Bioresponsive functional nanogels as an emerging platform for cancer therapy

ABSTRACT

Introduction: Bioresponsive nanogels with a crosslinked three-dimensional structure and an aqueous environment that undergo physical or chemical changes including swelling and dissociation in response to biological signals such as mild acidity, hyperthermia, enzymes, reducing agents, reactive oxygen species (ROS), and adenosine-5ʹ-triphosphate (ATP) present in tumor microenvironments or inside cancer cells have emerged as an appealing platform for targeted drug delivery and cancer therapy.

Areas covered: This review highlights recent designs and development of bioresponsive nanogels for facile loading and triggered release of chemotherapeutics and biotherapeutics. The in vitro and in vivo antitumor performances of drug-loaded nanogels are discussed.

Expert opinion: Bioresponsive nanogels with an excellent stability and safety profile as well as fast response to biological signals are unique systems that mediate efficient and site-specific delivery of anticancer drugs, in particular macromolecular drugs like proteins, siRNA and DNA, leading to significantly enhanced tumor therapy compared with the non-responsive counterparts. Future research has to be directed to the development of simple, tumor-targeted and bioresponsive multifunctional nanogels, which can be either constructed from natural polymers with intrinsic targeting ability or functionalized with targeting ligands. We anticipate that rationally designed nanotherapeutics based on bioresponsive nanogels will become available for future clinical cancer treatment.

Abbreviations: AIE, aggregation-induced emission; ATP, adenosine-5ʹ-triphosphate; ATRP, atom transfer radical polymerization; BSA, bovine serum albumin; CBA, cystamine bisacrylamide; CC, Cytochrome C; CDDP, cisplatin; CT, computed tomography; DC, dendritic cell; DiI, 1,1ʹ-dioctadecyl-3,3,3ʹ,3ʹ-tetramethylindocarbocyanine perchlorate; DOX, doxorubicin; dPG, dendritic polyglycerol; DTT, dithiothreitol; EAMA, 2-(N,N-diethylamino)ethyl methacrylate; EPR, enhanced permeability and retention; GrB, granzyme B; GSH, glutathione tripeptide; HA, hyaluronic acid; HAase, hyaluronidases; HCPT, 10-Hydroxycamptothecin; HEP, heparin; HPMC, hydroxypropylmethylcellulose; LBL, layer-by-layer; MTX, methotrexate; NCA, N-carboxyanhydride; OVA, ovalbumin; PAH, poly(allyl amine hydrochloride); PBA, phenylboronic acid; PCL, polycaprolactone; PDEAEMA, poly(2-diethylaminoethyl methacrylate); PDGF, platelet derived growth factor; PDPA, poly(2-(diisopropylamino)ethyl methacrylate); PDS, pyridyldisulfide; PEG, poly(ethylene glycol); PEGMA, polyethyleneglycol methacrylate; PEI, polyethyleneimine; PHEA, poly(hydroxyethyl acrylate); PHEMA, poly(2-(hydroxyethyl) methacrylate; PNIPAM, poly(N-isopropylacrylamide); PMAA, poly(methacrylic acid); PPDSMA, poly(2-(pyridyldisulfide)ethyl methacrylate); PTX, paclitaxel; PVA, poly(vinyl alcohol); QD, quantum dot; RAFT, reversible addition-fragmentation chain transfer; RGD, Arg-Gly-Asp peptide; ROP, ring-opening polymerization; ROS, reactive oxygen species; TMZ, temozolomide; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; VEGF, vascular endothelial growth factor.

KEYWORDS:

• Nanogels
• stimuli-sensitive
• drug delivery
• tumor microenvironment
• anticancer drug
• cancer therapy

Article highlights

• Introduction of rational designs, fabrication methods, and unique features of bioresponsive functional nanogels as advanced drug delivery systems.

• Recent designs and development of bioresponsive as well as dual-bioresponsive functional nanogels for triggered release of chemotherapeutics and biotherapeutics including proteins and nucleic acids.

• Novel fabrication methods of cancer-specific and bioresponsive multifunctional nanogels for targeted treatment of various solid tumors and blood cancers.

• Personal opinions on the future development of bioresponsive functional nanogels for cancer therapy.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer declaration of interest

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the National Key Research and Development Program of China [grant number 2017YFD0401301], [grant number 2017YFD0400203], [grant number 2017YFD0400402]; the National Natural Science Foundation of China (NSFC) [grant number 51703244], [grant number 81600178]; the Natural Science Foundation of Jiangsu Province [grant number BK20170730]; the Fundamental Research Funds for the Central Universities [grant number 2632017ZD01]; and the Jiangsu Specially-Appointed Professors Program to W Chen.