Redox Potential Ultrasensitive Nanoparticle for the Targeted Delivery of Camptothecin to HER2-Positive Cancer Cells

Background: Among all cancers, lung cancer has high mortality among patients in most of the countries in the world. Targeted delivery of anticancer drugs can significantly reduce the side effects and dramatically improve the effects of the treatment. Folate, a suitable ligand, can be modified to the surface of tumor-selective drug delivery systems because it can selectively bind to the folate receptor, which is highly expressed on the surface of lung tumor cells. Objective: This study aimed to construct a kind of folate-targeted topotecan liposomes for investigating their efficacy and mechanism of action in the treatment of lung cancer in preclinical models. Methods: We conjugated topotecan liposomes with folate, and the liposomes were characterized by particle size, entrapment efficiency, cytotoxicity to A549 cells and in vitro release profile. Technical evaluations were performed on lung cancer A549 cells and xenografted A549 cancer cells in female nude mice, and the pharmacokinetics of the drug were evaluated in female SD rats. Results: The folate-targeted topotecan liposomes were proven to show effectiveness in targeting lung tumors. The anti-tumor effects of these liposomes were demonstrated by the decreased tumor volume and improved therapeutic efficacy. The folate-targeted topotecan liposomes also lengthened the topotecan blood circulation time. Conclusion: The folate-targeted topotecan liposomes are effective drug delivery systems and can be easily modified with folate, enabling the targeted liposomes to deliver topotecan to lung cancer cells and kill them, which could be used as potential carriers for lung chemotherapy.

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Recent Advances in Curcumin Nanocarriers for the Treatment of Different Types of Cancer with Special Emphasis on In Vitro Cytotoxicity and Cellular Uptake Studies

Nanoscience &Nanotechnology-Asia ◽

10.2174/2210681209666190417144126 ◽

2020 ◽

Vol 10 (5) ◽

pp. 577-590

Author(s):

Jai B. Sharma ◽

Shailendra Bhatt ◽

Asmita Sharma ◽

Manish Kumar

Keyword(s):

Cancer Cells ◽

Cellular Uptake ◽

Anticancer Agents ◽

Targeted Delivery ◽

In Vitro Cytotoxicity ◽

Curcumin Nanoparticles ◽

Cytotoxicity Studies ◽

Delivery Technique ◽

Different Types

Background: The potential use of nanocarriers is being explored rapidly for the targeted delivery of anticancer agents. Curcumin is a natural polyphenolic compound obtained from rhizomes of turmeric, belongs to family Zingiberaceae. It possesses chemopreventive and chemotherapeutic activity with low toxicity in almost all types of cancer. The low solubility and bioavailability of curcumin make it unable to use for the clinical purpose. The necessity of an effective strategy to overcome the limitations of curcumin is responsible for the development of its nanocarriers. Objective: This study is aimed to review the role of curcumin nanocarriers for the treatment of cancer with special emphasis on cellular uptake and in vitro cytotoxicity studies. In addition to this, the effect of various ligand conjugated curcumin nanoparticles on different types of cancer was also studied. Methods: A systematic review was conducted by extensively surfing the PubMed, science direct and other portals to get the latest update on recent development in nanocarriers of curcumin. Results: The current data from recent studies showed that nanocarriers of curcumin resulted in the targeted delivery, higher efficacy, enhanced bioavailability and lower toxicity. The curcumin nanoparticles showed significant inhibitory effects on cancer cells as compared to free curcumin. Conclusion: It can be concluded that bioavailability of curcumin and its cytotoxic effect to cancer cells can be enhanced by the development of curcumin based nanocarriers and it was found to be a potential drug delivery technique for the treatment of cancer.

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Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer

Cancers ◽

10.3390/cancers13051132 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1132

Author(s):

Javier A. Menendez ◽

Adriana Papadimitropoulou ◽

Travis Vander Steen ◽

Elisabet Cuyàs ◽

Bharvi P. Oza-Gajera ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Promoter Activity ◽

Fatty Acid Synthase ◽

Endocrine Resistance ◽

Gene Promoter ◽

Her2 Positive ◽

Her2 Breast Cancer

The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on FASN gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of FASN gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity—an in vitro metric of tumorigenicity—of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas.

