Miktoarm Star Polymers: Branched Architectures in Drug Delivery

Abstract

Delivering active pharmaceutical agents to disease sites using soft polymeric nanoparticles continues to be a topical area of research. It is becoming increasingly evident that the composition of amphiphilic macromolecules plays a significant role in developing efficient nanoformulations. Branched architectures with asymmetric polymeric arms emanating from a central core junction have provided a pivotal venue to tailor their key parameters. The build-up of miktoarm stars offers vast polymer arm tunability, aiding in the development of macromolecules with adjustable properties, and allows facile inclusion of endogenous stimulus-responsive entities. Miktoarm star-based micelles have been demonstrated to exhibit denser coronae, very low critical micelle concentrations, high drug loading contents, and sustained drug release profiles. With significant advances in chemical methodologies, synthetic articulation of miktoarm polymer architecture, and determination of their structure-property relationships, are now becoming streamlined. This is helping advance their implementation into formulating efficient therapeutic interventions. This review brings into focus the important discoveries in the syntheses of miktoarm stars of varied compositions, their aqueous self-assembly, and contributions their formulations are making in advancing the field of drug delivery.

Keywords: drug delivery; heteroarm star polymers; macromolecules; micelles; miktoarm polymers; nanoformulations; self-assembly; soft nanoparticles; synthesis.

Figure 1

Miktoarm polymer architectures of varied compositions.

Figure 2

Examples of core-first synthesis (left) and arm-first synthesis (right) with examples of functionalities, monomers, and polymers.

Scheme 1

Development of an ABC miktoarm polymer based on polyisoprene (PI), polystyrene (PS), and polybutadiene (PB), using the chlorosilane method.

Scheme 2

Core-first synthesis of an ABC miktoarm polymer (A = PCL, B = PS, C = PtBA) from a multifunctional core, using varied polymerization techniques.

Scheme 3

Core-first synthesis of an AB₂ miktoarm polymer (A = PLLA, B = PNAM) from a multifunctional core using ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT).

Scheme 4

Synthesis of an ABC (A = PEG, B = PNIPAM, C = PDEAEMA) miktoarm star polymer using sequential arm-first (Steglich esterification, CuAAC “click” coupling) and core-first (core-initiated ATRP—atom transfer radical polymerization) methods.

Scheme 5

In-out synthesis of A_xB_y (A = PCL, B = PS) core-crosslinked star (CCS) polymers and their subsequent alkaline hydrolysis.

Figure 3

Schematic representation of PEG-PHLG CCS polymer synthesis using an in-out methodology. Reprinted with permission from reference [61]. Copyright 2016 Royal Society of Chemistry.

Figure 4

Aqueous self-assembly of AB₂ miktoarm polymers into micelles and polymersomes, depending on polymer hydrophilic fraction (red = hydrophobic, blue = hydrophilic).

Figure 5

Cartoon schematic (left) and comparative TEM micrograph (right) of a polymersome assembled from a PEG-PHis₂ miktoarm star polymer with emphasis on its hydrophobic bilayer. Reprinted with permission from reference [43]. Copyright 2012 Royal Society of Chemistry.

Figure 6

Fluorescent micrographs of macrophages treated with (A) curcumin-loaded PEG-PCL-TIF micelles, (B) unloaded PEG-PCL-TIF micelles, and (C) TIF control. Relative fluorescence intensities of macrophages treated with control media, TIF-loaded PEG-PCL micelles, curcumin-loaded PEG-PCL-TIF micelles, unloaded PEG-PCL-TIF micelles, free TIF, and free curcumin as a function of (D) treatment time and (E) dose concentration. Scale bar = 20 μm, inset scale bar = 10 μm. Statistically significant differences are represented by ** (p < 0.01), and *** (p < 0.001). Reprinted with permission from reference [49]. Copyright 2014 John Wiley and Sons.

Figure 7

Representation of PEG-PAA-PCL miktoarm polymer self-assembly and pH-responsive morphological changes.

Figure 8

Schematic representation of the effect of (a) physiological pH and (b) acidic pH on the morphology of self-assembled PEG-PCL-P2VP micelles. Reprinted with permission from reference [29]. Copyright 2012 Elsevier.

Figure 9

Schematic illustration of the micellar self-assembly of (BA)(AC)₂ miktoarm star polymers. Reprinted with permission from reference [65]. Copyright 2016 John Wiley and Sons.

Figure 10

(a) Scheme of A(AB)₃ (P140, P160), A₂(AB)₂ (P240), and A₃(AB) (P340) assembly into micelles, their response to GSH, (b) their size distributions from DLS, and (c) a representative TEM micrograph of A₂(AB)₂ (P240) micelles. Reprinted with permission from reference [57]. Copyright 2015 Royal Society of Chemistry.

Scheme 6

Structure and ¹O₂-response of PEG-PCL₂ miktoarm star polymers with β-aminoacrylate junctions to 660 nm light in the presence of Ce6.

Figure 11

Self-assembly and dual UV/temperature response of PEG-PNBM-PNIPAM miktoarm star polymers. Reprinted with permission from reference [66]. Copyright 2017 Elsevier.

Figure 12

Representation of (a) temperature and UV-induced morphological response of PAzo-PDEAA₃ micelles and (b) the corresponding proposed Nile Red release. Reprinted with permission from reference [46]. Copyright 2013 Royal Society of Chemistry.

Figure 13

Independent release of anionic FITC-dextran and cationic rhodamine B from PEG-qPDMAEMA₄ micelle/tannic acid-derived microcapsule cores and shells. Reprinted with permission from reference [64]. Copyright 2014 American Chemical Society.