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

Abstract

The efficacy of paclitaxel (PTX) is limited due to its poor solubility, poor bioavailability, and acquired drug resistance mechanisms. Designing paclitaxel prodrugs can improve its anticancer activity and enable formulation of nanoparticles. Overall, the aim of this work is to improve the potency of paclitaxel with prodrug synthesis, nanoparticle formation, and synergistic formulation with lapatinib. Specifically, we improve potency of paclitaxel by conjugating it to α-tocopherol (vitamin E) to produce a hydrophobic prodrug (Pro); this increase in potency is indicated by the 8-fold decrease in half maximal inhibitory concentration (IC50) concentration in ovarian cancer cell line, OVCA-432, used as a model system. The efficacy of the paclitaxel prodrug was further enhanced by encapsulation into pH-labile nanoparticles using Flash NanoPrecipitation (FNP), a rapid, polymer directed self-assembly method. There was an 1100-fold decrease in IC50 concentration upon formulating the prodrug into nanoparticles. Notably, the prodrug formulations were 5-fold more potent than paclitaxel nanoparticles. Finally, the cytotoxic effects were further enhanced by co-encapsulating the prodrug with lapatinib (LAP). Formulating the drug combination resulted in synergistic interactions as indicated by the combination index (CI) of 0.51. Overall, these results demonstrate this prodrug combined with nanoparticle formulation and combination therapy is a promising approach for enhancing paclitaxel potency.

7-Epitaxol Induces Apoptosis and Autophagy in Head and Neck Squamous Cell Carcinoma through Inhibition of the ERK Pathway

“…For instance, liposome-based paclitaxel formulations have been shown to exert lower levels of neurotoxicity in both in vitro and in vivo conditions compared to standard preparations [36]. Similarly, preparation of a hydrophobic prodrug by conjugating paclitaxel with vitamin E, as well as encapsulating the prodrug into nanoparticles, has been shown to significantly increase the anticancer efficacy of paclitaxel [37]. Taken together, these observations highlight the need for continuous upgradation in paclitaxel-based treatment strategies for better cancer management.…”

Polymeric Nanoparticle Delivery of Combination Therapy with Synergistic Effects in Ovarian Cancer

“…Achieving nanoparticles with tunable release of multiple drugs would be advantageous [ 28 , 30 , 31 ]. To tune the release rate of the drugs, various approaches have been used such as prodrug synthesis [ 128 ]. Alternatively, the different drugs can be loaded in different layers of the nanoparticles to achieve different release profiles [ 28 , 31 , 71 ].…”

Precision Polymer Particles by Flash Nanoprecipitation and Microfluidic Droplet Extraction

“…FNP requires both solvents to be fully miscible, with the polymer component insoluble in the nonsolvent added. Typically, this results in a hydrophobic polymer, such as PS, poly­(isoprene) (PI), poly­(butadiene) (PB), or mixtures, dissolved in an organic solvent, often tetrahydrofuran (THF), and jetted into the nonsolvent, commonly water. ,,,, THF–H 2 O solvent mixtures have been most frequently used, in conjunction with many polymeric solutes: poly­(butylacrylate)- b -poly­(acrylic acid) (PBA- b -PAA), , poly­(ethylene oxide)- b -poly­(styrene) (PEO- b -PS), ,,,,− poly­(ethylene glycol)- b -poly­(ϵ-caprolactone) (PEO- b -PCL), ,,,,,− poly­(styrene)- b -poly­(4-vinylpyridine) (PS- b -PVP), − poly­(styrene)- b -poly­(isoprene) (PS- b -PI), PCL, and PCL end group functionalized with coumarin, as well as poly­(ethylene glycol)- b -poly­(lactic acid) (PEG- b -PLA) ,,,,− ,, and poly­(ethylene glycol)- b -poly­(lactic- co -glycolic acid) (PEG- b -PLGA). ,,,,, Hydrophobic polymers, in combination with BCPs, can be added and comprise the NP core, e.g. , PS with PS- b -PEO ,, and poly­(lactic acid) (PLA) with PEG- b -PLA …”

“…Reports to date include the encapsulation of hydrophobic small molecules, e.g. , vitamins and vitamin precursors, ,,− ,,, fluorescent dyes, pesticides, pro-drugs, , chemotherapy drugs, ,,, and broad-spectrum antibiotics . The versatility of the approach also allows inorganic NPs to be suspended in inlet streams and incorporated into the polymeric NPs.…”