Selective cell targeting and specific macromolecule interactions represent crucial points for the development of novel nanotherapeutics [1]. Cell responses are triggered by chemical ligands that bind to membrane receptors or to intracellular targets, activating signal transduction pathways within the cell [2]. The current approaches used to regulate nanomaterial targeting and cell response mainly rely on conjugating ligands (mostly antibodies, peptides, or saccharides) to the surface of the nanocarriers employed for the delivery of therapeutics. Nevertheless, these methods present well-known limitations in vivo, including immune recognition, off- targeting, poor selectivity, and response [3,4]. In light of these challenges, polymers with complex topology and specific functionalities can be obtained through precise synthesis and modification approaches [5]. These bioactive macromolecules can be employed as drug delivery tools able to ensure the desired curative effects on cells [6]. By varying the polymers structure, architecture and composition, the physicochemical and self-assembly properties of the nanocarriers can be tuned to obtain tailored size, drug loading and release profile, stabilization and targeting, according to the specific biomedical application [7–11].

In this work, a new design-by- architecture approach is presented to identify the key factors fundamental to reach efficient interactions between the synthesized macromolecules and target biological systems, and drug nanodelivery. These factors include independently adjustable architectural parameters, such as main poly- mer chain and side chain length, number of arms/branches, monomeric units selected and their molar ratios, bioactive moiety density and position. For the purpose, a library of amphiphilic copolymers based on poly(ε-caprolactone) (PCL) and poly(polyethylene glycol methacrylate) (PPEGMA) or poly(glycerol methacrylate) (PGMA), combined with poly(glycidyl methacrylate) (PgMA) was synthesized and subsequently functionalized via click- chemistry reactions with thiolate compounds [12].

The functionalized micelles were then encapsulated with various synthetic drugs (chemotherapic and epigenetic) and their cytotoxicity was assessed in in vitro test. The thiolate copolymers present appealing mucoadhesive properties resulting from their ability to form strong covalent bonds with cysteine-rich subdomains of mucus glycoproteins, by means of a disulfide-thiol exchange process [13].

Therefore, such interactions could ensure marked adhesion with mucosal tissues, leading to the development of novel drug delivery platforms with increased retention time and localized release via multiple administration routes (as through the gastrointestinal tract) [13,14]. The obtained nanoassemblies could be further stabilized owing to the internal formation of disulfide bridges [15]. This work aims at understanding how the characteristics of micelles and drug loading performance vary depending on the polymer structure, composition, and the specific drug to deliver. In vitro tests may allow to select the best polymer characteristics for achieving the desired cellular responses and an optimal therapeutic delivery to the target site.

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