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Super Magnetic Niosomal Nanocarrier as a New Approach for Treatment of Breast Cancer: A Case Study on SK-BR-3 and MDA-MB-231 Cell Lines

International Journal of Molecular Sciences ◽

10.3390/ijms22157948 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7948

Author(s):

Elham Jamshidifar ◽

Faten Eshrati Yeganeh ◽

Mona Shayan ◽

Mohammad Tavakkoli Yaraki ◽

Mahsa Bourbour ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Cellular Uptake ◽

Targeted Delivery ◽

Breast Cancer Cells ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines ◽

Silica Layer

In the present study, a magnetic niosomal nanocarrier for co-delivery of curcumin and letrozole into breast cancer cells has been designed. The magnetic NiCoFe2O4 core was coated by a thin layer of silica, followed by a niosomal structure, allowing us to load letrozole and curcumin into the silica layer and niosomal layer, respectively, and investigate their synergic effects on breast cancer cells. Furthermore, the nanocarriers demonstrated a pH-dependent release due to the niosomal structure at their outer layer, which is a promising behavior for cancer treatment. Additionally, cellular assays revealed that the nanocarriers had low cellular uptake in the case of non-tumorigenic cells (i.e., MCF-10A) and related high viability but high cellular uptake in cancer cell lines (i.e., MDA-MB-231 and SK-BR-3) and related low viability, which is evidenced in their high cytotoxicity against different breast cancer cell lines. The cytotoxicity of the letrozole/curcumin co-loaded nanocarrier is higher than that of the aqueous solutions of both drugs, indicating their enhanced cellular uptake in their encapsulated states. In particular, NiCoFe2O4@L-Silica-L@C-Niosome showed the highest cytotoxicity effects on MDA-MB-231 and SK-BR-3 breast cancer cells. The observed cytotoxicity was due to regulation of the expression levels of the studied genes in breast cancer cells, where downregulation was observed for the Bcl-2, MMP 2, MMP 9, cyclin D, and cyclin E genes while upregulation of the expression of the Bax, caspase-3, and caspase-9 genes was observed. The flow cytometry results also revealed that NiCoFe2O4@L-Silica-L@C-Niosome enhanced the apoptosis rate in both MDA-MB-231 and SK-BR-3 cells compared to the control samples. The findings of our research show the potential of designing magnetic niosomal formulations for simultaneous targeted delivery of both hydrophobic and hydrophilic drugs into cancer cells in order to enhance their synergic chemotherapeutic effects. These results could open new avenues into the future of nanomedicine and the development of theranostic agents.

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Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells

Pharmaceuticals ◽

10.3390/ph14070624 ◽

2021 ◽

Vol 14 (7) ◽

pp. 624

Author(s):

Valentina Corvaglia ◽

Imène Ait Mohamed Amar ◽

Véronique Garambois ◽

Stéphanie Letast ◽

Aurélie Garcin ◽

...

Keyword(s):

Cancer Cells ◽

Topoisomerase I ◽

Ovarian Cancer Cells ◽

Cellular Functions ◽

Antibody Drug Conjugate ◽

Her2 Positive ◽

Dna Topoisomerase ◽

Antibody Conjugate ◽

A Site

Inhibition of protein–DNA interactions represents an attractive strategy to modulate essential cellular functions. We reported the synthesis of unique oligoamide-based foldamers that adopt single helical conformations and mimic the negatively charged phosphate moieties of B-DNA. These mimics alter the activity of DNA interacting enzymes used as targets for cancer treatment, such as DNA topoisomerase I, and they are cytotoxic only in the presence of a transfection agent. The aim of our study was to improve internalization and selective delivery of these highly charged molecules to cancer cells. For this purpose, we synthesized an antibody-drug conjugate (ADC) using a DNA mimic as a payload to specifically target cancer cells overexpressing HER2. We report the bioconjugation of a 16-mer DNA mimic with trastuzumab and its functional validation in breast and ovarian cancer cells expressing various levels of HER2. Binding of the ADC to HER2 increased with the expression of the receptor. The ADC was internalized into cells and was more efficient than trastuzumab at inhibiting their growth in vitro. These results provide proof of concept that it is possible to site-specifically graft high molecular weight payloads such as DNA mimics onto monoclonal antibodies to improve their selective internalization and delivery in cancer cells.

