Poly Ethylene Glycol (PEG)-Based Hydrogels for Drug Delivery in Cancer Therapy: A Comprehensive Review

Abstract

Hydrogel-based drug delivery systems (DDSs) can leverage therapeutically beneficial outcomes in cancer therapy. In this domain, polyethylene glycol (PEG) has become increasingly popular as a biomedical polymer and has found clinical use. Owing to their excellent biocompatibility, facile modifiability, and high drug encapsulation rate, PEG hydrogels have shown great promise as drug delivery platforms. Here, the progress in emerging novel designs of PEG-hydrogels as DDSs for anti-cancer therapy is reviewed and discussed, focusing on underpinning multiscale release mechanisms categorized under stimuli-responsive and non-responsive drug release. The responsive drug delivery approaches are discussed, and the underpinning release mechanisms are elucidated, covering the systems functioning based on either exogenous stimuli-response, such as photo- and magnetic-sensitive PEG hydrogels, or endogenous stimuli-response, such as enzyme-, pH-, reduction-, and temperature-sensitive PEG hydrogels. Special attention is paid to the commercial potential of PEG-based hydrogels in cancer therapy, highlighting the limitations that need to be addressed in future research for their clinical translation.

Keywords: PEG; cancer; drug delivery system; hydrogels; stimuli-responsiveness.

Figure 1

PEG‐based drug delivery systems for cancer treatment.

Figure 2

PEG‐hydrogel gradually degrades and releases the entrapped micelles under the existence of MMP enzyme. Reproduced with permission.^{[ 32 ]} Copyright 2020, American Chemical Society.

Figure 3

Nonmagnetic hypertonic saline‐based PEG‐hydrogel achieves both magnetic hyperthermia and pH‐sensitive chemotherapy in the MCF‐7 tumor‐bearing mice model. Reproduced with permission.^{[ 43 ]} Copyright 2019, American Chemical Society.

Figure 4

Illustration of the dual responsive strategies. This drug delivery system shows both redox and pH responsiveness. The PEG shell can break down under a weak acidic environment (pH 6.5), and then the drug is released under the presence of glutathione (GSH).

Figure 5

a) In situ oxygen‐ and heat‐generating anti‐cancer hydrogel.^{[ 60 ]} Reproduced with permission.^{[ 60 ]} Copyright 2019, Elsevier. b) NIR light‐responsive heat‐emitting biodegradable hydrogel. Reproduced with permission.^{[ 61 ]} Copyright 2019, Elsevier. c) Sprayable PTT PEG‐hydrogel for postsurgical treatment of cancer. Reproduced with permission under the terms of the Creative Commons license.^{[ 62 ]} Copyright 2018, the Authors. Published by Wiley‐VCH GmbH.

Figure 6

a) A dose‐adjustable in situ hydrogel platform based on PEG‐gold nanorods. Reproduced with permission.^{[ 63 ]} Copyright 2018, Elsevier. b) Nanosheet‐knotted injectable PEG‐hydrogels. Reproduced with permission.^{[ 64 ]} Copyright 2020, Royal Society of Chemistry. c) Injectable dual‐functional PEG‐hydrogel used for both PTT and chemotherapy. Reproduced with permission.^{[ 65 ]} Copyright 2018, Elsevier. d) PTT hydrogel and a pH‐triggered drug release system for the treatment of cancer. Reproduced with permission.^{[ 66 ]} Copyright 2017, Elsevier.

Figure 7

Typical diphase diagrams of polymer solutions with a) UCST and b) LCST properties.

Figure 8

Six main strategies utilized for the application of thermal responsive PEG‐hydrogel in cancer therapy.

Figure 9

Thermal responsive PEG‐hydrogel with controlled drug release property. a) A temperature‐sensitive PEG‐hydrogel to pH‐dependently release DDP. Reproduced with permission.^{[ 87 ]} Copyright 2017, Royal Society of Chemistry. b) A pH‐triggered degradable magnetite PEG‐hydrogel with high encapsulation and DOX release efficiencies. Reproduced with permission.^{[ 42 ]} Copyright 2018, Wiley Periodicals LLC. c) A pH‐sensitive therapeutic protein delivery system. Reproduced with permission.^{[ 88 ]} Copyright 2018, Royal Society of Chemistry. d) An injectable thermosensitive PEG‐thermogel with pH‐triggered cleavage property. Reproduced with permission.^{[ 89 ]} Copyright 2018, Elsevier. e) A dual stimuli‐responsive injectable hydrogel delivery system. Reproduced with permission.^{[ 90 ]} Copyright 2018, Elsevier.

Figure 10

a,b) A drug delivery system based on PEG hydrogel capable of monitoring the therapeutic process. Reproduced with permission.^{[ 99} , ^{100 ]} Copyright 2014, Elsevier, Copyright 2018, Elsevier. c) A positively charged thermo‐gel with easier endocytosis ability. Reproduced with permission.^{[ 101 ]} Copyright 2020, Royal Society of Chemistry. d) Thermo‐responsive PEG‐hydrogel for DNA delivery. Reproduced with permission.^{[ 102 ]} Copyright 2016, Springer Nature. e) An antibody delivery system based on PEG and PLGA co‐polymers to avoid postoperative recurrence of breast cancer. Reproduced with permission.^{[ 103 ]} Copyright 2019, National Center for Biotechnology Information.

Figure 11

Schematic illustrations showing the formation of three “ABA”three‐stage PEG‐based hydrogels:a) Dox‐loaded PEG”ABA” hydrogel; b)Vaccine‐loaded “ABA” hydrogel; c) vitamin E‐PEG‐vitamin E triblock”ABA” hydrogel. Reproduced with permission.^{[ 132} , ¹³³ , ^{134 ]} Copyright 2017, American Chemical Society, Copyright 2019, Elsevier, Copyright 2019, Elsevier.