Poster X7 - Ultrahigh Paclitaxel-loaded Nanoparticles for the Treatment of Triple Negative Breast Cancer

Introduction: Triple negative breast cancer (TNBC) accounts for over 15-20% of all breast cancers, and their treatment does not benefit from targeted therapies against estrogen, progesterone, and HER2 receptors. TNBC patients are often relegated to treatment with classical chemotherapies and have lower survival than other types of breast cancer patients. Motivated by the need to improve treatment of TNBCs, we designed polymeric nanoparticles (NPs) to achieve ‘ultrahigh’ loading (LC ≥ 35%) of the common chemotherapeutic paclitaxel (PTX) as a means to increase PTX maximum tolerated dose (MTD) and consequently anti-tumor efficacy. The NP system is comprised of ABA triblock copolymers that possess a tunable, ROS-triggered release mechanism. Herein, we have investigated the therapeutic efficacy in an orthotopic TNBC model of two NP compositions that have varied ROS sensitivity, yielding “slow” and “fast” drug release NP formulations.

Materials and

Methods: An ABA triblock copolymer library was synthesized with B blocks comprising varied ratios of H-bonding (hydroxyl) and π-π interacting (Benzyl, %B) groups. Nude mice were inoculated with 10^6 MDA-MB-231.Luc cells and treated at 150 mg/kg PTX (experimentally-determined NP formulation MTD) of either slow or fast release NPs or 20 mg/kg of Taxol as a gold standard treatment control once tumors reached a volume of ~75 mm^3 (Day 0). Mice received 5 treatments spaced every 10 days and the study ended on day 100 (n=8). Survival end-points were reached when tumors were ulcerated or exceeded 1000 mm^3.

Results, Conclusions, and Discussions: Polymers with higher benzyl composition (%B) displayed lower ROS responsivity and more sustained release profiles vs polymers with higher %hydroxyl. The slow release group showed complete tumor elimination in 3 out of 8 mice (Fig. 1A-B). The average tumor volume for fast release treatment groups by day 100 was 365.8 mm^3, while the average tumor volume was 73.37 mm^3 for slow release (Fig. 1C). The 80%B PTX NPs exhibited greater tumor inhibition compared to 40%B PTX NPs. In terms of survival, saline treated mice had a median survival time of 18 days and Taxol treated mice had a median survival of 30 days. Both fast and slow release had a median survival of 100 days; at day 100, one mouse in the fast group reached humane end-point (Fig. 1D). While both slow and fast release polymeric NPs demonstrated greater survival and decreased tumor volume, the slow release formulation showed the best efficacy.
The slow and fast release NP formulations demonstrated therapeutic efficacy superior to the clinical standard, Taxol. By day 100, the fast PTX release group showed 88% survival, while the slow release group maintained 100% survival. The slow release polymeric NP formulation eliminated tumors in some mice and prolonged survival, exhibiting sustained, potent anti-tumor activity greater than the fast release NPs and Taxol. Thus, this delivery system shows great clinical potential for treatment of TNBC.

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