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Targeted Delivery of a Sialic Acid-Blocking Glycomimetic to Cancer Cells Inhibits Metastatic Spread

ACS Nano ◽

10.1021/nn5061964 ◽

2015 ◽

Vol 9 (1) ◽

pp. 733-745 ◽

Cited By ~ 53

Author(s):

Christian Büll ◽

Thomas Jan Boltje ◽

Eric A. W. van Dinther ◽

Timo Peters ◽

Annemarie M. A. de Graaf ◽

...

Keyword(s):

Sialic Acid ◽

Cancer Cells ◽

Targeted Delivery ◽

Metastatic Spread

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A rapid nanobiosensing platform based on herceptin-conjugated graphene for ultrasensitive detection of circulating tumor cells in early breast cancer

Nanotechnology Reviews ◽

10.1515/ntrev-2021-0049 ◽

2021 ◽

Vol 10 (1) ◽

pp. 744-753

Author(s):

Zahra Rahimzadeh ◽

Seyed Morteza Naghib ◽

Esfandyar Askari ◽

Fatemeh Molaabasi ◽

Ali Sadr ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Detection ◽

Breast Cancer Cells ◽

Graphene Nanosheets ◽

Her2 Positive ◽

Promising Candidate ◽

Graphene Layers ◽

The Stability ◽

Positive Breast Cancer

Abstract In this paper, we use a simple and cheap approach for the synthesis of herceptin-conjugated graphene biosensor to detect the HER2-positive breast cancer cells. The bifunctional graphene-herceptin nanosheets are prepared from graphite by a simple ultrasonic-mediated technique. The prepared protein-mediated graphene is fully characterized. The results show the exfoliation of graphene layers in herceptin solution. Moreover, herceptin is effectively conjugated into the surface of graphene nanosheets. The synthesized herceptin-conjugated graphene is applied for breast cancer detection. The linear range of this biosensor is 1–80 cells, which is significant. The biosensor shows an excellent selectivity performance for detection of HER2-positive cancer cells. Likewise, the stability and functionality of the biosensor is about 40 days. Based on the results, this device is a promising candidate for rapid and selective detection of cancer cells.

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UCP-2 inhibitor enhanced the efficacy of trastuzumab against HER2 positive breast cancer cells

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-021-04303-4 ◽

2021 ◽

Author(s):

Jun Hua ◽

Zhe Zhang ◽

Lili Zhang ◽

Yan Sun ◽

Yuan Yuan

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Neoadjuvant Therapy ◽

Needle Biopsy ◽

Breast Cancer Cells ◽

Her2 Positive ◽

Trastuzumab Treatment ◽

Her2 Positive Breast Cancer ◽

Trastuzumab Therapy ◽

Positive Breast Cancer

Abstract Purpose This study aimed to investigate the possibility of UCP-2 inhibitor in reducing acquired resistance of trastuzumab to improve the outcome of patients receiving trastuzumab therapy by exploring the relationship between UCP-2 expression and HER2 signaling pathway and examining whether UCP-2 expression was modulated by trastuzumab treatment. Methods 32 women diagnosed with primary HER2-positive breast cancer were recruited in this study. Needle biopsy was obtained from patients before they received at least four cycles neoadjuvant therapy containing trastuzumab in combination with chemotherapy. Surgical tumor biopsy was obtained during surgical procedure after the neoadjuvant therapy. Levels of HER2 phosphorylation and UCP-2 expression were detected by immunohistochemistry (IHC) and compared between tumor needle biopsy tissue and surgical tumor samples of these patients, as well as in BT474 breast cancer cells before and after trastuzumab treatment. HER2-selective phosphorylation/kinase activity inhibitor ONT-380 was used to identify the correlation between HER2 phosphorylation level and UCP-2 expression. UCP-2 inhibitor Genipin was then used to evaluate the apoptosis index in BT474 cells treated with trastuzumab. Results UCP-2 expression was significantly elevated in surgical tumor samples from breast cancer patients receiving trastuzumab in a neoadjuvant setting. We further confirmed our findings in HER2-positive BT474 cell line and found that trastuzumab treatment induced phosphorylation of HER2 and the overexpression of UCP-2, and the latter can be reversed by HER2 selective kinase inhibitor ONT-380. Moreover, UCP-2 inhibitor Genipin significantly enhanced the proliferation suppression effects of trastuzumab and markedly promoted apoptosis. Conclusion Taken together, our study identified UCP-2 as a novel therapeutic target for HER2 positive breast cancer and UCP-2 inhibitor may have great potential to enhance the response rate and efficacy of trastuzumab therapy.

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