Development of Innovative Formulations for Breast Cancer Chemotherapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 24428

Special Issue Editors

Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
Interests: breast cancer; chemotherapy; drug delivery; drug targeting; gynecological cancers; microparticles; nanocarriers; nanomedicine; nanotheranostics
Special Issues, Collections and Topics in MDPI journals
Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
Interests: antimicrobial agents; breast cancer; cannabinoids; drug delivery; drug targeting; in situ-forming implants; nanomedicine; ovarian cancer; polymers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Breast cancer is a major health problem in women worldwide, being one of the most diagnosed cancers and one of the leading causes of cancer death. Chemotherapy represents one of main treatment options, especially in advanced stages of the disease or in certain breast cancer subtypes, such as triple negative breast cancer. However, the high toxicity, low aqueous solubility and rapid in vivo clearance of most antineoplastics limit their clinical use. To resolve these challenges, new innovative formulations, most of them based on micro and nanomedicine, are being investigated. The use of micro- and nanocarriers allows the intravenous administration of highly liposoluble chemotherapeutics without the use of toxic organic solvents, increasing their circulating time, facilitating their passage through biological barriers, and allowing their selective location at the tumor, increasing their efficacy and diminishing adverse effects consequence of their systemic distribution. Sustained drug release systems for local administration, nanocarriers with size tailored looking for a passive targeting, or functionalized with ligands specifically recognized by cancer cells are some of the strategies under research for both mono-chemotherapy or combination chemotherapy.

In the present Special Issue, manuscripts reporting original data or updated literature reviews covering some of these issues are welcome.

Prof. Dr. Ana Isabel Torres-Suárez
Prof. Dr. Ana Isabel Fraguas-Sánchez
Guest Editors

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Keywords

  • Antibody-Drugs Conjugates
  • Antineoplastics
  • HER-2 positive breast cancer
  • Liposomes
  • Metastatic Breast Cancer
  • Microparticles
  • Nanomedicine
  • Polymeric Micelles
  • Targeted Therapies
  • Triple Negative Breast Cancer

Published Papers (7 papers)

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Editorial

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3 pages, 194 KiB  
Editorial
Development of Innovative Formulations for Breast Cancer Chemotherapy
Cancers 2020, 12(11), 3281; https://doi.org/10.3390/cancers12113281 - 06 Nov 2020
Cited by 1 | Viewed by 1504
Abstract
Breast cancer is the most frequent neoplasm in the female population [...] Full article
(This article belongs to the Special Issue Development of Innovative Formulations for Breast Cancer Chemotherapy)

