PH-Responsive Lipid Nanocapsules: A Promising Strategy for Improved Resistant Melanoma Cell Internalization.

Jérémie Riou,Antoine Debuigne,Elise Lepeltier,Vincent Pautu,Nicolas Clere,Christine Jérôme,Adélie Mellinger,Catherine Passirani

doi:10.3390/cancers13092028

Jérémie Riou, Antoine Debuigne + Show 6 more

Open Access

https://doi.org/10.3390/cancers13092028

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Abstract

Despite significant advances in melanoma therapy, low response rates and multidrug resistance (MDR) have been described, reducing the anticancer efficacy of the administered molecules. Among the causes to explain these resistances, the decreased intratumoral pH is known to potentiate MDR and to reduce the sensitivity to anticancer molecules. Nanomedicines have been widely exploited as the carriers of MDR reversing molecules. Lipid nanocapsules (LNC) are nanoparticles that have already demonstrated their ability to improve cancer treatment. Here, LNC were modified with novel copolymers that combine N-vinylpyrrolidone (NVP) to impart stealth properties and vinyl imidazole (Vim), providing pH-responsive ability to address classical chemoresistance by improving tumor cell entry. These copolymers could be post-inserted at the LNC surface, leading to the property of going from neutral charge under physiological pH to positive charge under acidic conditions. LNC modified with polymer P5 (C18H37-P(NVP21-co-Vim15)) showed in vitro pH-responsive properties characterized by an enhanced cellular uptake under acidic conditions. Moreover, P5 surface modification led to an increased biological effect by protecting the nanocarrier from opsonization by complement activation. These data suggest that pH-sensitive LNC responds to what is expected from a promising nanocarrier to target metastatic melanoma.

Highlights

In recent years, cancer treatments have evolved considerably with the rise of new strategies for targeting the tumor microenvironment
Surface charges of Lipid nanocapsules (LNC) modified with pH-responsive polymers were directly linked to the pH: decreased pH led to an increased surface charge of pH-responsive LNC
The surface modification of lipid nanocapsules (BLK LNC), already composed of 15 units of PEG at the surface (Kolliphor® HS 15), was realized with the C18H37-P(NVP-co-vinyl imidazole (Vim)) copolymers reported in Table 1 and used as post-insertion agents thanks to a C18 mono carbon chain

Summary

Introduction

Cancer treatments have evolved considerably with the rise of new strategies for targeting the tumor microenvironment. Targeted therapies and monoclonal antibodies have improved the prognosis and survival of many cancer patients. Despite these significant advances, low response rates and multidrug resistance (MDR) have been described for certain molecules, reducing their efficacy. In metastatic melanoma, it has been reported that only 13 to 50% of patients respond to these new therapies with, sometimes, a delay of more than three months [1,2]. The reason why the same chemotherapeutic treatment yields different responses in patients can be attributed to the degree of resistance developed by the host tumor cells [3]. The most recurrent ones in chronic suninduced damage (CSD) and non-CSD melanoma affect genes in key signaling pathways involved in proliferation (BRAF, NRAS and NF1), growth and metabolism (PTEN and KIT), cell identity (AT-rich interaction domain 2 (ARID2)), resistance to apoptosis (TP53), cell cycle control (cyclin-dependent kinase inhibitor 2A (CDKN2A), and replicative lifespan (telomerase reverse transcriptase (TERT)) [5]

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