Abstract
Polymeric nanomaterials that degrade in acidic environments have gained considerable attention in nanomedicine for intracellular drug delivery and cancer therapy. Among various acid-degradable linkages, spirocyclic acetals have rarely been used to fabricate such vehicles. In addition to acid sensitivity, they benefit from conformational rigidity that is otherwise not attainable by their non-spirocyclic analogs. Herein, amphiphilic spirocyclic polyacetals are synthesized by Cu-catalyzed alkyne–azide “click” polymerization. Unlike conventional block copolymers, which often form core–shell structures, these polymers self-assemble to form core amphiphilic assemblies capable of encapsulating Nile red as a hydrophobic model drug. In vitro experiments show that while release from these materials can occur at neutral pH with preservation of their integrity, acidic pH accelerates efficient cargo release and leads to the complete degradation of assemblies. Moreover, cellular assays reveal that these materials are fully cytocompatible, interact with the plasma membrane, and can be internalized by cells, rendering them as potential candidates for cancer therapy and/or drug delivery.
Highlights
Drug delivery systems are a necessity nowadays due to the limitations of most drugs, which often include low water solubility, high toxicity, low metabolic stability, and poor bioavailability
Owing to the rigidity and hydrophobicity of the spirocyclic linkages, we demonstrate that these polymers undergo self-assembly to form core-amphiphilic spherical large-compound micelles (LCM) [8] capable of encapsulating the hydrophobic dye Nile red, used as a model drug
To construct our target polymers via CuAAC “click” polymerization, we envisioned the synthesis of dialkyne-decorated spirocyclic acetal and diazide-functionalized poly(ethylene glycol) (PEG)
Summary
Drug delivery systems are a necessity nowadays due to the limitations of most drugs, which often include low water solubility, high toxicity, low metabolic stability, and poor bioavailability. This, coupled with the ability to self-assemble amphiphilic polymers to nano-sized materials with a variety of morphologies, including spherical micelles and vesicles, one-dimensional worms and cylinders as well as toroids, has rendered polymer-based nanomaterials promising candidates for applications in nanomedicine [8,9] This includes their use as carriers for hydrophilic and hydrophobic small molecules, proteins, polynucleotides, and imaging contrast agents [10,11]. Materials responsive to almost every conceivable stimulus, including temperature, light, mechanical force, pH, and electron transfer (oxidation−reduction) have been developed [12,13,14] Among these triggers, a change in the acidity, i.e., pH, is interesting for developing responsive/degradable nanomaterials. This is because, when it comes to the delivery of any drug, the pH change from
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