Research

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15 pages, 3396 KiB  
Article
CRIF1-CDK2 Interface Inhibitors Enhance Taxol Inhibition of the Lethal Triple-Negative Breast Cancer
Cancers 2022, 14(4), 989; https://doi.org/10.3390/cancers14040989 - 16 Feb 2022
Cited by 8 | Viewed by 2216
Abstract
Paclitaxel (taxol), a chemotherapeutic agent, remains the standard of care for the lethal triple-negative breast cancer (TNBC). However, over 50% of TNBC patients become resistant to chemotherapy and, to date, no solution is available. CR6-interacting factor 1 (CRIF1) is reported to act as [...] Read more.
Paclitaxel (taxol), a chemotherapeutic agent, remains the standard of care for the lethal triple-negative breast cancer (TNBC). However, over 50% of TNBC patients become resistant to chemotherapy and, to date, no solution is available. CR6-interacting factor 1 (CRIF1) is reported to act as a negative regulator of the cell cycle by interacting with cyclin-dependent kinase 2 (CDK2). In our study, two selective CRIF1–CDK2 interface inhibitors were used to investigate whether they could exert anti-proliferative activity on the TNBC cell lines. When combined with taxol treatment, these two inhibitors can advance the cells from G0/G1 to S and G2/M phases, producing irreparable damage to the cells, which then undergo apoptosis. Moreover, they enhanced the reduction in cell proliferation induced by taxol in TNBC cells, thereby improving sensitivity to taxol in these cell lines. Importantly, the inhibitors did not regulate the cell cycle in normal cells, indicating their high selectivity towards TNBC cells. Overall, the resistance to the anti-proliferative effects induced by taxol can be significantly reduced by the combined treatment with selective CRIF1–CDK2 interface inhibitors, making a conceptual advance in the CDK-related cancer treatment. Full article
(This article belongs to the Special Issue Development of Innovative Formulations for Breast Cancer Chemotherapy)
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27 pages, 7879 KiB  
Article
Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core–Shell-Radiosensitizer for Breast Cancer Therapy
Cancers 2021, 13(21), 5571; https://doi.org/10.3390/cancers13215571 - 07 Nov 2021
Cited by 12 | Viewed by 4614
Abstract
Globally, breast cancer (BC) poses a serious public health risk. The disease exhibits a complex heterogeneous etiology and is associated with a glycolytic and oxidative phosphorylation (OXPHOS) metabolic reprogramming phenotype, which fuels proliferation and progression. Due to the late manifestation of symptoms, rigorous [...] Read more.
Globally, breast cancer (BC) poses a serious public health risk. The disease exhibits a complex heterogeneous etiology and is associated with a glycolytic and oxidative phosphorylation (OXPHOS) metabolic reprogramming phenotype, which fuels proliferation and progression. Due to the late manifestation of symptoms, rigorous treatment regimens are required following diagnosis. Existing treatments are limited by a lack of specificity, systemic toxicity, temporary remission, and radio-resistance in BC. In this study, we have developed CD44 and folate receptor-targeting multi-functional dual drug-loaded nanoparticles. This composed of hyaluronic acid (HA) and folic acid (FA) conjugated to a 2-deoxy glucose (2DG) shell linked to a layer of dichloroacetate (DCA) and a magnesium oxide (MgO) core (2DG@DCA@MgO; DDM) to enhance the localized chemo-radiotherapy for effective BC treatment. The physicochemical properties of nanoparticles including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy were thoroughly examined. Mechanistically, we identified multiple component signaling pathways as important regulators of BC metabolism and mediators for the inhibitory effects elicited by DDM. Nanoparticles exhibited sustained DDM release properties in a bio-relevant media, which was responsive to the acidic pH enabling eligibility to the control of drug release from nanoparticles. DDM-loaded and HA–FA-functionalized nanoparticles exhibited increased selectivity and uptake by BC cells. Cell-based assays revealed that the functionalized DDM significantly suppressed cancer cell growth and improved radiotherapy (RT) through inducing cell cycle arrest, enhancing apoptosis, and modulating glycolytic and OXPHOS pathways. By highlighting DDM mechanisms as an antitumor and radio-sensitizing reagent, our data suggest that glycolytic and OXPHOS pathway modulation occurs via the PI3K/AKT/mTOR/NF-κB/VEGFlow and P53high signaling pathway. In conclusion, the multi-functionalized DDM opposed tumor-associated metabolic reprogramming via multiple signaling pathways in BC cells as a promising targeted metabolic approach. Full article
(This article belongs to the Special Issue Development of Innovative Formulations for Breast Cancer Chemotherapy)
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15 pages, 3325 KiB  
Article
Targeted Liposomal Chemotherapies to Treat Triple-Negative Breast Cancer
Cancers 2021, 13(15), 3749; https://doi.org/10.3390/cancers13153749 - 26 Jul 2021
Cited by 12 | Viewed by 3261
Abstract
Triple-negative breast cancers (TNBCs) are highly aggressive and recurrent. Standard cytotoxic chemotherapies are currently the main treatment options, but their clinical efficacies are limited and patients usually suffer from severe side effects. The goal of this study was to develop and evaluate targeted [...] Read more.
