Research progress in the application of in situ hydrogel system in tumor treatment

Figures & data

Figure 1. Schematic process of formation of in situ hydrogel and sustained release of drugs from the hydrogel into tumor cells.

Table 1. The in situ hydrogel systems in tumor treatment studied in recent years.

Gelling mechanism	Materials	Therapeutic agents	Cancer cell (in vitro)	Tumor model (in vivo)	References
pH	Hyaluronic acid and fluorescein isothiocyanate conjugated mesoporous silica nanocomposites	Doxorubicin	SKBR3	–	Chen and Liu (2016)
pH	N-carboxyethyl chitosan and dibenzaldehyde-terminated polyethylene glycol	Doxorubicin	HepG2	–	Qu et al. (2017)
pH	Chitosan-grafted dihydrocaffeic acid and oxidized amylopectin	Doxorubicin	HCT116	–	Liang et al. (2019)
pH	Dextran phosphate	Prospidine	HeLa and HepG2	Liver cancer	Solomevich et al. (2019)
Temperature	Polyethylene glycol and monomethoxy poly(ethylene glycol)-poly(caprolactone)	Cisplatin and Paclitaxel	A549	Lung cancer	Wu et al. (2014)
Temperature	Tamoxifen gallate liposomes	Tamoxifen	–	Breast cancer	Shaker et al. (2016)
Temperature	Graphene oxide, folic acid and hyaluronic acid-chitosan-g-poly (N-isopropylacrylamide)	Doxorubicin	MCF-7	Breast cancer	Fong et al. (2017)
Temperature	Negatively charged survivin antisense oligonucleotide and positively charged	Survivin antisense oligonucleotide	MCF-7	Breast cancer	Zhao et al. (2019)
Temperature	Chitosan, β-glyceryl phosphate and polyethylene imine modified superparamagnetic graphene oxide	Doxorubicin	MCF-7	Breast cancer	Zhu et al. (2015)
Temperature	Oxaliplatin and tannic acid polymer nanoparticles	Oxaliplatin and Tannic Acid	HCT26	Colorectal cancer	Ren et al. (2019)
Magnetic field	PEGylated iron oxide nanoparticles	Paclitaxel	–	Breast cancer	Wu et al. (2018)
Magnetic field	Alginate and xanthan gum	Levodopa	SH-SY5Y	–	Kondaveeti et al. (2018)
Magnetic field	α-amino acid residues, CoFe2O4 and Fe3O4	Doxorubicin	HeLa	–	Casolaro et al. (2014)
Light	Hemoglobin and polyethylene glycol	Near infrared	A549	Lung cancer	Lee et al. (2018)
Light	Hyaluronic acid, catechol compounds, gallic acid and iron ions	Near infrared	KB, 4T1 and A375	breast cancer, and melanoma	Ko et al. (2019)
Light	Azobenzene and DNA	Doxorubicin	CEM	–	Kang et al. (2011)
Temperature-pH	Poly-N-isopropylacrylamide polymer	Anastrozole	MCF-7	–	Singh et al. (2019)
Temperature-pH	PEG monomethacrylate, and acrylic acid	5-fluorouracil	HepG2	–	Yue et al. (2019)
Temperature-pH	Plunik and polyacrylic acid	Epirubicin	–	Colon adenocarcinoma	Lo et al. (2012)
Temperature-magnetic field	Magnetic iron oxide nanoparticles	Magnetic heat	U87-MG	Glioblastoma	Zhang and Song (2016)
Ion strength/pH	Self-assembling peptide RADA16-I	Emodin	A549 and HepG2	–	Wei et al. (2019)
Ion strength/pH	Self-assembling peptide RADA16-I	Mangiferin	DLD-1 and KYSE 30	–	Meng et al. (2019)
pH-light	Black phosphorus nanosheets, dibenzaldehyde functionalized polymers and polyaspartic hydrazide polymers	Doxorubicin	MDA-MB-231	Breast cancer	Wu et al. (2019)

Table 2. List of some FDA approved in situ hydrogels.

