Bioinspired Membrane-Disruptive Macromolecules as Drug-Free Therapeutics

Abstract

Membrane-disruptive, drug-free macromolecular therapeutics may help overcome cancer drug-resistance. Their inability to distinguish cancerous from normal cells, however, results in significant off-target toxicity. Note that the tumor has a slightly acidic microenvironment (pH 6.5–6.8) in contrast to the alkaline microenvironment in normal tissues (pH 7.4) and that host-defense peptides (HDPs) and their synthetic mimetics need to be net cationic to be membrane-disruptive. We herein endow polymer mimetics of HDPs with acid-triggered cationicity, to make them membrane-disruptive at only tumor pH. For these polymer mimetics, there exists a maximal threshold of chain length that determines whether the micelle of a mimetic inherits its pH-sensitive activity. Using the most and least active micelles as representatives, we find that their distinct potency in disrupting membranes arises because of their striking tendency to dissociate upon exposure to tumor pH. As expected, these micelles exhibit in vitro cytotoxicity profiles that correlate with their membrane-disruptive activity profiles. When administered intravenously, these micellesirrespective of their distinct activity profilesunanimously exhibit long systemic circulation as do PEGylated micelle nanoparticles, despite of their lacking stealth materials, owing to the zwitterionic nature of their surfaces at blood pH. Nevertheless, the pH-sensitive micelle achieves significantly higher tumor uptake and strikingly better therapeutic efficacy than its completely inactive analogue. More important, the pH-sensitive micelle exhibits undetectable off-target toxicity, owing to its pH-sensitivity. Clearly, making HDPs and their mimetics sensitive to tumor-characteristic cues (e.g., acidic pH) is efficient in minimizing their off-target toxicity, thereby offering membrane-disruptive, drug-free macromolecular therapeutics for fighting against cancer drug-resistance.

Bioactive Synthetic Polymers

“…Yang and co‐workers utilized ternary random copolymers capable of undergoing pH‐dependent disassembly as a means to minimize off‐target toxicity. [ 109 ] The polymers consisted of hydrophobic hexyl methacrylate as a hydrophobic monomer with methacrylic acid and dimethylaminoethyl methacrylate as conditionally anionic and cationic monomers, respectively (Figure 12b). The compositions of the two ionic monomers were set at 30%, garnering neutral to slightly anionic polymers at pH 7.4 but switching to cationic at pH 6.8.…”

“…Targeting cancer cells via concealment of active polymers. a) A zwitterionic polypeptide presenting negligible cytotoxicity at pH 7.4 is deprotected into the cytotoxic cationic anticancer polypeptide under intratumor (pH 6.8) conditions; [108] b) nanoprecipitated particle undergoes dissolution into ternary random copolymers presenting a net cationic charge under acidic conditions (pH 6.8); [109] and c) a hydrophobic cationic block residing in the core of a micelle is released in a tumor environment by way of a pH-sensitive linker. [110] was confirmed through scanning electron microscopy, which showed abnormalities, such as budding and pore formation in comparison to the smooth intact surfaces of untreated cells.…”

Membrane Stabilization of Poly(ethylene glycol)-b-polypeptide-g-trehalose Assists Cryopreservation of Red Blood Cells

“…In addition, a cationic polymer with high membrane-disruptive activity exhibited membrane-targeting cytotoxicity profiles. 55 Thus, the suitable balance of cationic charge and hydrophobicity with low toxicity to normal cells was obtained. 45 Cryopreservation of RBCs.…”

“…It may be due to the content of amino groups with a cationic charge in glycopeptides that was reduced after glycosylation of trehalose. In addition, a cationic polymer with high membrane-disruptive activity exhibited membrane-targeting cytotoxicity profiles . Thus, the suitable balance of cationic charge and hydrophobicity with low toxicity to normal cells was obtained …”

Cancer-microenvironment triggered self-assembling therapy with molecular blocks

“…13 It is also expected that the membrane disruptive mechanism would be applicable to any type of cancer cells, even drug-resistant cancers, because of the simple physical effects. 14,15 Overall, cancer microenvironment-targeting therapy using MBs could overcome the issues of using conventional pharmacotherapy.…”