Triple-negative breast cancers (TNBCs) are highly aggressive and recurrent. Standard cytotoxic chemotherapies are currently the main treatment options, but their clinical efficacies are limited and patients usually suffer from severe side effects. The goal of this study was to develop and evaluate targeted liposomes-delivered combined chemotherapies to treat TNBCs. Specifically, the IC50 values of the microtubule polymerization inhibitor mertansine (DM1), mitotic spindle assembly defecting taxane (paclitaxel, PTX), DNA synthesis inhibitor gemcitabine (GC), and DNA damage inducer doxorubicin (AC) were tested in both TNBC MDA-MB-231 and MDA-MB-468 cells. Then we constructed the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) tagged liposomes and confirmed its TNBC cell surface binding using flow cytometry, internalization with confocal laser scanning microscopy, and TNBC xenograft targeting in NSG female mice using In Vivo Imaging System. The safe dosage of anti-EGFR liposomal chemotherapies, i.e., <20% body weight change, was identified. Finally, the in vivo anti-tumor efficacy studies in TNBC cell line-derived xenograft and patient-derived xenograft models revealed that the targeted delivery of chemotherapies (mertansine and gemcitabine) can effectively inhibit tumor growth. This study demonstrated that the targeted liposomes enable the new formulations of combined therapies that improve anti-TNBC efficacy. Full article
(This article belongs to the Special Issue Development of Innovative Formulations for Breast Cancer Chemotherapy)
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17 pages, 2889 KiB  
Article
Albumin-Based Nanoparticles for the Delivery of Doxorubicin in Breast Cancer
Cancers 2021, 13(12), 3011; https://doi.org/10.3390/cancers13123011 - 16 Jun 2021
Cited by 18 | Viewed by 4413
Abstract
Albumin-based nanoparticles are an emerging platform for the delivery of various chemotherapeutics because of their biocompatibility, safety, and ease of surface modification for specific targeting. The most widely used method for the preparation of albumin nanoparticles is by desolvation process using glutaraldehyde (GLU) [...] Read more.
Albumin-based nanoparticles are an emerging platform for the delivery of various chemotherapeutics because of their biocompatibility, safety, and ease of surface modification for specific targeting. The most widely used method for the preparation of albumin nanoparticles is by desolvation process using glutaraldehyde (GLU) as a cross-linker. However, limitations of GLU like toxicity and interaction with drugs force the need for alternative cross-linkers. In the present study, several cross-linking systems were evaluated for the preparation of Bovine Serum Albumin (BSA) nanoparticles (ABNs) encapsulating Doxorubicin (Dox). Based on the results obtained from morphological characterization, in vitro release, and therapeutic efficacy in cells, N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP)-modified ABNs (ABN-SPDP) was chosen. Since ABN-SPDP are formed with disulfide linkage, the drug release is facilitated under a highly reducing environment present in the tumor sites. The cytotoxicity studies of those ABN-SPDP were performed in three different breast cell lines, highlighting the mechanism of cell death. The Dox-encapsulated ABN-SPDP showed toxicity in both the breast cancer cells (MCF-7 and MDA-MB-231), but, remarkably, a negligible effect was observed in non-tumoral MCF-10A cells. In addition to the hydrophilic Dox, this system could be used as a carrier for hydrophobic drugs like SN38. The system could be employed for the preparation of nanoparticles based on human serum albumin (HSA), which further enhances the feasibility of this system for clinical use. Hence, the albumin nanoparticles developed herein present an excellent potential for delivering various drugs in cancer therapy. Full article
(This article belongs to the Special Issue Development of Innovative Formulations for Breast Cancer Chemotherapy)
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16 pages, 3496 KiB  
Article
Nature-Inspired Nanoparticles as Paclitaxel Targeted Carrier for the Treatment of HER2-Positive Breast Cancer
Cancers 2021, 13(11), 2526; https://doi.org/10.3390/cancers13112526 - 21 May 2021
Cited by 6 | Viewed by 2149
Abstract
Despite the advances made in the fight against HER2-positive breast cancer, the need for less toxic therapies and strategies that avoid the apparition of resistances is indisputable. For this reason, a targeted nanovehicle for paclitaxel and trastuzumab, used in the first-line treatment of [...] Read more.
Despite the advances made in the fight against HER2-positive breast cancer, the need for less toxic therapies and strategies that avoid the apparition of resistances is indisputable. For this reason, a targeted nanovehicle for paclitaxel and trastuzumab, used in the first-line treatment of this subtype of breast cancer, had already been developed in a previous study. It yielded good results in vitro but, with the aim of further reducing paclitaxel effective dose and its side effects, a novel drug delivery system was prepared in this work. Thus, polydopamine nanoparticles, which are gaining popularity in cancer nanomedicine, were novelty loaded with paclitaxel and trastuzumab. The effectiveness and selectivity of the nanoparticles obtained were validated in vitro with different HER2-overexpressing tumor and stromal cell lines. These nanoparticles showed more remarkable antitumor activity than the nanosystem previously designed and, in addition, to affect stromal cell viability rate less than the parent drug. Moreover, loaded polydopamine nanoparticles, which notably increased the number of apoptotic HER2-positive breast cancer cells after treatment, also maintained an efficient antineoplastic effect when validated in tumor spheroids. Thereby, these bioinspired nanoparticles charged with both trastuzumab and paclitaxel may represent an excellent approach to improve current HER2-positive breast cancer therapies. Full article
(This article belongs to the Special Issue Development of Innovative Formulations for Breast Cancer Chemotherapy)
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Review

