1.Hyaluronic Acid-Shelled Disulfide-Cross-Linked Nanopolymersomes for Ultrahigh-Efficiency Reactive Encapsulation and CD44-Targeted Delivery of Mertansine Toxin.
Zhang Y;Wu K;Sun H;Zhang J;Yuan J;Zhong Z ACS Appl Mater Interfaces. 2018 Jan 17;10(2):1597-1604. doi: 10.1021/acsami.7b17718. Epub 2018 Jan 4.
It was and remains a big challenge for cancer nanomedicines to achieve high and stable drug loading with fast drug release in the target cells. Here, we report on novel hyaluronic acid-shelled disulfide-cross-linked biodegradable polymersomes (HA-XPS) self-assembled from hyaluronic acid-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate) diblock copolymer for ultrahigh-efficiency reactive encapsulation and CD44-targeted delivery of mertansine (DM1) toxin, a highly potent warhead for clinically used antibody-drug conjugates. Remarkably, HA-XPS showed quantitative encapsulation of DM1 even with a high drug loading content of 16.7 wt %. DM1-loaded HA-XPS (HA-XPS-DM1) presented a small size of ∼80 nm, low drug leakage under physiological conditions, and fast glutathione-triggered drug release. MTT assays revealed that HA-XPS was noncytotoxic while HA-XPS-DM1 was highly potent to MDA-MB-231 cells with an IC;50; comparable to that of free DM1. The in vitro and in vivo inhibition experiments indicated that HA-XPS could actively target MDA-MB-231 cells. Notably, HA-XPS-DM1 while causing little adverse effect could effectively inhibit tumor growth and significantly prolong survival time in MDA-MB-231 human breast tumor-bearing mice.
2.Dual HER2 blockade: preclinical and clinical data.
Patel TA;Dave B;Rodriguez AA;Chang JC;Perez EA;Colon-Otero G Breast Cancer Res. 2014 Aug 1;16(4):419. doi: 10.1186/s13058-014-0419-5.
The estrogen receptor and human epidermal growth factor receptor (HER) signaling pathways are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. Not surprisingly, targeting these pathways provides the most effective therapies in appropriately selected patients. However, de novo and acquired resistance remain major obstacles to successful treatment. By increasing the understanding of the molecular mechanisms of combined HER2-targeted therapies, we aim to be better able to select patients who would respond to these treatments and understand some of the mechanisms of resistance to HER2-targeted treatments. Recent studies have demonstrated an increased effectiveness of dual targeted HER2 therapies against HER2-amplified breast cancer as compared with single blockade. These studies have resulted in the recent US Food and Drug Administration approval of the combination of taxane chemotherapy with pertuzumab and trastuzumab in the first-line metastatic setting as well as an accelerated approval in the neoadjuvant setting. Another mechanism for overcoming resistance to HER2 targeted therapies is the antibody-drug conjugate trastuzumab-emtansine, which targets the HER2 receptor conjugated to the potent antimicrotubule agent mertansine, allowing for intracellular release of the cytotoxic drug.
3.Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study.
Tolcher AW;Ochoa L;Hammond LA;Patnaik A;Edwards T;Takimoto C;Smith L;de Bono J;Schwartz G;Mays T;Jonak ZL;Johnson R;DeWitte M;Martino H;Audette C;Maes K;Chari RV;Lambert JM;Rowinsky EK J Clin Oncol. 2003 Jan 15;21(2):211-22.
PURPOSE: ;To determine the maximum tolerated dose and pharmacokinetics of cantuzumab mertansine, an immunoconjugate of the potent maytansine derivative (DM1) and the humanized monoclonal antibody (huC242) directed to CanAg, intravenously (i.v.) once every 3 weeks and to seek evidence of antitumor activity.;PATIENTS AND METHODS: ;Patients with CanAg-expressing solid malignancies were treated with escalating doses of cantuzumab mertansine administered i.v. every 3 weeks. The pharmacokinetic parameters of cantuzumab mertansine, the presence of plasma-shed CanAg, and the development of both human antihuman and human anti-DM1 conjugate antibodies also were characterized.;RESULTS: ;Thirty-seven patients received 110 courses of cantuzumab mertansine at doses ranging from 22 to 295 mg/m2. Acute, transient, and reversible elevations of hepatic transaminases were the principal toxic effects. Nausea, vomiting, fatigue, and diarrhea were common but rarely severe at the highest dose levels. Dose, peak concentration, and area under the concentration-time curve correlated with the severity of transaminase elevation. The mean (+/- SD) clearance and terminal elimination half-life values for cantuzumab mertansine averaged 39.