Nanoscopic vehicles that stably encapsulate drug molecules and release them in response to a specific trigger are of great interest due to implications in therapeutic applications, especially for cancer therapy. For this purpose, we have synthesized highly stable polymeric nanogels, in which the kinetics of guest molecule release can be fine-tuned by control over cross-linking density. The polymer nanogel precursor is based on a random copolymer that contains oligoethyleneglycol (OEG) and pyridyldisulfide (PDS) units as side-chain functionalities. By introducing variations into the precursor polymer, such as molecular weight and the relative percentages of hydrophilic OEG units and hydrophobic PDS functionalities, we have achieved significant control over nanogel size. We show that the noncovalently encapsulated guest molecules can be released in response to a redox trigger, glutathione (GSH). Stability of dye encapsulation inside the nanogels and tunability in the release of guest molecules have been demonstrated through in vitro fluorescence resonance energy transfer (FRET) experiments. We show in vitro doxorubicin delivery into breast cancer cells (MCF-7) with nanogels of different cross-linking density to demonstrate that it plays a key role in the stable encapsulation of hydrophobic drug molecules and the cell-uptake efficiencies.

The stability of encapsulation in self-assembly systems is limited during blood circulation because of a requisite concentration for assembly formation. For deliberate molecular design for stable encapsulation, targeting, and triggered release, we have developed a facile synthetic method for highly stable, polymeric nanogels using a simple intra/interchain cross-linking reaction. We show a simple, emulsion-free method for the preparation of biocompatible nanogels that provides the ability to encapsulate hydrophobic guest molecules and surface functionalization which has potential for targeted delivery. We show that the noncovalently encapsulated guest molecules can be released in response to a biologically relevant stimulus.

Exchange dynamics of lipophilic guest molecules, encapsulated in supramolecular nanoassemblies in aqueous solutions, have implications in evaluating the stability of drug delivery vehicle. This is because exchange dynamics is related to the propensity of a nanocarrier to be leaky. We describe a fluorescence resonance energy transfer (FRET) based method to evaluate guest exchange dynamics in the aqueous phase. We have utilized this method to analyze the stability of encapsulation in polymeric nanogels and other related amphiphilic nanoassemblies.

A facile methodology to prepare water-dispersible nanogels based on pentafluorophenyl acrylate and polyethylene glycol methacrylate random copolymer and diamine cross-linkers has been developed. Cross-linking reaction was characterized by FTIR and 19F NMR. We show that those nanogels : (i) are water-dispersible; (ii) can conveniently encapsulate lipophilic guest molecules; (iii) can be prepared with different nanosizes; (iv) are engineered to allow for surface decoration with additional functional groups.

Polymer-based nanoassemblies have emerged as viable platforms for the encapsulation and delivery of lipophilic molecules. Among the criteria that such carriers must meet, if they are to be effective, are the abilities to efficiently solubilize lipophilic guests within an assembled scaffold and to stably encapsulate the molecular cargo until desired release is achieved through the actions of appropriately chosen stimuli. The former feature, dictated by the inherent loading capacity of a nanocarrier, is well studied and it has been established that slight variations in assembly structure, such as introducing hydrophobic content, can improve miscibility with the lipophilic guests and increase the driving force for encapsulation. However, such clear correlations between assembly properties and the latter feature, nanocarrier encapsulation stability, are not yet established. For this purpose, we have investigated the effects of varying hydrophobic content on the loading parameters and encapsulation stabilities of self-crosslinked polymer nanogels. Through investigating this nanogel series, we have observed a fundamental relationship between nanoassembly structure, loading capacity and encapsulation stability. Furthermore, a combined analysis of data from different loading amounts suggests a model of loading-dependent encapsulation stability that underscores an important correlation between the principal features of noncovalent encapsulation in supramolecular hosts.