Multiple hydrogen-bonded supramolecular polymers tend to form stable spherical micelles with oppositely charged anticancer drugs in biological environments, which improves cellular drug uptake and more effectively induces apoptosis in cancer cells.

Functionalized amphiphilic polymers consisting of hydrophilic poly(ethylene glycol) pendant groups and a hydrophobic poly(epichlorohydrin) backbone can spontaneously self-organize into single-chain polymeric nanoparticles (SCPNs) in water, without exhibiting concentration-dependent effects or requiring additional reactive additives or subsequent purification. These SCPNs can effectively encapsulate the anticancer drug doxorubicin and have a high drug-loading capacity, desirable particle size distribution, and excellent drug-entrapment stability in serum-containing media or buffer solutions at various pH values; these unique physical and biological properties will be crucial to the achievement of smart drug delivery nanocarriers based on functional micelles. Cytotoxicity assays confirmed that the drug-loaded SCPNs were not cytotoxic toward normal cells but were significantly cytotoxic toward tumor cells under normal physiological conditions. Our results suggest that the drug-loaded SCPNs exert selective, targeted cytotoxic effects in cancer cells, without affecting healthy cells. Importantly, cellular uptake and flow cytometric assays confirmed that the drug-loaded SCPNs effectively targeted and entered the tumor cells via endocytosis and subsequently effectively promoted apoptotic cell death. Thus, this SCPN system has the ability to improve the overall therapeutic efficacy and safety of cancer chemotherapy.

Physically cross-linked supramolecular polymers composed of a hydrophobic poly­(epichlorohydrin) backbone with hydrogen-bonding cytosine pendant groups and hydrophilic poly­(ethylene glycol) (PEG) side chains spontaneously self-assemble to form highly controlled, reversible supramolecular polymer networks (SPNs) because of cytosine-induced transient cross-linking. Owing to their simple synthesis procedure and ease of tuning the cytosine and PEG contents to obtain varying degrees of SPNs within the polymer matrix, the resulting polymers exhibit a unique surface morphology, wide-range tunable mechanical/rheological properties, and surface wettability behavior as well as high biocompatibility and structural stability in normal cell- and red blood cell-rich media. Cell culture experiments and fluorescent images clearly demonstrated that the incorporation of cytosine and PEG units into the SPN-based polymer substrates efficiently promoted cellular attachment and accelerated cell growth. Importantly, scratch wound-healing assays revealed that the cytosine-functionalized substrates promoted rapid cell spreading and migration into the damaged cellular surface and accelerated the wound-healing rate. These results indicate that the presence of cytosine units within polymer substrates is crucial for the construction of multifunctional tissue engineering scaffolds with tailorable physical characteristics in order to promote cell adhesion, proliferation, and differentiation.

pH-Responsive hydrogen-bonded supramolecular micelles, composed of a water-soluble poly(ethylene glycol) polymer with two terminal sextuple hydrogen bonding groups, can spontaneously organize in aqueous media to give well-defined, uniformly sized spherical micelles. The supramolecular micelles exhibit a number of unique physical characteristics, such as interesting amphiphilic behavior, desirable micellar size and nanospherical morphology, excellent biocompatibility, tailorable drug-loading capacities, and high structural stability in media containing serum or red blood cells. In addition, the drug release kinetics of drug-loaded micelles can be easily manipulated to achieve the desired release profile by regulating the environmental pH, thus these micelles are highly attractive candidates as an intelligent drug carrier system for cancer therapy. Cytotoxicity assays showed that the drug-loaded micelles induced pH-dependent intracellular drug release and exerted strong antiproliferative and cytotoxic activities toward cancer cells. Importantly, cellular uptake and flow cytometric analyses confirmed that a mildly acidic intracellular environment significantly increased cellular internalization of the drug-loaded micelles and subsequent drug release in the cytoplasm and nucleus of cancer cells, resulting in more effective induction of apoptotic cell death. Thus, this system may provide an efficient route toward achieving the fundamental properties and practical realization of pHsensitive drug-delivery systems for chemotherapy.