Supramolecular block copolymers as novel UV and NIR responsive nanocarriers based on a photolabile coumarin unit

Highlights

• A versatile supramolecular approach to coumarin-containing block copolymers is described.

• Encapsulation and UV and NIR photorelease properties of polymeric micelles has been studied.

• Light response of supramolecular nanocarriers is similar to covalent materials.

Abstract

A new series of amphiphilic block copolymers has been prepared by ring opening polymerization (ROP) of cyclic carbonates using PEG as initiator. The light responsive unit [7–(diethylaminocoumarin)–4–yl]methyl ester has been introduced by a modular and versatile supramolecular approach, while a reference covalent copolymer has been synthesized for the shake of comparison. Synthesized copolymers showed monomodal narrow distributions and were able to self-assemble into spherical micelles when dispersed in water. UV irradiation allowed us the modification of the self-assemblies morphology, as proved by means of fluorescence spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). Both the supramolecular and covalent functionalized block copolymers were able to encapsulate small fluorescent probes as payload and to release them upon UV and NIR irradiation.

Introduction

Polymeric nanoparticles have been considered attractive nanocarriers for regulated release of drugs as a way to overcome toxicity and solubility issues associated with high drug dosages, and improval of target selectivity by modifying the surface of the carrier for directed delivery [1], [2], [3], [4], [5], [6]. Amongst several possibilities, polymer micelles usually formed by spontaneous assembly of amphiphilic block copolymers (BCs) in water have appeared particularly attractive to encapsulate and transport small hydrophobic drugs for biomedical purposes. One of the reasons is that, due to their small size (usually < 100 nm), polymer micelles might accumulate at tumors sites through passive targeting by the enhanced permeation and retention (EPR) effect [7], [8]. Besides, their size, stability or drug loading ability can be tuned by changing structural parameters such as the chemical nature and length of the polymeric segments [3], [9] that in turn can be precisely adjusted combining controlled polymerizations techniques with postpolymerization modification strategies [10], [11].

Performance of the polymeric micelles can be enhanced by incorporating sensitive units in the nanoparticle (to pH, temperature, light or to a chemical) so externally regulated delivery of the drug can be realized. Light is a rapid, noninvasive, and clean stimulus that can be spatially and temporally controlled. By introducing a photosensitive unit as a pendant substituent of the hydrophobic block, light action has been used to induced the destabilization of the micellar assemblies and the concurrent release of any encapsulated active [12], [13], [14], [15], [16]. A variety of light responsive units have been tested for this purpose including azobenzenes, spiropyrans, o–nitrobenzyl esters or coumarin esters [17], [18], [19], [20], [21], [22]. In most of these cases, release is activated with UV light but to avoid the phototoxicity effects of UV exposure and increase penetration depth in tissues, near infrared (NIR) stimulation is preferred for biomedical applications [23], [24]. Thus, the organic units 2–diazonaphtoquinone (DNQ) [25], [26] and o–nitrobenzyl esters [27] have been integrated in micellar systems to release hydrophobic cargoes under NIR (via two-photon absorption) light stimulation. Because of its large two–photon absorption cross section, amphiphilic BCs with the [7–(diethyaminocoumarin)–4–yl]methyl ester moiety have also been investigated [28], [29]. Micelles formed by amphiphilic BC of poly(ethylene glycol) and a coumarin polymethacrylate were able to release a fluorescent probe under NIR light induced cleavage of the coumarin ester [28]. Also BCs containing a coumarin functionalized polypeptide have shown to enable NIR light release of Rifampicin and Paclitaxel [29].

To engineer stimuli-responsive polymers, different postpolymerization modification chemistries have been proposed [30], [31], [32]. In this context, noncovalent postpolymerization modifications to incorporate lateral functionalities are interesting approaches as they allow great versatility at minimum synthetic cost [33], [34], [35]. Hydrogen bond mediated side chain functionalization is of particular relevance due to its strength and directionality, specially when multiple hydrogen bonds are formed together. Highly specific interactions between nucleobases or analogues pairs with complementary hydrogen bond have been exploited to adjust the properties of supramolecular polymers and their self–assembly abilities [36]. Inspired by the work of Rotello and co–workers with the 2,6–diacylaminopyridine/thymine pair (DAP/T) [37], we recently described the light induced release ability of assemblies of supramolecular amphiphilic block copolymers [17]. The polymers were formed by a poly(ethylene glycol) hydrophilic segment and a polymethacrylate hydrophobic segment with pendant 2,6–diacylaminopyridine units to which a thymine 4–isobutyloxyazobenzene was grafted through a triple H–bond. The self–assemblies were used to load and trigger the delivery of small fluorescent molecules under UV light stimulation.

In an extension of this approach, here we report on a series of light–responsive BCs consisting of a degreadable aliphatic polycarbonate hydrophobic blocks that can be functionalized with UV/NIR–cleavable coumarins either by covalent or noncovalent approaches. Aliphatic polycarbonates show low toxicity, biotoxicity, biocompatibility and biodegradability. Besides, they are readily affordable by ring opening polymerization (ROP) of cyclic carbonate monomers with pendant alkyne and alkene functional groups, which allows to introduce additional functionalities [38], [39], [40], [41], [42], i.e. by thiol–ene [43], [44], [45] or Cu(I) catalyzed azide–alkyne cycloaddition (CuAAC) chemistries [46], [47].

Directed by the above mentioned issues, the objective of the present work was the fabrication of NIR light triggered drug delivery systems from supramolecular degradable amphiphilic BCs focussing on the [7–(diethyaminocoumarin)–4–yl]methyl ester NIR sensitive group, previously validated by Zhao and co–workers [28], [29]. To circumvent tedious synthesis of coumarin monomers and to avoid the use of metallic catalysts, we devised a modular synthetic approach where the lateral anchoring of the light responsive coumarin by H–bond recognition using the DAP/T motif (Fig. 1). For this purpose, we combined the organocatalyzed ROP of a cyclic allyl carbonate with two sequential postpolymerization modification steps: (i) the covalent integration of the DAP nucleobase analogue by thiol–ene reaction, (ii) the noncovalent integration by H–bond of the light responsive coumarin with a thymine unit. Besides, a covalent model was prepared for comparative purposes using an alternative synthetic pathway (Fig. 1) based on our experience on lateral functionalization using CuAAC chemistry [48], [49].