Impact of Tumor HER2/ERBB2 Expression Level on HER2-Targeted Liposomal Doxorubicin-Mediated Drug Delivery: Multiple Low-Affinity Interactions Lead to a Threshold Effect

Abstract

Numerous targeted nanotherapeutics have been described for potential treatment of solid tumors. Although attention has focused on antigen selection and molecular design of these systems, there has been comparatively little study of how cellular heterogeneity influences interaction of targeted nanoparticles with tumor cells. Antigens, such as HER2/ERBB2, are heterogeneously expressed across different indications, across patients, and within individual tumors. Furthermore, antigen expression in nontarget tissues necessitates optimization of the therapeutic window. Understanding the performance of a given nanoparticle under different regimens of antigen expression has the ability to inform patient selection and clinical development decisions. In this work, HER2-targeted liposomal doxorubicin was used as a modeltargeted nanoparticle to quantitatively investigate the effect of HER2 expression levels on delivery of doxorubicin to the nucleus. We find quantitatively greater nuclear doxorubicin delivery with increasing HER2 expression, exhibiting a threshold effect at approximately 2 Â 10 5 HER2 receptors/cell. Kinetic modeling indicated that the threshold effect arises from multiple low-affinity interactions between the targeted liposome and HER2. These results support previous data showing little or no uptake into human cardiomyocytes, which express levels of HER2 below the threshold. Finally, these results suggest that HER2-targeted liposomal doxorubicin may effectively target tumors that fall below traditional definitions of HER2-positive tumors, thereby expanding the potential population of patients that might benefit from this agent. Mol Cancer Ther; 12(9); 1816-28. Ó2013 AACR.

Tuning polypeptide-based micellar carrier for efficient combination therapy of ErbB2-positive breast cancer

“…Moreover, we can also hypothesize that H-bonding between exposed amide groups of the disordered polypeptide chains and drug molecules in the core of PEG-P(D,L-Leu) micelles would favor micellar drug solubilization in addition to other interaction forces. Our observations are in accordance with the behavior of micellar carriers with conformationally rigid hydrophobic P(L-Leu) segments in the cores where decreased cargo loading was observed [2,19,50]. Drug release data from PEG-P(D,L-Leu)/m showed that the individual drug release rates practically did not change for binary drug formulations compared to the single drug-loaded micelles: over 90% of drugs were released within 24 hours at physiological pH, both in the presence as well as absence of FBS (Fig.…”

“…The present study is focused on human epidermal growth factor 2 positive (ErbB2+) breast cancer, accounting for about 20% of all breast cancer cases diagnosed. Oncogenic ErbB2 signaling results in hyperproliferation of the cancer cells, increases cell survival, promotes invasion and early metastasis, and is a relatively poor prognosis for the patient [2,3]. Inclusion of targeted therapy with humanized antibody trastuzumab (Herceptin) that interferes with ErbB2 signaling into conventional chemotherapy regimen significantly improved response rates, time of progression, and survival, and has become the mainstay of treatment for patients with this aggressive breast cancer subtype [4–7].…”

Functionalized immunostimulating complexes with protein A via lipid vinyl sulfones to deliver cancer drugs to trastuzumab-resistant HER2-overexpressing breast cancer cells

“…As expected, the uptake of ISCOMs conjugated with Tmab was dependent on the level of overexpression of HER2, being significantly higher for HCC1954 (Figure 4), and as a consequence, the drug delivery system was more efficient on HCC1954 cells ( Figure 5). These results are in full agreement with those reported by Hendriks et al, 35 who found that the cytotoxic effect of liposomal NPs conjugated with Tmab and loaded with Dox was higher as the cells attain higher levels of the receptor.…”

“…Although there exist few articles reporting the development of NPs with the same purpose as our study, 35,42,43 International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 34.217.195.47 on 13-May-2018 For personal use only.…”

Dual HER2 Targeting with Trastuzumab and Liposomal-Encapsulated Doxorubicin (MM-302) Demonstrates Synergistic Antitumor Activity in Breast and Gastric Cancer

“…However, unlike PLD, following deposition in the tumor microenvironment, anti-HER2 antibodies on the surface of MM-302 specifically increase targeting to HER2-overexpressing tumor cells with a resultant increase in antitumor activity relative to PLD in multiple preclinical models (15,16). Additional work has elucidated a critical threshold of surface HER2 expression, approximately 200,000 HER2 receptors per cell for efficient binding and uptake of MM-302 (17). Importantly, cardiomyocytes do not possess the requisite number of HER2 receptors required to efficiently mediate the uptake of MM-302, potentially mitigating safety concerns (18,19).…”