tumor targeting.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationCaspase-8 executes cell death receptor-mediated apoptosis, whereas activation of caspase-9 is initiator of mitochondria-dependent apoptosis signaling pathway.
“In the apoptotic pathways, caspase-8 has been identified to execute the cell death receptor-mediated apoptosis, whereas the activation of caspase-9 has been considered as the initiator of mitochondria-dependent apoptosis signaling pathway.56”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [56] Yang, 2019, Int J Nanomed source
Not checked in the free run.
May combine two claims.
Interpretationown dataMDPAS micelles containing miR-519c plasmid could reverse MDR by inhibiting ABCG2 expression and decrease resistance of cancer cells to chemotherapeutics.
“These results demonstrated that MDPAS micelles containing miR-519c plasmid could reverse MDR by inhibiting the ABCG2 expression and decrease the resistance of cancer cells to chemotherapeutics.”
Quote in the paperSubstantial claim- Rests on an assumption: Delivery of the miR-519c plasmid leads to functional miR-519c that inhibits ABCG2 expression and drug efflux.
May combine two claims.
InterpretationreasoningMDPAS micelles exhibited high accumulation in the nucleus, caused by the targeting ability of AS1411 aptamer to nucleolin expressed on the nucleus.
“Besides, MDPAS micelles exhibited a high accumulation in the nucleus, which was caused by the targeting ability of AS1411 aptamer to the nucleolin expressed on the nucleus.”
Quote in the paperSubstantial claim- Rests on an assumption: Nucleolin is expressed on the nucleus.
May combine two claims.
Interpretationown dataCombinational therapy mediated by MDPAS micelles could efficiently inhibit tumor growth, achieving enhanced treatment efficacy through synergistic effect of therapeutic drug and gene.
“These results suggested that the combinational therapy mediated by MDPAS micelles could efficiently inhibit the tumor growth, achieving an enhanced treatment efficacy through the synergistic effect of therapeutic drug and gene.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMicelles significantly inhibited cell proliferation and further led to tumor growth inhibition.
“suggesting that the micelles could significantly inhibit the cell proliferation and further lead to the tumor growth inhibition.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCo-delivery of DOX and miR-519c plasmid could facilitate intracellular accumulation of DOX and potentially achieve a synergistic anti-cancer effect.
“Thus, the co-delivery of DOX and miR-519c plasmid could facilitate the intracellular accumulation of DOX and potentially achieve a synergistic anti-cancer effect.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMDPAS micelles maintained stability to prevent quick elimination in blood and possessed excellent tumor-targeting capacity.
“Thus, these results demonstrated that MDPAS micelles maintained the stability to prevent the quick elimination in the blood and also possessed an excellent tumor-targeting capacity”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAn AS1411 aptamer-modified micelle system based on PEG-PLA was successfully developed to realize tumor-targeting co-delivery of DOX and miR-519c and anti-cancer treatment in synergistic pattern of two components.
“In summary, an AS1411 aptamer-modified micelle system was successfully developed based on PEG-PLA to realize the tumor-targeting co-delivery of DOX and miR-519c and the anti-cancer treatment in a synergistic pattern of two components.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMDPAS micelle possesses prominent tumor-targeting ability via specific recognition of nucleolin over-expressed on cancer cells and efficient internalization in AS1411 aptamer-dependent pathway.
“The MDPAS micelle has been demonstrated to possess prominent tumor-targeting ability via the specific recognition of nucleolin over-expressed on cancer cells and the efficient internalization in an AS1411 aptamer-dependent pathway.”
Quote in the paperSubstantial claim- Rests on an assumption: Nucleolin is over-expressed on cancer cells (including HepG2) and the AS1411 aptamer specifically recognizes it, enabling tumor targeting.
May combine two claims.
InterpretationreasoningCo-delivery of DOX and miR-519c by MDPAS micelle could reverse MDR effect by inhibiting ABCG2-dependent drug efflux and increasing intracellular DOX concentration, facilitating suppression of tumor growth and desirable therapeutic efficacy.
“Meanwhile, the co-delivery of DOX and miR-519c by MDPAS micelle could reverse the MDR effect by inhibiting the ABCG2-dependent drug efflux and increasing the intracellular DOX concentration, which could facilitate the suppression of tumor growth and obtain a desirable therapeutic efficacy in cancer treatment.”
