(264d) Growth Rate Dissipation of Metastatic Triple Negative Breast Cancer Attributed to Slow Tumor-Clearing and Deep Tumor-Penetrating Chemotherapy | AIChE

(264d) Growth Rate Dissipation of Metastatic Triple Negative Breast Cancer Attributed to Slow Tumor-Clearing and Deep Tumor-Penetrating Chemotherapy

Authors 

Howe, A. - Presenter, Johns Hopkins University
Prasad, A. G., Johns Hopkins University
Stras, S., Rutgers University
Sofou, S., Johns Hopkins University
Metastatic and/or recurrent Triple Negative Breast Cancer (TNBC) is currently incurable. TNBC accounts for 12-17% of breast carcinomas with the lowest 5-year survival rates among all breast cancer patients due to high proliferation and reoccurrence outside the breast combined with lack of effective targeted therapeutic modalities. Platinum-derived compounds receive extensive clinical use because of their DNA damaging activity to which TNBC tumors frequently show sensitivity. However, clinical efficacy is still limited.

To enhance the efficacy of tumor delivered platinum compounds, we engineered the release and adhesion properties of lipid nanocarriers encapsulating cisplatin with the following two aims: 1) to improve the uniformity in intratumoral drug distributions, and 2) to prolong the exposure of cancer cells to administered therapeutics with the goal of better controlling their growth (and/or spreading).

We have previously demonstrated in 3D multicellular spheroids (used as surrogates of the tumor avascular regions) that uniform intratumoral distributions is facilitated by nanocarriers engineered to release their (rapidly diffusing) therapeutic contents in the tumor interstitium enabling deep tumor-penetration of therapeutics. Key to this approach is to use drug nanocarriers that do not become internalized by cells - so as to maximize the fraction of released drug that may penetrate deeper in the tumor - and, to choose therapeutic agents (for example, cisplatin) which are efficiently transported across the cell membranes independent of the local extracellular milieu.

In this study, to effectively translate this strategy in vivo, the intratumoral residence times of such drug-loaded nanocarriers are now designed to be increased so as to maximize the time-integrated dose delivered at the tumor. To increase the nanocarriers' tumor residence times, we introduce an 'adhesion switch' on the nanocarriers' surface with the aim to slow down their tumor-clearing kinetics. The switch is designed to promote nanoparticle adsorption on cancer cells and/or the extracellular matrix while keeping their internalization by cells to a minimum.

Herein, we present evidence that lipid-based nanocarriers (liposomes) loaded with cisplatin and designed to combine the above two distinct mechanisms, improve the intratumoral drug uniformity and prolong the carriers' tumor residence times. We demonstrate that they result in slow tumor clearance and enable significant decrease of the rate of growth of metastatic TNBC tumors in vivo.

These findings, support the potential of nanocarriers' properties such as the interstitial release of therapeutics by slow tumor-clearing carriers to collectively improve the efficacy of chemotherapeutics and to better control the growth of metastatic TNBC.