Interstitial Release of Cisplatin from Triggerable Liposomes Enhances Efficacy against Triple Negative Breast Cancer Solid Tumor Analogues.

Liposomal cisplatin, a promising triple negative breast cancer treatment modality, has been shown to decrease toxicities associated with cisplatin's free agent form. However, the heterogeneous intratumoral distributions of the liposomes themselves, combined with limited release of cisplatin from them contribute to limited penetration of cisplatin within tumors reducing efficacy. This study uses pH-responsive liposomes designed to release cisplatin within the acidic tumor interstitium (7.0 > pH ≥ 6.0) with a dual aim (1) to improve the penetration of the free drug within tumors on the assumption of greater diffusivities based on the free drug's much smaller size than its carrier's size and (2) to increase the availability of the free agent near cancer cells deep into the tumor. On cell monolayers treated with pH-releasing liposomal cisplatin, acidification of the extracellular solution resulted in decreased LD50 values, which were significantly lower than the LD50 values for non-pH-releasing liposomal cisplatin. In multicellular spheroids with acidic interstitia, pH-releasing liposomal cisplatin significantly decreased spheroid volumes relative to non-pH-releasing liposomal cisplatin. Improved efficacy was correlated with increased spheroid penetration of a fluorescent cisplatin surrogate. These findings demonstrate that interstitial release of cisplatin by pH-responsive liposomes may improve the intratumoral distributions of the free drug enhancing efficacy.