A large proportion of pharmaceutical compounds exhibit poor water solubility, impacting their delivery. These compounds can be passively encapsulated in the lipid bilayer of liposomes to improve their water solubility, but the loading capacity and stability are poor, leading to burst drug leakage. The solvent-assisted active loading technology (SALT) was developed to promote active loading of poorly soluble drugs in the liposomal core to improve the encapsulation efficiency and formulation stability. By adding a small volume (~5 vol%) of a water miscible solvent to the liposomal loading mixture, we achieved complete, rapid loading of a range of poorly soluble compounds and attained a high drug-to-lipid ratio with stable drug retention. This led to improvements in the circulation half-life, tolerability, and efficacy profiles. In this mini-review, we summarize our results from three studies demonstrating that SALT is a robust and versatile platform to improve active loading of poorly water-soluble compounds. We have validated SALT as a tool for improving drug solubility, liposomal loading efficiency and retention, stability, palatability, and pharmacokinetics (PK), while retaining the ability of the compounds to exert pharmacological effects.
Metastatic progression and treatment-resistance of breast cancer has been associated with epithelial-mesenchymal-transition including downregulation of E-cadherin (CDH1) expression, which can be initiated by inflammatory mediators such as COX-2. Recently, E-cadherin-mediated, cluster-based metastasis and treatment resistance has become more appreciated, though the mechanisms that maintain E-cadherin expression in this context are unknown. Through studies of inflammatory breast cancer and an in vitro tumor cell emboli culture paradigm, we identified a role for COX-2, a target gene of C/EBPδ, or its metabolite PGE2 in promoting protein stability of E-cadherin, α-catenin and p120 catenin through inhibition of GSK3β, without affecting CDH1 mRNA. The COX-2 inhibitor celecoxib downregulated E-cadherin complex proteins and caused cell death. Co-expression of E-cadherin and COX-2 was seen in breast cancer patients with poor outcome and, along with inhibitory GSK3β phosphorylation, in patient-derived xenografts of triple negative breast cancer. Celecoxib alone decreased E-cadherin protein expression within xenograft tumors, reduced circulating tumor cells and clusters, and in combination with paclitaxel attenuated or regressed lung metastases. This study uncovered a mechanism by which metastatic breast cancer cells can maintain E-cadherin-mediated cell-cell adhesions and cell survival, suggesting that patients with COX-2+/E-cadherin+ breast cancer may benefit from targeting of the PGE2 signaling pathway.
Previously we reported the establishment of a pair of primary HCC cell lines from LIX-004, a patient-derived HCC xenograft model. LIXC004-NA was developed from an untreated PDX tumor; LIXC004-SR was generated from a PDX tumor progressed despite long term in vivo treatment with sorafenib. The two cell lines displayed similar response to sorafenib treatment in vitro. However, LIXC004-NA is sensitive and LIXC004-SR is resistant to sorafenib treatment in vivo. IHC and in vitro functional studies revealed activation of alternative angiogenic pathways as one of the potential reasons for the sorafenib resistance of LIXC004-SR. To fully explore different mechanisms/pathways, we performed a) micro-array analyses; b) whole exome sequencing; c) RNA-seq analyses of the two cell lines; d) metabolomic analyses of the cell lines in vitro culture in the presence and absence of different therapeutics; e) RNAseq analyses of the tumors derived from these two cell lines. The combination of different types of -omic analyses is our systematic approach to address the potential mechanisms of drug resistance without bias. The two cell lines shared a lot of the genetic mutation and expression profile for most genes. Differentially mutated or expressed genes were also identified at basal level. More changes were observed with the treatment of different therapeutics as well as analyses of the xenograft derived from the cell lines. Pathway analyses are performed to explore the underlying mechanisms for the development of drug resistance. Citation Format: Gang Hu, Alicia Du, Yong Huang, Kunyan Liu, Fubo Xie, Xuzhen Tang, Xueyan Yang, Qi Gu, Yixin Zhang, Weikang Tao, Yingjia Zhang, Wei Tang, He Zhou. Multiple -omic analyses of a pair of primary HCC tumor cell lines with different drug response revealed the mechanisms of drug resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4425. doi:10.1158/1538-7445.AM2015-4425
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