Optimization of Amphiphilic Miktoarm Star Copolymers for Anticancer Drug Delivery

Abstract

The preparation of various types of miktoarm star polymers with precisely controlled structures (A2B, ABC, AB2C2, etc.) has made significant progress due to the considerable advances in the synthetic strategies, including multistep protections/deprotections, orthogonality, and integration of different polymerization techniques. However, compared to the well-developed synthesis methodologies, the investigations on miktoarm star copolymers as drug delivery vehicles remain relatively unexplored, especially for the relationship of their branched structures and properties as drug delivery systems. To elucidate this structure–property relationship of amphiphilic miktoarm star polymers, we prepared four different amphiphilic miktoarm star copolymers with the respectively identical molecular weights (MWs) of hydrophilic and hydrophobic moieties but different star structures using heteroinitiators that were synthesized by protection/deprotection strategies for integrated ring-opening polymerization of hydrophobic ε-caprolactone and atom transfer radical polymerization of hydrophilic oligo (ethylene glycol) monomethyl ether methacrylate (OEGMA). Further screening of an optimal formulation for anticancer drug delivery by the stability of micelles, in vitro drug loading capacity, drug release properties, cellular uptake efficacy, and cytotoxicity of doxorubicin (DOX)-loaded micelles showed that PCL3POEGMA1 micelles possessed the lowest critical micelle concentration, the highest drug loading content, and enhanced therapeutic efficiency for DOX release of all the synthesized four star copolymer constructs. This study thus provides preliminary guidelines and rationalities for the construction of amphiphilic miktoarm star polymers toward enhanced anticancer drug delivery.

Miktoarm Star Polymers: Branched Architectures in Drug Delivery

“…The miktoarm polymers were found to have no significant cytotoxicities, could be self-assembled into micelles, and were able to efficiently encapsulate and deliver doxorubicin (DOX) to cells. Interestingly, the most hydrophobic PCL 3 POEGMA derived micelles had the lowest CMC, the highest DOX encapsulation efficiency, and the best therapeutic efficiency for DOX release [ 70 ].…”

“…Rather than strictly increasing hydrophobic block sizes, one study attempted to change the ratio of hydrophilic and hydrophobic segments through four different A 2 B, A 2 B 2 , AB 3 , and A 3 B (A = PCL, B = POEGMA) miktoarm star polymers [ 70 ]. It was found that increasing the number of PCL arms to POEGMA resulted in the largest increase in micelle stability, with a minimum CMC of 2.66 mg/L for the A 3 B miktoarm star.…”

“…Micellar drug retention has generally been associated with more sustained drug release and dampening burst release [ 32 , 48 , 55 , 70 ], which has the benefit of increasing drug bioavailability. This could be the result of strong interactions and more sites of association between the encapsulated drug and multiple hydrophobic chains [ 27 , 52 , 70 , 133 ]. In a study of A(AB) 3 , A 2 (AB) 2 , and A 3 (AB) (A = PEG, B = PCL) miktoarm stars, camptothecin loading percentages ranged from 3.6 to 10.8%, with higher loadings in assemblies of miktoarm stars with more PCL blocks [ 57 ].…”

Preparation of Doxorubicin-Loaded Amphiphilic Poly(D,L-Lactide-Co-Glycolide)-b-Poly(N-Acryloylmorpholine) AB2 Miktoarm Star Block Copolymers for Anticancer Drug Delivery

“…The miktoarm-block copolymers demonstrate exclusive phase-separation behavior either in solution or in bulk compared with linear-block copolymers due to the organization of the polymers, in which two constructional blocks are connected to a distinct confluence point [ 8 , 9 , 10 , 11 ]. This ability imparts miktoarm-block copolymers with wide potentials for use as nanocarriers of drugs compared with corresponding linear-block copolymers [ 12 , 13 , 14 , 15 , 16 ]. The synthesis of AB 2 miktoarm-block copolymers is mostly practicable with a classification of different polymerization methods.…”

Tunable thermoresponsive β‐cyclodextrin‐based star polymers

“…Many examples of this strategy exist in the context of cancer therapy. [29][30][31][32] Aside from the unique inherent properties of star polymers, a stimuli-responsive character can be embedded in them as well. Various stimuli such as light, 33 pH (used in our previous work) 14 and heat 34 can be used (and combined 35 ) as triggers to induce a specific response from the star polymer.…”