Photosensitive Nano-drug Delivery For Controlled Release

In recent years there has been an increasing global interest in the formation of nanostructure polymeric materials based on their intriguing aggregation phenomena, long circulation time, as well as tremendous potential applications as the nano-carrier systems for various hydrophobic drugs. In most applications it is highly desirable to be able to control the release of encapsulated substances by triggering a change in nano-drug carriers properties via an external stimulus. recently much research effort has been focused on the issue of attempting to incorporate environmentally responsive moieties into polymer systems to render them susceptible to appropriate stimuli, such as temperature, pH, redox-potentials, the level of enzymes, light, and specific donor molecules.Among all applied stimuli, light stands out as a clean and noninvasive one and has been widely used as an external trigger in biological systems. As for the pH and oxidation responsive systems, for photo-responsive systems, the release of entrapped drugs in Nano-drug carriers can be rapidly induced at a specific location and time upon stimuli. Unlike the pH and oxidation responsive systems which require that the chemical environment be modified by the addition of acids or other reagents that may not compatible with the target site, light is an external stimulus that does not require any chemical environmental change.So that, our effort has been focused on the issue of attempting to incorporate light responsive moieties(2-nitro benzyl alcohol or 2-nitro ethanol) into polymer systems to render them susceptible to light, and two novel types of nano-drug carriers were designed.They are described as below:we designed two novel types of monomers 1-(2-nitrophenyl)ethyl methacrylate (NEMA, MA) and 2-(2-nitrophenyl)propyl methacrylate (NPMA, MB) which provide photoresponsive structured in NPs,and could be photoswitched from hydrophobic to hydrophilic environments by generating carboxylic acid upon UV light. Meanwhile, three novel types crosslinking agents, 2-nitrophenyl ethylene glycol dimethacrylate (CL1), 6-(2-nitrophenyl)-4,9-dioxo-5,8-dioxa-3,10–diazadodecane-1, 12 -diyl bis(2-methylacrylate) (CL2), and 10-(2-nitrophenyl) -8,13- dioxo-9, 12-dioxa-7,14-diazaicosane-1,20-diyl bis(2-methylacrylate) (CL3) were also incorporated to provide grafted structure in hydrophobic block which could also induce the hydrophobic- hydrophilic switch by generating carboxylic acid or amine upon UV light, respectively.Our approach entails a cross-linked nanoparticle (NPs) which, in its initial state, is hydrophobic but, upon UV, transforms to a hydrophilic structure, namely a hydrogel particle, which caused the release of encapsulants. The NPs (PMA/CLA,PMB/CLA and PMA/CLB) were prepared using MA or MB as monomer and EGDMA(CLA) or HDMA(CLB) as crosslinking reagent in inverse suspension. Without UV, the NPs are stable and do not release encapsulants. As they were exposed to UV, the protecting groups were cleaved, causing the desired hydrophobic to hydrophilic transformation. Nile Red (NR), a model hydrophobic guest molecule, was used for the studies of NPs formation and encapsulation. NR has high solubility and displays stronger fluorescence in the hydrophobic environment of copolymer micelles, while its fluorescence becomes much weaker when it is released into water due to its low solubility. To study the photo-controlled release of guest substances from NPs, fluorescence emission of NR at 609 nm was used to determine the efficiency of triggered release due to the dramatic change of fluorescence intensity of NR between inside NPs and outside NPs. When the monomer conversion rate was low (LNps), the fluorescence intensity of NR in LNps gradually decreased with UV irradiation and the intensity dropped to about 40-55% of its original value after 15 min photo irradiation. The fluorescence intensity continued to fall when the irradiate sample was stored at dark for another hour or longer, which was due to the large number of unreacted monomers. When it was exposed under UV, Nps mainly fused each other between the particles.When the monomer conversion rate was high, the fluorescence intensity of NR in NPs(PMA/CLA) gradually decreased with UV irradiation and the intensity dropped to about 85% of its original value after 600s UV irradiation, and for NPs (PMB/CLA) it dropped to about 90% after 450s UV irradiation. And NPs(PMB/CLA) was more photosensitive than NPs(PMA/CLA). The fluorescence intensity did not fall when the irradiate sample was stored at dark.Amphiphilic block copolymers can self-assemble to form colloidal size aggregates or micelles. Block copolymer aggregates, like small-molecule surfactants, can assume a range of different morphologies in dilute solution, including spheres, rods, vesicles, compound micelles, and others. In the past years, micelles prepared from block copolymers have been well investigated.we also designed and synthesized the new photocleavable cross-linkers (CL1, CL2 and CL3) for methyl methacrylate atom transfer radical polymerization (ATRP). Different ratios of the photocleavable cross-linker to methyl methacrylate monomer (MMA) were used and six series block copolymers (A0, A, B0, B, C, D) were synthesized with PEO2000-Br or PEO5000-Br as the macroinitiator. GPC and 1~H-NMR studies showed that linear polymer molecules could be cross-linked by the photocleavable linker. The fluorescence studies of the encapsulated Nile Red (NR) showed that there were lower critical micelle concentrations (CACs) for the polymer A, B and C than polymer A0 and B0. The capacity of formation the micelles will be increased as the growth of the hydrophobic block. And DLS and SEM confirmed the formation of polymer micelles. And the grafted structures in the core of micelles could improve the stability of micelles observably.Photolysis experiments demonstrated that NR encapsulated in the polymer micelles could be released upon UV irradiation (365 nm, 11 mW/cm~2) due to the breakage of the photocleavable linker and the generation of more hydrophilic acid or amino moieties, which destabilized polymer micelles. Obviously, when the polymer concentration was much lower than the CAC of polymers, there was no change of the fluorescence intensity which indicated that the micelles have not formed under the CAC and there was almost no NR loading capacity under this condition. However, when the concentration of polymers was higher than the CAC, the release of NR was clearly observed with the decrease of fluorescence intensity upon light irradiation. And the light sensitivity of series C is lower than series B, which is due to the hydrophilic of amino is lower than carboxyl. And a long length of hydrophobic block did not increase the photosensitivity of micelles. These studies showed a new strategy for the possibility of photo-controllable drug release for hydrophobic drugs, but not for drug like DOX which is both water-soluble oil-soluble.