RESUMEN
Paclitaxel (PTX) is one of the most widely utilized chemotherapeutics globally. However, the extremely poor water solubility of paclitaxel necessitates a mechanism of delivery within blood. Fluid lipid PTX nanocarriers (lipids in the chain-melted state) show promise as PTX delivery vectors, but remain limited by their solubility of PTX within the membrane. To improve pharmacokinetics, membrane surfaces are typically coated with polyethylene glycol (PEG). Recent work has demonstrated the generation of a population of micelles within fluid lipid formulations containing a 2kDa PEG-lipid at a 10 mol% ratio. Driven by the positive curvature of the PEG-lipid (i.e. area of head group > area of tails), micelle-containing formulations were found to exhibit significantly higher uptake in cancer cells, cytotoxicity, and in vivo antitumor efficacy compared to formulations containing solely liposomes. Here, we describe the custom synthesis of a library of high-curvature micelle-inducing PEG-lipids and examine the effects of PEG chain length, chain branching (single- or double-PEG-lipid), and cationic charge on PTX solubility and cytotoxicity. We examined PEG-lipids at standard (10 mol%) and high (100-x mol%, where x=PTX mol%) formulation ratios. Remarkably, all formulations containing the synthesized high-curvature PEG-lipids had improved PTX solubility over unPEGylated formulations and commercially available DOPE-5k. The highest PTX solubility was found within the 100-xPTX mol% PEG-lipid micellar formulations, with particles made from 2k2 (two PEG2k chains) encapsulating 13 mol% PTX for up to 24 h. The pancreatic cancer cell line PC3 exhibited higher sensitivity to formulations containing PEG-lipid at 100-xPTX mol%, the most potent of which being formulations made from 2k2 (IC50 = 14 nM). The work presented here suggests formulations employing high-curvature PEG-lipids, particularly the double-PEG-lipid 2k2, hold great potential as next-generation PTX delivery systems owing to their high PTX solubility, enhanced cell cytotoxicity, and ability for precision targeting by affixation of ligands to the PEG molecules.
RESUMEN
Lipid nanoparticles (LNPs) have been commonly used as a vehicle for nucleic acids, such as small interfering RNA (siRNA); the surface modification of LNPs is one of the determinants of their delivery efficiency especially in systemic administration. However, the applications of siRNA-encapsulated LNPs are limited due to a lack effective systems to deliver to solid tumors. Here, we report a smart surface modification using a charge-switchable ethylenediamine-based polycarboxybetaine for enhancing tumor accumulation via interaction with anionic tumorous tissue constituents due to selective switching to cationic charge in response to cancerous acidic pH. Our polycarboxybetaine-modified LNP could enhance cellular uptake in cancerous pH, resulting in facilitated endosomal escape and gene knockdown efficiency. After systemic administration, the polycarboxybetaine-modified LNP accomplished high tumor accumulation in SKOV3-luc and CT 26 subcutaneous tumor models. The siPLK-1-encapsulated LNP thereby accomplished significant tumor growth inhibition. This study demonstrates a promising potential of the pH-responsive polycarboxybetaine as a material for modifying the surface of LNPs for efficient nucleic acid delivery.