<p>Evaluation of Cytotoxic Effect of Cholesterol End-Capped Poly(<em>N</em>-Isopropylacrylamide)s on Selected Normal and Neoplastic Cells</p>

Abstract

Purpose: Efficient intracellular delivery of a therapeutic compound is an important feature of smart drug delivery systems (SDDS). Modification of a carrier structure with a cellpenetrating ligand, ie, cholesterol moiety, is a strategy to improve cellular uptake. Cholesterol end-capped poly(N-isopropylacrylamide)s offer a promising foundation for the design of efficient thermoresponsive drug delivery systems. Methods: A series of cholesterol end-capped poly(N-isopropylacrylamide)s (PNIPAAm) with number-average molar masses ranging from 3200 to 11000 g•mol-1 were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization from original xanthate-functionalized cholesterol and self-assembled into micelles. The physicochemical characteristics and cytotoxicity of cholesterol end-capped poly(N-isopropylacrylamide)s have been thoroughly investigated. Results: Phase transition temperature dependence on the molecular weight and hydrophilic/ hydrophobic ratio in the polymers were observed in water. Biological test results showed that the obtained materials, both in disordered and micellar form, are non-hemolytic, highly compatible with fibroblasts, and toxic to glioblastoma cells. It was found that the polymer termini dictates the mode of action of the system. Conclusion: The cholesteryl moiety acts as a cell-penetrating agent, which enables disruption of the plasma membrane and in effect leads to the restriction of the tumor growth. Cholesterol end-capped PNIPAAm showing in vitro anticancer efficacy can be developed not only as drug carriers but also as components of combined/synergistic therapy.

Magnetic Particles with Polymeric Shells Bearing Cholesterol Moieties Sensitize Breast Cancer Cells to Low Doses of Doxorubicin

“…However, it can be supposed that this effect is related to several factors, such as zeta potential value, differences in hydrodynamic diameter, effects related to the presence/absence of the PNIPAAm/PNVCL layer, the number and availability of cholesteryl moieties present at the surface of the particles. It is in line with our previous studies, which showed that homopolymers bearing a cholesteryl moiety can disrupt plasma membranes and cause leakage of lactate dehydrogenase (LDH) from treated neoplastic cells [ 11 ]. It should be emphasized that, based on our results ( Figure S6 ) and previously published studies, the viability of breast cancer cells after treatment with DOX at the concentration of 0.5 µM caused only a slight reduction of viability (10–15%) compared to untreated cells [ 35 ].…”

“…N -isopropylacrylamide (NIPAAm, 99 %, Acros Organics, Geel, Belgium) was recrystallized from toluene–hexane (60:40, v/v ) prior to use. Potassium O -ethyl carbonodithioate (KSCSOEt) was synthesized according to the well-known procedure [ 11 ]. All organic solvents were purchased from Avantor Performance Materials Poland S.A. (Gliwice, Poland) and were distilled before use.…”

“…Our previous studies revealed that nanosystems based on amino silica-modified iron oxide nanoparticles significantly improve the killing efficiency of ceragenin, decreasing the viability of lung and colon cancer cells [ 10 ]. Recently, we also synthesized thermoresponsive cholesterol end-capped poly( N -isopropylacrylamide)s and evaluated their cytotoxic effect on glioblastoma cells [ 11 ]. The studies showed that the cholesteryl moiety present at the end of the PNIPAAm chain acts as a cell-penetrating agent which enables disruption of the plasma membrane and in effect leads to the restriction of tumor growth.…”

Polymeric Drug Delivery Systems Bearing Cholesterol Moieties: A Review

“…These approaches result in polymers with one cholesteryl moiety. In the context of drug delivery, recent studies [91] show that even with a relatively long polymer ballast, it is possible to take advantage of the properties of cholesterol present at the polymer chain end. In such systems, cholesterol plays primarily a guiding role, but it can also integrate into the biological membrane, which may allow releasing drug molecules in the immediate vicinity or even inside a pathological cell.…”

“…However, at the same time, they allow for further copolymerization or appropriate modification, e.g., to the thiol group [98], which opens up a variety of possibilities from the Michael reaction to the formation of disulfides. The majority of the methods used in the synthesis of polymeric drug delivery systems with an incorporated cholesterol molecule are controlled radical polymerizations such as ATRP [54,79,[102][103][104][105][106][107][108], RAFT [91] or NMP [100] (Table 1). This is due to the possibility of controlling the dispersion of the system, which translates into stability in biological properties and accuracy in predicting the behavior of the carrier in the human body.…”