29
views
0
recommends
+1 Recommend
1 collections
    0
    shares

      International Journal of Nanomedicine (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the application of nanotechnology in diagnostics, therapeutics, and drug delivery systems throughout the biomedical field. Sign up for email alerts here.

      105,621 Monthly downloads/views I 7.033 Impact Factor I 10.9 CiteScore I 1.22 Source Normalized Impact per Paper (SNIP) I 1.032 Scimago Journal & Country Rank (SJR)

      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Trastuzumab Targeted Neratinib Loaded Poly-Amidoamine Dendrimer Nanocapsules for Breast Cancer Therapy

      research-article

      Read this article at

      ScienceOpenPublisherPMC
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Human epidermal growth factor receptor2 (Her2) positive breast cancer represents 25% of breast cancer cases. Targeted therapy with Her2 monoclonal antibody, trastuzumab (TZ), represents the first-line treatment for this type of breast cancer. In addition, neratinib, an irreversible inhibitor of the HER-2 receptor tyrosine kinase, has recently been approved as adjuvant therapy to TZ. This study aims to formulate (TZ)-grafted dendrimers loaded with neratinib, allowing a dual treatment alongside reducing the associated resistance as well as targeted therapy.

          Methods

          TZ was conjugated on the surface of dendrimer using hetero-cross linker, MAL-PEG-NHS, and the zeta potential, and in vitro release of neratinib from dendrimers was characterized. Formulated dendrimers were also fluorescently conjugated with fluorescein isothiocyanate to visualize and quantify their SKBR-3 cellular uptake.

          Results

          The G4 PAMAM dendrimer showed successful encapsulation of neratinib and a sustained release profile. Comparative in vitro studies revealed that these TZ-targeted dendrimers loaded with neratinib were more selective and have higher antiproliferation activity against SKBR-3 cells compared to neratinib alone and neratinib loaded dendrimer.

          Conclusion

          In the current study, neratinib loaded in plain and trastuzumab-grafted dendrimer were successfully prepared. Enhanced cellular uptake of trastuzumab conjugated dendrimers was shown, together with a higher cytotoxic effect than plain neratinib dendrimers. These findings suggest the potential of TZ-conjugated dendrimers as targeting carrier for cytotoxic drugs, including neratinib.

          Most cited references15

          • Record: found
          • Abstract: found
          • Article: not found

          Resistance to Trastuzumab in Breast Cancer.

          HER2 is a transmembrane oncoprotein encoded by the HER2/neu gene and is overexpressed in approximately 20 to 25% of invasive breast cancers. It can be therapeutically targeted by trastuzumab, a humanized IgG1 kappa light chain monoclonal antibody. Although trastuzumab is currently considered one of the most effective treatments in oncology, a significant number of patients with HER2-overexpressing breast cancer do not benefit from it. Understanding the mechanisms of action and resistance to trastuzumab is therefore crucial for the development of new therapeutic strategies. This review discusses proposed trastuzumab mode of action as well as proposed mechanisms for resistance. Mechanisms for resistance are grouped into four main categories: (1) obstacles preventing trastuzumab binding to HER2; (2) upregulation of HER2 downstream signaling pathways; (3) signaling through alternate pathways; and (4) failure to trigger an immune-mediated mechanism to destroy tumor cells. These potential mechanisms through which trastuzumab resistance may arise have been used as a guide to develop drugs, presently in clinical trials, to overcome resistance. The mechanisms conferring trastuzumab resistance, when completely understood, will provide insight on how best to treat HER2-overexpressing breast cancer. The understanding of each mechanism of resistance is therefore critical for the educated development of strategies to overcome it, as well as for the development of tools that would allow definitive and efficient patient selection for each therapy. (Clin Cancer Res 2009;15(24):7479-91).
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer.

            Neratinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor. The efficacy and safety of neratinib were evaluated in two cohorts of patients with advanced ErbB2-positive breast cancer-those with and those without prior trastuzumab treatment-in an open-label, multicenter, phase II trial. Patients in the two cohorts (prior trastuzumab, n = 66; no prior trastuzumab, n = 70) received oral neratinib 240 mg once daily. The primary end point was the 16-week progression-free survival (PFS) rate for the evaluable population (prior trastuzumab, n = 63; no prior trastuzumab, n = 64), as assessed by independent review. The 16-week PFS rates were 59% for patients with prior trastuzumab treatment and 78% for patients with no prior trastuzumab treatment. Median PFS was 22.3 and 39.6 weeks, respectively. Objective response rates were 24% among patients with prior trastuzumab treatment and 56% in the trastuzumab-naïve cohort. The most common adverse events were diarrhea, nausea, vomiting, and fatigue. Diarrhea was the most frequent grades 3 to 4 adverse event, occurring in 30% of patients with prior trastuzumab treatment and in 13% of patients with no prior trastuzumab treatment, which prompted dose reductions in 29% and 4% of patients, respectively, but treatment discontinuation in only one patient. No neratinib-related, grades 3 or 4 cardiotoxicity was reported. Oral neratinib showed substantial clinical activity and was reasonably well tolerated among both heavily pretreated and trastuzumab-naïve patients who had advanced, ErbB2-positive breast cancer. Diarrhea was the most common adverse effect but was manageable with antidiarrheal agents and dose modification.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              PAMAM dendrimer-based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality.

              Poly(amidoamine) (PAMAM) dendrimer-based multifunctional cancer therapeutic conjugates have been designed and synthesized. The primary amino groups on the surface of the generation 5 (G5) PAMAM dendrimer were neutralized through partial acetylation, providing enhanced solubility of the dendrimer (in conjugation of FITC (fluorescein isothiocyanate)) and preventing nonspecific targeting interactions (in vitro and in vivo) during delivery. The functional molecules fluorescein isothiocyanate (FITC, an imaging agent), folic acid (FA, targets overexpressed folate receptors on specific cancer cells), and paclitaxel (taxol, a chemotherapeutic drug) were conjugated to the remaining nonacetylated primary amino groups. The appropriate control dendrimer conjugates have been synthesized as well. Characterization of the G5 PAMAM dendrimer and its nanosize conjugates, including the molecular weight and number of primary amine groups, has been determined by multiple analytical methods such as gel permeation chromatography (GPC), nuclear magnetic resonance spectroscopy (NMR), potentiometric titration, high-performance liquid chromatography (HPLC), and UV spectroscopy. These multifunctional dendrimer conjugates have been tested in vitro for targeted delivery of chemotherapeutic and imaging agents to specific cancer cells. We present here the synthesis, characterization, and functionality of these dendrimer conjugates.
                Bookmark

                Author and article information

                Journal
                Int J Nanomedicine
                Int J Nanomedicine
                IJN
                intjnano
                International Journal of Nanomedicine
                Dove
                1176-9114
                1178-2013
                30 July 2020
                2020
                : 15
                : 5433-5443
                Affiliations
                [1 ]Department of Pharmaceutics, College of Pharmacy, King Saud University , Riyadh, Saudi Arabia
                [2 ]Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University , Riyadh, Saudi Arabia
                [3 ]Department of Optometry, College of Applied Medical Sciences, King Saud University , Riyadh, Saudi Arabia
                [4 ]Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , Riyadh, Saudi Arabia
                [5 ]Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, MI, USA
                Author notes
                Correspondence: Fadilah Sfouq Aleanizy Email faleanizy@ksu.edu.sa
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0002-6161-3121
                http://orcid.org/0000-0002-9320-0516
                http://orcid.org/0000-0003-2058-3058
                http://orcid.org/0000-0003-3843-0586
                http://orcid.org/0000-0002-6983-8587
                http://orcid.org/0000-0002-0922-8541
                http://orcid.org/0000-0003-3430-2157
                http://orcid.org/0000-0001-5288-5953
                Article
                256898
                10.2147/IJN.S256898
                7398757
                9bbcb859-a4dd-4be2-abe4-18b91cbbd0a2
                © 2020 Aleanizy et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 04 April 2020
                : 08 July 2020
                Page count
                Figures: 8, Tables: 2, References: 22, Pages: 11
                Categories
                Original Research

                Molecular medicine
                neratinib,targeted dendrimer,trastuzumab,her2-positive,breast cancer
                Molecular medicine
                neratinib, targeted dendrimer, trastuzumab, her2-positive, breast cancer

                Comments

                Comment on this article