Nanocapsules for 5-fluorouracil delivery decorated with a poly(2-ethylhexyl methacrylate-co-7-(4-trifluoromethyl)coumarin acrylamide) cross-linked wall

Abstract

The first synthesis of polymer vesicles with reverse cross-linked walls from poly[2-ethylhexylmethacrylateco-(7-(4-trifluoromethyl)coumarin acrylamide)] P(EHMA/FMCA) is reported. The synthesis, carried out under UV light (l = 350 nm), was achieved via radical photopolymerization of hydrophobic compounds saturating the bilayer of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposome template. The polymerization reaction with coumarin moieties has a pivotal role, because the polymer chains become cross-linked as a result of the dimerization of the coumarin side chains of the formed polymers and, in this way, spherical capsules are obtained. Moreover, thanks to the incorporation of coumarin moieties, as an additional bonus, a nanometer-thick porous, fluorescent wall was formed, avoiding the use of additional cross-linking reagents, which might deactivate the encapsulated payloads. We present a new paradigm of release drug delivery systems combining a long shelf-life with the ability for rapid release using external factors such as light. To demonstrate this concept, target compounds such as hydrophilic dyes (Lucifer yellow (LY), phenosafranin (PhS)) and the drug 5-fluorouracil (5-FU)) were incorporated inside the stable, hollow, polymeric nanocapsules. The goal of these applications depends on the versatile strategy that is used for the preparation of highly emissive nanometer-sized polymer capsules with surface functionalities and optical properties for diagnostic applications.

Free radical polymerization of caffeine‐containing methacrylate monomers

“…Supporting Information Figure S1 displays the 1 H NMR spectrum for CMA. 2‐ethylhexyl methacrylate (EHMA), which is a well‐studied monomer providing a low glass transition temperature ( T g ), served as a comonomer to observe the influence of caffeine on thermomechanical properties . Conventional free radical copolymerization in dioxane of commercially available EHMA, CMA, and V‐501 as a radical initiator, as represented in Scheme , generated copolymers containing covalently bound caffeine.…”

Crosslinked polymer nanocapsules

“…As demonstrated by Jung et al , CPNCs with covalently immobilized surfactant moieties were obtained by crosslinking copolymerization of surfactants with the loaded monomers . Recently, Miksa and co‐workers synthesized CPNCs with reverse‐crosslinked poly[(2‐ethylhexyl methacrylate)‐ co ‐(7‐(4‐trifluoromethyl)coumarin acrylamide)] walls, with coumarin side groups that can undergo reversible photodimerization crosslinking ( λ > 310 nm) and cleavage ( λ < 250 nm) . Pinkhassik and co‐workers reported a simple and scalable method to create CPNCs by crosslinking radical polymerization of monomers loaded in liposome walls at near‐physiological temperatures (35–40 °C) for 1 to 2 h .…”

“…77 Recently, Miksa and co-workers synthesized CPNCs with reverse-crosslinked poly[(2-ethylhexyl methacrylate)-co-(7-(4-trifluoromethyl)coumarin acrylamide)] walls, with coumarin side groups that can undergo reversible photodimerization crosslinking ( > 310 nm) and cleavage ( < 250 nm). 91 Pinkhassik and co-workers reported a simple and scalable method to create CPNCs by crosslinking radical polymerization of monomers loaded in liposome walls at near-physiological temperatures (35-40 ∘ C) for 1 to 2 h. 92 Such mild crosslinking conditions may allow in situ encapsulation of sensitive cargoes for biomedical applications. They also studied the loading of hydrophobic monomer to the hydrophobic wall domains in the bilayer structure of liposome membranes, and their work suggested no considerable occurrence of fusion of liposomes during monomer loading.…”

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

“…Agarwal et al [253] synthesized micelledrug conjugates of {PEO-b-poly(n-butyl methacrylate-co-4-methyl-[7-(methacryloyl)-oxyethyloxy]coumarin)} by covalent bonding of anticancer drug 5-fluorouracil to the coumarin units under UV irradiation. Furthermore, Miksa et al [198] prepared nanocapsules for 5-fluorouracil delivery decorated with a poly(2-ethylhexyl methacrylateco-7-(4-trifluoromethyl)coumarin acrylamide) cross-linked wall which fulfilled the versatile strategy of release drug combining a long shelflife with the ability for rapid release using external factors such as light ( Figure 26). In this case a monomer of 2-ethyhexyl methacrylate was used as a "linactant" -line active molecule that reduce the line tension thereby modulating the lipid bilayer membrane texture [254][255][256][257].…”

“…Light is a useful trigger to manipulate ion channels externally, because does not change the chemical environment of the studied system. The synthetic molecules called "molecular photoswitches" e.g., photocaged small molecules like coumarin derivatives [198] or azobenzenes [199], spiropyranes [200], and malachite green leuconitriles [196] can change their structure and properties upon light irradiation. These dyes are often characterized by having two or more isomeric forms.…”