pH-sensitive charge-conversion cinnamaldehyde polymeric prodrug micelles for effective targeted chemotherapy of osteosarcoma in vitro.

Introduction: Chemotherapy is a common strategy for the treatment of osteosarcoma. However, its therapeutic efficacy is not ideal due to the low targeting, lowbioavailability, and high toxicity of chemotherapy drugs. Nanoparticles can improve the residence time of drugs at tumor sites through targeted delivery. This new technology can reduce the risk to patients and improve survival rates. To achieve this goal, we developed a pHsensitive charge-conversion polymeric micelle [mPEG-b-P(C7-co-CA) micelles] for osteosarcoma-targeted delivery of cinnamaldehyde (CA). Methods: First, an amphiphilic cinnamaldehyde polymeric prodrug [mPEG-b-P(C7-co-CA)] was synthesized through Reversible Addition-Fragmentation Chain Transfer Polymerization (RAFT) polymerization and post-modification, and self-assembled into mPEG-b-P(C7-co-CA) micelles in an aqueous solution. The physical properties of mPEG-b-P(C7-co-CA) micelles, such as critical micelle concentration (CMC), size, appearance, and Zeta potential were characterized. The CA release curve of mPEG-b-P(C7-co-CA) micelles at pH 7.4, 6.5 and 4.0 was studied by dialysis method, then the targeting ability of mPEG-b-P(C7-co-CA) micelles to osteosarcoma 143B cells in acidic environment (pH 6.5) was explored by cellular uptakeassay. The antitumor effect of mPEG-b-P(C7-co-CA) micelles on 143B cells in vitro was studied by MTT method, and the level of reactive oxygen species (ROS) in 143B cells after mPEG-b-P(C7-co-CA) micelles treatment was detected. Finally, the effects of mPEG-b-P(C7-co-CA) micelles on the apoptosis of 143B cells were detected by flow cytometry and TUNEL assay. Results: An amphiphilic cinnamaldehyde polymeric prodrug [mPEG-b-P(C7-co-CA)] was successfully synthesized and self-assembled into spheric micelles with a diameter of 227 nm. The CMC value of mPEG-b-P(C7-co-CA) micelles was 25.2 mg/L, and it showed a pH dependent release behavior of CA. mPEG-b-P(C7-co-CA) micelles can achieve chargeconversion from a neutral to a positive charge with decreasing pHs. This charge-conversion property allows mPEG-b-P(C7-co-CA) micelles to achieve 143B cell targeting at pH 6.5. In addition, mPEG-b-P(C7-co-CA) micelles present high antitumor efficacy and intracellular ROS generation at pH 6.5 which can induce 143B cell apoptosis. Discussion: mPEG-b-P(C7-co-CA) micelles can achieve osteosarcoma targeting effectively and enhance the anti-osteosarcoma effect of cinnamaldehyde in vitro. This research provides a promising drug delivery system for clinical application and tumor treatment.

Chain-shattering polymeric sulfur dioxide prodrug micelles for redox-triggered gas therapy of osteosarcoma.

Sulfur dioxide (SO2) based gas therapy has received great attention recently. Nevertheless, it is still a challenge to fabricate a SO2 delivery system to achieve effective delivery and on-demand stimuli triggered release at tumor sites. Herein, a chain-shattering polymeric SO2 prodrug micelle system was fabricated for effective SO2 based gas therapy. First, an amphiphilic polymer (mPEG-P(HDI-DN)) was prepared by polycondensation of poly(ethylene glycol) methyl ether, hexamethylene diisocyanate and monomer containing SO2. mPEG-P(HDI-DN) can self-assemble into spherical micelles with a diameter of around 50-90 nm. Triggered release of SO2 from micelles can be achieved in the presence of GSH with the degradation of mPEG-P(HDI-DN) into small molecules. The in vitro experiment proved that mPEG-P(HDI-DN) micelles can enter into osteosarcoma cells and inhibit the growth of osteosarcoma cells by increasing the ROS level in cells. The in vivo experiments demonstrate that mPEG-P(HDI-DN) micelles can inhibit the growth of osteosarcoma effectively without obvious tissue toxicity. These results indicate that this chain-shattering polymeric SO2 prodrug micelle system is a promising candidate for effective SO2 based gas therapy.

SOX12 Promotes Stem Cell-Like Phenotypes and Osteosarcoma Tumor Growth by Upregulating JAGGED1.

SOX12 plays a role in promoting the growth of some tumors; however, its role in osteosarcoma remains unclear. From gene expression omnibus (GEO) and tumor alterations relevant for genomics-driven therapy (TARGET) databases, Kaplan-Meier analyses were conducted to establish relationships between SOX12 expression and osteosarcoma survival and recurrence in osteosarcoma patients. We also performed in vitro and in vivo assays to determine SOX12 function in osteosarcoma etiology. SOX12 expression was increased in osteosarcoma; high SOX12 expression levels were related to a poor prognosis and a high disease recurrence in patients. Moreover, SOX12 expression in osteosarcoma cell lines was increased, similar to osteosarcoma cancer stem cells. We also observed that SOX12 knockdown inhibited the spheroidization and expression of stemness markers in osteosarcoma cells and tumor formation in nude mice. In addition, SOX12 knockdown inhibited JAGGED1 and HES1 expression. Similarly, JAGGED1 knockdown also inhibited the formation of osteosarcoma cancer stem cells into pellets and reduced the expression of stemness markers and tumor formation capabilities in nude mice. Finally, during SOX12 knockdown, JAGGED1 overexpression rescued osteosarcoma cells from spheroidizing. SOX12 promotes stem cell-like phenotypes and osteosarcoma tumor growth by upregulating JAGGED1.

TUG1, SPRY4-IT1, and HULC as valuable prognostic biomarkers of survival in cancer: A PRISMA-compliant meta-analysis.

BACKGROUND: Long noncoding RNAs (LncRNAs) are involved in the development and progression of various cancers. Accumulating evidences indicated that expression of lncRNAs was related to the prognosis of tumors. METHODS: Here, 3 well-known lncRNAs associated with cancer were gathered to prove the potential role of lncRNAs as novel predictors of survival in human cancer. This meta-analysis collected all eligible studies about TUG1, SPRY4-IT1, and HULC and explored the relationship between lncRNAs expression and lymph node metastasis (LNM) or overall survival (OS). A comprehensive, computerized literature search was undertaken by using PubMed, EMBASE, Cochrane Library, and Web of Science (up to October 10, 2017). Strength of association between 3 lncRNAs and cancer prognosis was assessed by computing the hazard ratios (HR) with its corresponding 95% confidence interval (CI). According to the inclusion and exclusion criteria, respectively, 10, 9, and 7 studies of 3 lncRNAs were included in this meta-analysis. RESULTS: In the current meta-analysis, it could be concluded that the expression of these 3 lncRNAs in tumor tissues is not a direct evidence of LNM. In general, there was a significant negative correlation between TUG1 levels and OS time (pooled HR 1.54, 95% CI 1.06-2.24), SPRY4-IT1 levels and OS time (pooled HR 2.12, 95% CI 1.58-2.86) and HULC levels and OS time (pooled HR 2.10, 95% CI 1.18-3.73). It could be revealed from the result that high level expression of these 3 lncRNAs might be correlated with a bad prognosis. CONCLUSIONS: In conclusion, the current meta-analysis demonstrated that TUG1, SPRY4-IT1, and HULC might serve as a moderate predictor of survival in human cancer.