Polymeric micelles targeted against CD44v6 receptor increase niclosamide efficacy against colorectal cancer stem cells and reduce circulating tumor cells in vivo

Huang

Clinical & Translational Med

et al. 2022

Background Chimeric antigen receptor T‐cell (CAR‐T) therapy for acute myeloid leukaemia (AML) has thus far been elusive, in part due to target restriction and phenotypic heterogeneity of AML cells. Mutations of the FMS‐like tyrosine kinase 3 (FLT3) and DNA methyltransferase 3A (DNMT3A) genes are common driver mutations that present with a poor prognosis in AML patients. We found that AML patients with FLT3 or DNMT3A mutations had higher expression of CD44 isoform 6 (CD44v6) compared to normal specimens. Therefore, we intended to demonstrate CD44v6 could be a specific option for AML with FLT3 or DNMT3A mutations. Methods Internal tandem duplication (ITD) mutations of FLT3 (FLT3/ITD) knock‐in clone and DNMT3A‐R882H mutant clones of SKM‐1 cells were generated using CRISPR/Cas9 and lentiviral transfection, respectively. CD44v6 CAR‐T cells were constructed by transfecting T cells with lentivirus containing CD44v6 CAR. CD44v6 expression in AML cell lines, AML patients and healthy donors was evaluated by flow cytometry. DNA methylation assays were used to analyse the mechanisms of FLT3 and DNMT3A mutations affecting CD44v6 expression. Results Aberrant overexpression of CD44v6 was observed in AML cell lines with FLT3 or DNMT3A mutations compared to the wild‐type SKM‐1 or K562 cells. AML patients with FLT3 or DNMT3A mutations had higher expression of CD44v6 compared to normal specimens. Then we constructed CD44v6 CAR‐T cells and found that CD44v6 CAR‐T specifically lysed CD44v6+ cells, accompanied by cytokines release. No significant killing effect was observed from CD44v6‐ AML cells and normal cells after co‐culture with CD44v6 CAR‐T. These results were also observed in vivo. Furthermore, we found that FLT3 or DNMT3A mutations induced CD44v6 overexpression by downregulating the CpG methylation of CD44 promoter. Conclusions Collectively, CD44v6 is a promising target of CAR‐T for AML patients with FLT3 or DNMT3A mutations.

Section: Discussionmentioning

confidence: 99%

CD44v6 chimeric antigen receptor T cell specificity towards AML with FLT3 or DNMT3A mutations

Huang

Clinical & Translational Med

et al. 2022

“…To the best of our knowledge, this is the first study in which MSN-based Nic delivery has been reported. The amount of Nic loaded inside COOH-Chi-MSNs was 8.1 ± 1.3%, which is comparatively higher than the Nic loaded in polymeric micelles (∼1%) reported by Andrade et al and lower than the Nic loaded in polydopamine NPs (∼30%) reported by Mhatre et al 13,34 Moreover, Dox loaded in COOH-Chi-MSNs was 16.1 ± 0.6%, which is significantly higher than Dox loaded in chitosan-coated MSNs (1.39%) reported by Khatami et al and lower than Dox loaded in MSNs (∼61%) reported by Kajani et al 35,36 Furthermore, as evident by the imaging and flow cytometer-based uptake analysis, COOH-Chi-FMSNs were being internalized in all three breast cancer cell types in significant amounts. It is expected that NP-based delivery of drugs at the tumor site will minimize side effects and the requirement of repeated doses of free drugs.…”

Section: Discussionmentioning

confidence: 52%

Mesoporous Silica Nanoparticle-Based Combination of Niclosamide and Doxorubicin: Effect of Treatment Regimens on Breast Cancer Subtypes

Lohiya

Katti

2021

ACS Appl. Bio Mater.

Overexpressed Wnt/β-catenin signaling acts as a major cancer driver and plays an important role in the development of resistance against cancer chemotherapy. Therefore, the combinatorial approach of downregulating Wnt/βcatenin signaling along with using a chemotherapeutic agent may improve cancer therapy. However, systemic administration of free anticancer agents is nonspecific and poses serious side effects. Hence, the present study aimed at developing mesoporous silica nanoparticle (MSN)-based targeted combination therapy of a Wnt signaling inhibitor, niclosamide (Nic), and a conventional anticancer agent, doxorubicin (Dox). The results demonstrated the reproducible synthesis of highly stable and monodispersed sub-100 nm spherical shaped NPs. In vitro cytotoxicity studies demonstrated that the individual drug formulations caused concentration-dependent cytotoxicity to all of the three breast cancer subtypes, with higher concentrations being more cytotoxic. Further, sequential and concurrent combination of Nic-loaded MSNs with Dox-loaded MSNs was synergistic and caused significantly enhanced death in all breast cancer subtypes. Quantification of the combinatorial efficacy suggested that multiple combinatorial pairs were synergistic in all of the breast cancer types for both (sequential and concurrent) treatment regimens. However, the extent of synergism varied between the two treatment regimens in different clinical subtypes of breast cancer. Overall, the combination of Nic-loaded MSNs with Dox-loaded MSNs holds promise to be developed as an efficient therapeutic option for breast cancer irrespective of the clinical subtype in both sequential and concurrent treatment regimens.

“…Their nanodelivery system is characterized by specificity, optimal ligand orientation and low toxicity. Finally, they produced a NP capable of strongly binding to a CD44v6-derived peptide and, more crucially, to cells with endogenous CD44v6 expression, as opposed to CD44v6-negative cells [ 98 , 99 ].…”

Section: Specific Targeting Of Cancer Cellsmentioning

confidence: 99%

Glycans as Targets for Drug Delivery in Cancer

Diniz

Coelho

Duarte

et al. 2022

Cancers

Self Cite

Innovative strategies have been proposed to increase drug delivery to the tumor site and avoid cytotoxicity, improving the therapeutic efficacy of well-established anti-cancer drugs. Alterations in normal glycosylation processes are frequently observed in cancer cells and the resulting cell surface aberrant glycans can be used as direct molecular targets for drug delivery. In the present review, we address the development of strategies, such as monoclonal antibodies, antibody–drug conjugates and nanoparticles that specific and selectively target cancer-associated glycans in tumor cells. The use of nanoparticles for drug delivery encompasses novel applications in cancer therapy, including vaccines encapsulated in synthetic nanoparticles and specific nanoparticles that target glycoproteins or glycan-binding proteins. Here, we highlight their potential to enhance targeting approaches and to optimize the delivery of clinically approved drugs to the tumor microenvironment, paving the way for improved personalized treatment approaches with major potential importance for the pharmaceutical and clinical sectors.