Dataset Information

Dual-targeting nanomicelles with CD133 and CD44 aptamers for enhanced delivery of gefitinib to two populations of lung cancer-initiating cells.

ABSTRACT: Lung cancer is an aggressive type of cancer that is associated with a high mortality rate. Lung cancer-initiating cells are populations of self-renewing cancer cells with pluripotent differentiation ability. Cancers typically originate from multiple phenotypically distinct cancer-initiating cells. CD133 and CD44 are specific markers that maybe used to distinguish lung cancer-initiating cells. The ability to target a variety of subsets of cancer-initiating cells instead of targeting only one population of cancer initiating-cells has the potential to increase the cancer therapeutic efficacy. In the present study, CD133 and CD44 aptamer-conjugated nanomicelles loaded with gefitinib (CD133/CD44-NM-Gef) were developed to target CD133⁺ and CD44⁺ lung cancer-initiating cells. The therapeutic efficacy of CD133/CD44-NM-Gef against lung cancer-initiating cells was assessed by evaluating cell proliferation, tumorsphere formation and detection of CD44⁺ and CD133⁺ cells using flow cytometry. The results indicated that CD133/CD44-NM-Gef targeted CD133⁺ and CD44⁺ lung cancer-initiating cells and exhibited greater therapeutic efficacy against lung cancer-initiating cells than single-target and non-targeted nanomicelles, suggesting that CD133/CD44-NM-Gef represents a promising treatment for lung cancer by specifically targeting lung cancer-initiating cells. To the best of our knowledge, the present study was the first to report on drug delivery via nanomedicines targeted to multiple populations of cancer-initiating cells using aptamers. As cancer is typically derived from phenotypically distinct cancer-initiating cells, the nanomicelle-based multiple targeting strategy provided is promising for targeting multiple subsets of cancer-initiating cell within a tumor.

SUBMITTER: Huang X

PROVIDER: S-EPMC6909660 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Dual-targeting nanomicelles with CD133 and CD44 aptamers for enhanced delivery of gefitinib to two populations of lung cancer-initiating cells.

Huang Xiaolong X Wan Jun J Leng Dewen D Zhang Yingying Y Yang Shuo S

Experimental and therapeutic medicine 20191119 1

Lung cancer is an aggressive type of cancer that is associated with a high mortality rate. Lung cancer-initiating cells are populations of self-renewing cancer cells with pluripotent differentiation ability. Cancers typically originate from multiple phenotypically distinct cancer-initiating cells. CD133 and CD44 are specific markers that maybe used to distinguish lung cancer-initiating cells. The ability to target a variety of subsets of cancer-initiating cells instead of targeting only one popu ...[more]

PMID: 31853290

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Project description:BackgroundCancer stem cells (CSCs) possess the characteristics associated with normal stem cells and are responsible for cancer initiation, recurrence, and metastasis. CD133 is regarded as a CSCs marker of osteosarcoma, which is the most common primary bone malignancy in childhood and adolescence. Salinomycin, a polyether ionophore antibiotic, has been shown to kill various CSCs, including osteosarcoma CSCs. However, salinomycin displayed poor aqueous solubility that hinders its clinical application. The objective of this study was to develop salinomycin-loaded nanoparticles to eliminate CD133(+) osteosarcoma CSCs.MethodsThe salinomycin-loaded PEGylated poly(lactic-co-glycolic acid) nanoparticles (SAL-NP) conjugated with CD133 aptamers (Ap-SAL-NP) were developed by an emulsion/solvent evaporation method, and the targeting and cytotoxicity of Ap-SAL-NP to CD133(+) osteosarcoma CSCs were evaluated.ResultsThe nanoparticles are of desired particle size (~150 nm), drug encapsulation efficiency (~50%), and drug release profile. After 48 hours treatment of the Saos-2 CD133(+) osteosarcoma cells with drugs formulated in Ap-SAL-NP, SAL-NP, and salinomycin, the concentrations needed to kill 50% of the incubated cells were found to be 2.18, 10.72, and 5.07 μg/mL, respectively, suggesting that Ap-SAL-NP could be 4.92 or 2.33 fold more effective than SAL-NP or salinomycin, respectively. In contrast, Ap-SAL-NP was as effective as SAL-NP, and less effective than salinomycin in Saos-2 CD133(-) cells, suggesting that Ap-SAL-NP possess specific cytotoxicity toward Saos-2 CD133(+) cells. Ap-SAL-NP showed the best therapeutic effect in Saos-2 osteosarcoma xenograft mice, compared with SAL-NP or salinomycin. Significantly, Ap-SAL-NP could selectively kill CD133(+) osteosarcoma CSCs both in vitro and in vivo, as reflected by the tumorsphere formation and proportion of Saos-2 CD133(+) cells.ConclusionOur results suggest that CD133 is a potential target for drug delivery to osteosarcoma CSCs and that it is possible to significantly inhibit the osteosarcoma growth by killing CD133(+) osteosarcoma CSCs. We demonstrated that Ap-SAL-NP have the potential to target and kill CD133(+) osteosarcoma CSCs.

