Polycarboxybetaine in advanced drug delivery systems: From structure-function relationship to therapeutic applications

Abstract

Zwitterionic polycarboxybetaines (PCBs), combining quaternary ammonium cations and carboxylate anions in their repeating units, have emerged as promising materials for drug delivery applications. Their exceptional hydration, biocompatibility, and antifouling properties make them attractive alternatives to polyethylene glycol (PEG), particularly given growing concerns about immunogenicity of PEG. PCBs can be functionalized through various methods, including modification of side-chain moieties, adjustment of spacer length between charged groups, and incorporation of responsive elements. When applied to delivery drug, PCBs have been successfully developed into multiple formats including micelles, hydrogels, liposomes, and nanoparticles. Notably, in protein drug delivery, PCBs demonstrate significant advantages such as enhancing protein stability, extending circulation time, improving penetration through biological barriers, and reducing immunogenicity. Despite these promising features, several challenges remain, including complex synthesis requirements, limited mechanical properties, and pending FDA approval as pharmaceutical excipients. This review provides a comprehensive analysis of PCBs from the structure-function relationship, synthesis methods, and applications in drug delivery systems, while examining current limitations and future prospects.

Keywords: Antifouling; Drug delivery systems; Hydration; Polycarboxybetaine.

Graphical abstract

Fig. 1

Chemical structure of CBs. Left: Two most common forms of PCBs: poly(carboxybetaine methacrylate) (PCBMA)and poly(carboxybetaine acrylamide) (PCBAA). The spacer between amine and the methacrylate group of carboxybetaine methacrylate can be functionalized to derive PCB analogs. Middle: CBs cross-linker including CBMA cross-linker (CBMAX) and CBAA cross-linker (CBAAX) is used for the preparation of zwitterionic hydrogel. Right: Further functionalization can be realized through esterification or amidation of the carboxyl group.

Fig. 2

SFG spectra of pCBAA1, pCBAA2, and pSBMA in water (Leng et al., 2016). Copyright 2016, adapted with permission from Leng et al. under the Creative Commons Attribution-Non Commercial License.

Fig. 3

Milestones for the study of PCBs.

Fig. 4

Two PCB arms were grown from an initiator with two catechol groups via atom transfer radical polymerization (Gao et al., 2010). Copyright 2010, adapted with permission from Gao et al. under the Creative Commons Attribution-Non Commercial License.

Fig. 5

Schematic diagram of the BBB penetration of BCPB-F and BCPB (Wang et al., 2022). Copyright 2022, adapted with permission from Wang et al. under the Creative Commons Attribution-Non Commercial License.

Fig. 6

Ultra-low-CMC micelles and their unusual ability to stabilize cargoes in extremely diluted conditions with micelle concentrations far below the CMC of common micelles (Lu et al., 2018). Copyright 2018, adapted with permission from Lu et al. under the Creative Commons Attribution-Non Commercial License.

Fig. 7

Schematic diagram of DSPE-PCB lipoplexes for siRNA delivery with enhanced siRNA endosomal/lysosomal escape ability. (a) Resistant nonspecific protein adsorption. (b) Cellular endocytosis. (c) Protonation of DSPE-PCB in endosomes/lysosomes. (d) mRNA Cleavage (Li et al., 2014). Copyright 2014, adapted with permission from Li et al. under the Creative Commons Attribution-Non Commercial License.

Fig. 8

Stability of PEG, PCB M_n (similar molecular weight) and PCB R_h (similar hydrodynamic size) conjugated with enzyme CT. (a) Activity of conjugates after 8 h incubation in 5 M urea. (b,c) Relative activity of PEG and PCB Mn conjugates (b) and PEG and PCB R_h conjugates (c) after 10 min incubation at different temperatures (Keefe and Jiang, 2012). Copyright 2012, adapted with permission from Keefe and Jiang under the Creative Commons Attribution-Non Commercial License.

Fig. 9

The effect of PCB on the protein drugs.

Fig. 10

Encapsulation of Uricase in Zwitterionic PCB Nanocages for Enhanced Immunologic Protection and Gout Treatment Efficacy. (A) Encapsulation of uricase with zwitterionic PCB NC. (B) Schematic illustration of the sequence of events after native uricase, PEGylated uricase, and uricase encapsulated by PCB NC enter the blood stream. Both antiuricase and anti-PEG antibodies are produced after multiple injections of PEG-uricase conjugate, leading to the loss of efficacy in gout treatment. PCB NC shields uricase from immune recognition and produces no antipolymer or antiuricase antibodies, leading to enhanced pharmacokinetics and improved efficacy in gout treatment (Li et al., 2018c). Copyright 2018, adapted with permission from Li et al. under the Creative Commons Attribution-Non Commercial License.