Rapid Self-Assembly of Polymer Nanoparticles for Synergistic Codelivery of Paclitaxel and Lapatinib via Flash NanoPrecipitation

Abstract

Taxol, a formulation of paclitaxel (PTX), is one of the most widely used anticancer drugs, particularly for treating recurring ovarian carcinomas following surgery. Clinically, PTX is used in combination with other drugs such as lapatinib (LAP) to increase treatment efficacy. Delivering drug combinations with nanoparticles has the potential to improve chemotherapy outcomes. In this study, we use Flash NanoPrecipitation, a rapid, scalable process to encapsulate weakly hydrophobic drugs (logP < 6) PTX and LAP into polymer nanoparticles with a coordination complex of tannic acid and iron formed during the mixing process. We determine the formulation parameters required to achieve uniform nanoparticles and evaluate the drug release in vitro. The size of the resulting nanoparticles was stable at pH 7.4, facilitating sustained drug release via first-order Fickian diffusion. Encapsulating either PTX or LAP into nanoparticles increases drug potency (as indicated by the decrease in IC-50 concentration); we observe a 1500-fold increase in PTX potency and a six-fold increase in LAP potency. When PTX and LAP are co-loaded in the same nanoparticle, they have a synergistic effect that is greater than treating with two single-drug-loaded nanoparticles as the combination index is 0.23 compared to 0.40, respectively.

Self-Assembly of pH-Labile Polymer Nanoparticles for Paclitaxel Prodrug Delivery: Formulation, Characterization, and Evaluation

“…Increased proportion in the subG 1 phase has been attributed to shorter arrest in the G 2 /M phase with rapid DNA fragmentation leading to cell death overtime [17,18]. Overall, these results are comparable to previous reports [14] and support the observed increase in potency of the prodrug compared to paclitaxel.…”

“…To further increase the potency, we next examined formulating the prodrug into nanoparticles since encapsulation of hydrophobic drugs into nanoparticles can increase their potency [9,14,19,20]. Thus, we used Flash NanoPrecipitation (FNP), a rapid, scalable, polymer directed self-assembly method [8,21].…”

“…Thus, we used Flash NanoPrecipitation (FNP), a rapid, scalable, polymer directed self-assembly method [8,21]. Building on our previous work, we incorporated the prodrug into a pH-labile nanoparticle based on a tannic acid (TA) coordination complex with iron [14,22]. Our goal was to apply the fundamental understanding of the self-assembly process to achieve prodrug loaded nanoparticles that were less than 200 nm in diameter and uniform by dynamic light scattering (DLS) (that could enable passive targeting [23,24]).…”

“…As a starting point we used the formulation parameters that resulted in~100 nm PTX-loaded nanoparticles, uniform by DLS with the highest drug loading. Specifically, we formulated prodrug loaded nanoparticles using a prodrug concentration at 1 mg/mL in the organic stream at a constant 2:1 ratio of the BCP:core as previously described for paclitaxel loaded nanoparticles (PTX NPs) [14]. However, the resulting dispersion was not uniform by DLS with a peak at 184 ± 11 nm and a secondary peak at 26 ± 2 nm.…”

“…In this study, we use Flash NanoPrecipitation of tannic acid and iron as a pH-labile nanoparticle platform for enhancing paclitaxel potency. Formulation of tannic acid iron nanoparticles incorporating weakly hydrophobic drugs such as paclitaxel has recently been reported [14]. Building on this work, our aim is to improve the potency of paclitaxel with a combination of prodrug synthesis, nanoparticle formation, and formulation with lapatinib with synergistic effects.…”