Self-Assembled Disulfide Bond Bearing Paclitaxel-Camptothecin Prodrug Nanoparticle for Lung Cancer Therapy.

Jingyan Gao,Xiaodong Ma,Dongqing Wang,Yuezhou Zhang,Hongbo Zhang,Lirong Zhang,Jiaqi Yan,Huaguang Cui

doi:10.3390/pharmaceutics12121169

Abstract

Self-assembled prodrugs (SAPDs), which combine prodrug strategy and the merits of self-assembly, not only represent an appealing type of therapeutics, enabling the spontaneous organization of supramolecular nanocomposites with defined structures in aqueous environments, but also provide a new method to formulate existing drugs for more favorable outcomes. To increase drug loading and combination therapy, we covalently conjugated paclitaxel (PTX) and camptothecin (CPT) through a disulfide linker into a prodrug, designated PTX-S-S-CPT. The successful production of PTX-S-S-CPT prodrug was confirmed by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). This prodrug spontaneously undergoes precipitation in aqueous surroundings. Taking advantage of a flow-focusing microfluidics platform, the prodrug nanoparticles (NPs) have good monodispersity, with good reproducibility and high yield. The as-prepared prodrug NPs were characterized with dynamic light scattering (DLS) and transmission electron microscopy (TEM), demonstrating spherical morphology of around 200 nm in size. In the end, the self-assembled NPs were added to mouse embryonic fibroblast (MEF), mouse lung adenocarcinoma and Lewis lung carcinoma (LLC) cell lines, and human non-small cell lung cancer cell line A549 to evaluate cell viability and toxicity. Due to the redox response with a disulfide bond, the PTX-S-S-CPT prodrug NPs significantly inhibited cancer cell growth, but had no obvious toxicity to healthy cells. This prodrug strategy is promising for co-delivery of PTX and CPT for lung cancer treatment, with reduced side effects on healthy cells.

Highlights

The mission of medicinal chemists is identifying chemical entities with potential therapeutic utility and value using both computational [1] and synthetic [2] approaches
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An intense peak was observed at 1715 cm−1 (Figure 3B), which indicates the absorption of the C=O of carboxylic acid and suggests the successful synthesis of PTX-S-S-COOH

Summary

Introduction

The mission of medicinal chemists is identifying chemical entities with potential therapeutic utility and value using both computational [1] and synthetic [2] approaches. The successful identification of pharmacodynamically potent compounds does not always lead to a drug development project. The delivery at the site of action at the appropriate time is a crucial for the active pharmaceutical ingredients (APIs) to fully and properly function, since improper position compromises the potency but may lead to unwanted toxicity. Successful drug delivery is often a challenge given the many pharmacokinetic (PK) hurdles it needs to overcome. More than six decades ago, Albert coined the term “prodrug” [3], referring to compounds bearing little or no pharmacological activity but, after administration, are metabolized to the active parent drug through enzymatic/chemical processes

Methods

Results

Conclusion