Abstract
Simple SummaryGreat advances have been made in the treatment of an aggressive subtype of breast cancer, known as HER2-positive subtype. However, the antitumor therapy most widely employed in the clinical fight against it has severe side effects, and the apparition of treatment resistances is frequent. To overcome these drawbacks, nano-sized particles had already been developed as targeted vehicles for the drug and the antibody that are usually administered as first-line treatment for this subtype of breast cancer. These nanoparticles showed better results than the drug that they transported. Nevertheless, to further reduce the drug effective dose and its toxicity to normal tissues, other nanoparticles, more advantageous than the previous ones, were developed in the current work. Compared to the previous nanoparticles, those prepared here proved to be more efficacious, and their potential administration may constitute an excellent approach to improve the outcomes of patients suffering from HER2-positive breast cancer. 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.
Highlights
As the overexpression of this tyrosine kinase (TK) receptor does not occur under normal physiological conditions [3], on the other hand, it has allowed the development of anti-human epidermal growth factor receptor-2 (HER2) targeted agents that have dramatically improved the survival rate of patients suffering from HER2-positive (HER2+) breast cancer (BC) [2]
Even though ethanol is the alcohol normally used in this synthesis procedure [17,23,24], 2-PrOH was chosen because it had been found in a previous work that its employment allowed
PDA NP surface charge, which was–27.4 ± 1.5 mV, was determined, and PDA NPs were characterized by transmission electron microscopy (TEM) to analyze their morphology and to obtain a size–range histogram (Figure 1b)
Summary
HER2, overexpressed in other types of solid tumors [3,4], can dimerize with other members of its receptor family, and this fact leads to cancer cell proliferation and survival, angiogenesis and metastasis [4]. Trastuzumab (Tmab) has been shown to induce tumor regression through different molecular mechanisms and to significantly increase overall survival of patients in multiple trials [6,7]. For this reason, it is nowadays an established part of adjuvant HER2+ BC treatment along with taxanes [6,8]. The two most important ones are its inherent cardiotoxicity and the apparition of acquired Tmab resistances, which cause
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