Reversibly crosslinked nanocarriers for on-demand drug delivery in cancer treatment

Abstract

Polymer micelles have proven to be one of the most versatile nanocarriers for anticancer drug delivery. However, the in vitro and in vivo stability of micelles remains a challenge due to the dynamic nature of these self-assembled systems, which leads to premature drug release and nonspecific biodistribution in vivo. Recently, reversibly crosslinked micelles have been developed to provide solutions to stabilize nanocarriers in blood circulation. Increased stability allows nanoparticles to accumulate at tumor sites efficiently via passive and/or active tumor targeting, while cleavage of the micelle crosslinkages, through internal or external stimuli, facilitates on-demand drug release. In this review, various crosslinking chemistries as well as the choices for reversible linkages in these nanocarriers will be introduced. Then, the development of reversibly crosslinked micelles for on-demand drug release in response to single or dual stimuli in the tumor microenvironment is discussed, for example, acidic pH, reducing microenvironment, enzymatic microenvironment, photoirradiation and the administration of competitive reagents postmicelle delivery.

Figure 1. Chemistries used in form of core crosslinked micelles

(A) Micelles with crosslinked ionic cores; (B) core-crosslinked micelles containing near-IR fluorescent dyes; (C) polyphosphoester-core-crosslinked nanogel; (D) acid-labile-core-crosslinked micelles; (E) UV-induced core-crosslinked micelles; (F) cinnamoyl-based core-crosslinked micelles; (G) core-crosslinked micelles via click chemistry; and (H) micelles with a disulfidecrosslinked core. (A) Data from [87]; (B) Data from [88]; (C) Data from [72]; (D) Data from [41]; (E) Data from [69]; (F) Data from [63]; (G) Data from [89]; (H) Data from [81].

Figure 2. Reaction strategies of shell-crosslinked micelles

(A) Shell-crosslinked micelles via acid-catalyzed sol-gel process; (B) shell-crosslinked micelles using diamine as linker; (C) shell click-crosslinked nanoparticles; (D) reversible-shell-crosslinked micelles; (E) crosslinking through the styrenyl side chains; (F) shell crosslinking via RAFT method; and (G) reduction-sensitive shell-crosslinked micelles. (A) Data from [93]; (B) Data from [94]; (C) Data from [73]; (D&G) Data from [95]; (E) Data from [90]; (F) Data from [96].

Figure 3. Intermediate layer crosslinked micelles

(A) Micelles formed by pH-responsive triblock copolymer; (B) crosslinked micelles via one-pot synthesis method; and (C) reversible-boronate-crosslinked micelles. (A) Data from [97]; (B) Data from [98]; (C) Data from [28].

Figure 4. Structure and functionalization of telodendrimer

DCM: Dichloromethane; TFA: Trifluoroacetic acid.

Figure 5

Boronic acid and catechol-containing telodendrimer and the crosslinking and decrosslinking of reversible-boronate-crosslinked micelles for paclitaxel delivery.