posted on 2023-11-16, 12:34authored byMalcolm Lim, Nicholas L. Fletcher, Jodi M. Saunus, Amy E. McCart Reed, Haarika Chittoory, Peter T. Simpson, Kristofer J. Thurecht, Sunil R. Lakhani
Breast cancer brain
metastases (BM) are associated with a dismal
prognosis and very limited treatment options. Standard chemotherapy
is challenging in BM patients because the high dosage required for
an effective outcome causes unacceptable systemic toxicities, a consequence
of poor brain penetration, and a short physiological half-life. Nanomedicines
have the potential to circumvent off-target toxicities and factors
limiting the efficacy of conventional chemotherapy. The HER3 receptor
is commonly expressed in breast cancer BM. Here, we investigate the
use of hyperbranched polymers (HBP) functionalized with a HER3 bispecific-antibody
fragment for cancer cell-specific targeting and pH-responsive release
of doxorubicin (DOX) to selectively deliver and treat BM. We demonstrated
that DOX-release from the HBP carrier was controlled, gradual, and
greater in endosomal acidic conditions (pH 5.5) relative to physiologic
pH (pH 7.4). We showed that the HER3-targeted HBP with DOX payload
was HER3-specific and induced cytotoxicity in BT474 breast cancer
cells (IC50: 17.6 μg/mL). Therapeutic testing in
a BM mouse model showed that HER3-targeted HBP with DOX payload impacted
tumor proliferation, reduced tumor size, and prolonged overall survival.
HER3-targeted HBP level detected in ex vivo brain samples was 14-fold
more than untargeted-HBP. The HBP treatments were well tolerated,
with less cardiac and oocyte toxicity compared to free DOX. Taken
together, our HER3-targeted HBP nanomedicine has the potential to
deliver chemotherapy to BM while reducing chemotherapy-associated
toxicities.