Quote in the paperSubstantial claim- Rests on an assumption: Delivery of the miR-519c plasmid leads to functional miR-519c that inhibits ABCG2 expression and drug efflux.
The paper relies on this without support.
Micelles are unsatisfactory for clinical applications due to their limited cellular uptake efficiency and lack of tumor-targeting ability.
“Nevertheless, the micelles are still unsatisfactory to fulfill the requirements in clinical applications due to their limited cellular uptake efficiency and lack of tumor-targeting ability.”
The paper relies on this without support.
Nucleolin is expressed on the nucleus.
“Besides, MDPAS micelles exhibited a high accumulation in the nucleus, which was caused by the targeting ability of AS1411 aptamer to the nucleolin expressed on the nucleus.”
The paper relies on this without support.
Nucleolin is over-expressed on cancer cells (including HepG2) and the AS1411 aptamer specifically recognizes it, enabling tumor targeting.
“via the specific recognition of nucleolin over-expressed on cancer cells”
The paper relies on this without support.
Delivery of the miR-519c plasmid leads to functional miR-519c that inhibits ABCG2 expression and drug efflux.
“the delivery of miR-519c plasmid could efficiently achieve the knockdown of ABCG2”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
AS1411-modified micelles simultaneously deliver chemotherapeutics and genes to overcome multidrug resistance.
“Liang et al. also used AS1411 aptamers to modify micelles to improve their targeting functions. The system simultaneously delivers chemotherapeutics and genes to overcome the multidrug resistance of tumors.256”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [256]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Reported micelle size falls outside the stated range
MinorThe stated diameter range ends at 300 nm, but the subsequently reported MDPAS diameter is 315 ± 2.15 nm.
“Three micelles exhibited a uniform and spherical nanostructure with hydrodynamic diameter ranging from 240 to 300 nm.”
“The hydrodynamic diameter values of M, MDP and MDPAS micelles were determined to be 240 ± 4.99, 280 ± 2.01 and 315 ± 2.15 nm, respectively.”
Biodistribution time point differs between methods and figure caption
MinorThe methods say tissues were collected at 24 h for the last time point, whereas the Figure 6 caption labels the last fluorescence-intensity time point as 12 h.
“The mice were sacrificed and observed at 1 h, 4 h and 24 h post-injection, followed by the collection of heart, liver, spleen, lung, kidney and tumor tissues.”
“(B–D) The mean fluorescence intensity of different organs and tumor tissues at 1, 4 and 12 h post-injection, respectively.”
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Flagged first, then by citations
Cited by
Sorted by citations
Smart nanoparticles for cancer therapy
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- Authors
- Liang, X., Wang, Y., Shi, H., Dong, M., Han, H., & Li, Q.
- Affiliations
- Jilin University (CN)
- Corresponding author
- Li, Quanshun
- Venue
- International Journal of Nanomedicine
- Publisher
- Informa UK Limited
- Published
- 2021-03
- Volume
- Volume 16
- Pages
- 2569-2584
- ISSN
- 1176-9114 (ISSN-L)
- 1178-2013
- PMC
- PMC8019667
- OpenAlex
- W3147659779
- Semantic Scholar
- 06839362778e25e06b711923a18bede7385b9225
- Cited by
- 41
- References
- 61
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 4 · 2023: 14 · 2022: 5 · 2021: 2
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Nanomedicine (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
- Funders
- Jilin Province Development and Reform Commission (2021C041-4, 81872928, 32000897, 2020YFA0907003, 20190201288JC, 32071267)
- National Natural Science Foundation of China (81872928, 32071267, 20190201288JC, 32000897, 2020YFA0907003, 32071267, 81872928 and 32000897, 2021C041-4)
- People's Government of Jilin Province (20190201288JC)
- Jilin University
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- nucleolin, AS1411 aptamer, micelles, doxorubicin, hepatocellular carcinoma, multidrug resistance, ABCG2, drug efflux, co-delivery, gene therapy, active targeting, tumor growth inhibition
- MeSH terms
- Nucleolin, Animals, Antibiotics, Antineoplastic, Cell Cycle, Cell Movement, Doxorubicin, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Mice, Inbred BALB C, Mice, Nude, Micelles, Oligodeoxyribonucleotides, Phosphoproteins, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Drug Delivery Systems, RNA-Binding Proteins, Apoptosis, Drug Resistance, Multiple, Xenograft Model Antitumor Assays, MicroRNAs, Cell Proliferation, Mice, Aptamers, Nucleotide
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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