Project description:BackgroundMultiple studies in recent years have identified highly tumorigenic populations of cells that drive tumor formation. These cancer stem cells (CSCs), or tumor-initiating cells (TICs), exhibit properties of normal stem cells and are associated with resistance to current therapies. As pancreatic adenocarcinoma is among the most resistant human cancers to chemo-radiation therapy, we sought to evaluate the presence of cell populations with tumor-initiating capacities in human pancreatic tumors. Understanding which pancreatic cancer cell populations possess tumor-initiating capabilities is critical to characterizing and understanding the biology of pancreatic CSCs towards therapeutic ends.Methodology/principal findingsWe have isolated populations of cells with high ALDH activity (ALDH(high)) and/or CD133 cell surface expression from human xenograft tumors established from multiple patient tumors with pancreatic adenocarcinoma (direct xenograft tumors) and from the pancreatic cancer cell line L3.6pl. Through fluorescent activated cell sorting (FACs)-mediated enrichment and depletion of selected pancreatic cancer cell populations, we sought to discriminate the relative tumorigenicity of cell populations that express the pancreatic CSC markers CD133 and aldehyde dehydrogenase (ALDH). ALDH(high) and ALDH(low) cell populations were further examined for co-expression of CD44 and/or CD24. We demonstrate that unlike cell populations demonstrating low ALDH activity, as few as 100 cells enriched for high ALDH activity were capable of tumor formation, irrespective of CD133 expression. In direct xenograft tumors, the proportions of total tumor cells expressing ALDH and/or CD133 in xenograft tumors were unchanged through a minimum of two passages. We further demonstrate that ALDH expression among patients with pancreatic adenocarcinoma is heterogeneous, but the expression is constant in serial generations of individual direct xenograft tumors established from bulk human pancreatic tumors in NOD/SCID mice.Conclusions/significanceWe conclude that, in contrast to some previous studies, cell populations enriched for high ALDH activity alone are sufficient for efficient tumor-initiation with enhanced tumorigenic potential relative to CD133(+) and ALDH(low) cell populations in some direct xenograft tumors. Although cell populations enriched for CD133 expression may alone possess tumorigenic potential, they are significantly less tumorigenic than ALDH(high) cell populations. ALDH(high)/CD44(+)/CD24(+) or ALDH(low)/CD44(+)/CD24(+) phenotypes do not appear to significantly contribute to tumor formation at low numbers of inoculated tumor cells. ALDH expression broadly varies among patients with pancreatic adenocarcinoma and the apparent expression is recapitulated in serial generations of direct xenograft tumors in NOD/SCID. We have thus identified a distinct population of TICs that should lead to identification of novel targets for pancreatic cancer therapy.

Dataset Information

Dual-targeting nanomicelles with CD133 and CD44 aptamers for enhanced delivery of gefitinib to two populations of lung cancer-initiating cells.

Publications

Dual-targeting nanomicelles with CD133 and CD44 aptamers for enhanced delivery of gefitinib to two populations of lung cancer-initiating cells.

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