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33 pages, 2754 KiB  
Review
Actively Targeted Nanomedicines in Breast Cancer: From Pre-Clinal Investigation to Clinic
Cancers 2022, 14(5), 1198; https://doi.org/10.3390/cancers14051198 - 25 Feb 2022
Cited by 27 | Viewed by 4976
Abstract
Breast cancer is one of the most frequently diagnosed tumors and the second leading cause of cancer death in women worldwide. The use of nanosystems specifically targeted to tumor cells (active targeting) can be an excellent therapeutic tool to improve and optimize current [...] Read more.
Breast cancer is one of the most frequently diagnosed tumors and the second leading cause of cancer death in women worldwide. The use of nanosystems specifically targeted to tumor cells (active targeting) can be an excellent therapeutic tool to improve and optimize current chemotherapy for this type of neoplasm, since they make it possible to reduce the toxicity and, in some cases, increase the efficacy of antineoplastic drugs. Currently, there are 14 nanomedicines that have reached the clinic for the treatment of breast cancer, 4 of which are already approved (Kadcyla®, Enhertu®, Trodelvy®, and Abraxane®). Most of these nanomedicines are antibody–drug conjugates. In the case of HER-2-positive breast cancer, these conjugates (Kadcyla®, Enhertu®, Trastuzumab-duocarmycin, RC48, and HT19-MMAF) target HER-2 receptors, and incorporate maytansinoid, deruxtecan, duocarmicyn, or auristatins as antineoplastics. In TNBC these conjugates (Trodelvy®, Glembatumumab-Vedotin, Ladiratuzumab-vedotin, Cofetuzumab-pelidotin, and PF-06647263) are directed against various targets, in particular Trop-2 glycoprotein, NMB glycoprotein, Zinc transporter LIV-1, and Ephrin receptor-4, to achieve this selective accumulation, and include campthotecins, calicheamins, or auristatins as drugs. Apart from the antibody–drug conjugates, there are other active targeted nanosystems that have reached the clinic for the treatment of these tumors such as Abraxane® and Nab-rapamicyn (albumin nanoparticles entrapping placlitaxel and rapamycin respectively) and various liposomes (MM-302, C225-ILS-Dox, and MM-310) loaded with doxorubicin or docetaxel and coated with ligands targeted to Ephrin A2, EPGF, or HER-2 receptors. In this work, all these active targeted nanomedicines are discussed, analyzing their advantages and disadvantages over conventional chemotherapy as well as the challenges involved in their lab to clinical translation. In addition, examples of formulations developed and evaluated at the preclinical level are also discussed. Full article
(This article belongs to the Special Issue Development of Innovative Formulations for Breast Cancer Chemotherapy)
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