Product name	Gelling mechanism	Materials	Active ingredient	Indication	Approved
Atridox	Temperature	PLGA	Doxycycline hyclate	Adult parodontitis	1998
Sandostatin	Temperature	PLGA	Octreotide acetate	Acromegaly	1988
Atrisorb D	Temperature	PLGA	Doxycycline hyclate	Periodontal tissue regeneration	2000
Sublocad	Temperature	PLGA	Buprenorphine	Analgesic	2017
Perseris	Temperature	PLGA	Risperidone	Acute and chronic schizophrenia	2018
Azasite	Temperature	Poloxamer 407	Lidocaine hydrochloric acid	Bacterial conjunctivitis	2007
Lupron depot	pH	PLGA	Leuprolide acetate	Advanced prostate cancer	1995
Eligard	pH	PLGA	Leuprolide acetate	Advanced prostate cancer	2002
Pilopine HS	pH	Carbopol 940	Pilocarpine hydrochloric acid	Glaucoma	1984
Timoptic XE	Ion strength	Gellan gum	Timolol Maleate	Glaucoma	1993

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Qu J, Zhao X, Ma PX, et al. (2017). pH-responsive self-healing injectable hydrogel based on N-carboxyethyl chitosan for hepatocellular carcinoma therapy. Acta Biomater 58:168–80.

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Liang Y, Zhao X, Ma PX, et al. (2019). pH-responsive injectable hydrogels with mucosal adhesiveness based on chitosan-grafted-dihydrocaffeic acid and oxidized pullulan for localized drug delivery. J Colloid Interface Sci 536:224–34.

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Solomevich SO, Bychkovsky PM, Yurkshtovich TL, et al. (2019). Biodegradable pH-sensitive prospidine-loaded dextran phosphate based hydrogels for local tumor therapy. Carbohydr Polym 226:115308.

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Wu Z, Zou X, Yang L, et al. (2014). Thermosensitive hydrogel used in dual drug delivery system with paclitaxel-loaded micelles for in situ treatment of lung cancer. Colloids Surf B Biointerfaces 122:90–8.

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Shaker DS, Shaker MA, Klingner A, et al. (2016). In situ thermosensitive tamoxifen citrate loaded hydrogels: an effective tool in breast cancer loco-regional therapy. J Drug Deliv Sci Technol 35:155–64.

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Fong YT, Chen CH, Chen JP. (2017). Intratumoral delivery of doxorubicin on folate-conjugated graphene oxide by in-situ forming thermo-sensitive hydrogel for breast cancer therapy. Nanomaterials 7:388–411.

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Zhao D, Song H, Zhou X, et al. (2019). Novel facile thermosensitive hydrogel as sustained and controllable gene release vehicle for breast cancer treatment. Eur J Pharm Sci 134:145–52.

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Zhu X, Zhang H, Huang H, et al. (2015). Functionalized graphene oxide-based thermosensitive hydrogel for magnetic hyperthermia therapy on tumors. Nanotechnology 26:365103.

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Ren Y, Li X, Han B, et al. (2019). Improved anti-colorectal carcinomatosis effect of tannic acid co-loaded with oxaliplatin in nanoparticles encapsulated in thermosensitive hydrogel. Eur J Pharm Sci 128:279–89.

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Wu H, Song L, Chen L, et al. (2018). Injectable magnetic supramolecular hydrogel with magnetocaloric liquid-conformal property prevents the post-operative recurrence in a breast cancer model. Acta Biomater 74:302–11.

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Kondaveeti S, Semeano ATS, Cornejo DR, et al. (2018). Magnetic hydrogels for levodopa release and cell stimulation triggered by external magnetic field. Colloids Surf B Biointerfaces 167:415–24.

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Casolaro M, Casolaro I, Bottari S, et al. (2014). Long-term doxorubicin release from multiple stimuli-responsive hydrogels based on α-amino-acid residues. Eur J Pharm Biopharm 88:424–33.

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Ko S, Park JY, Oh YK. (2019). A microbial siderophore-inspired self-gelling hydrogel for noninvasive anticancer phototherapy. Cancer Res 79:6178–89.

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Kang H, Liu H, Zhang X, et al. (2011). Photoresponsive DNA-cross-linked hydrogels for controllable release and cancer therapy. Langmuir 27:399–408.

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Singh A, Vaishagya K, Verma RK, et al. (2019). Temperature/pH-triggered PNIPAM-based smart nanogel system loaded with anastrozole delivery for application in cancer chemotherapy. AAPS Pharm Sci Tech 20:213–26.

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Yue Z, Che YJ, Jin Z, et al. (2019). A facile method to fabricate thermo- and pH-sensitive hydrogels with good mechanical performance based on poly (ethylene glycol) methyl ether methacrylate and acrylic acid as a potential drug carriers. J Biomater Sci Polym Ed 30:1375–98.

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Lo YL, Hsu CY, Lin HR. (2012). pH-and thermo-sensitive pluronic/poly (acrylic acid) in situ hydrogels for sustained release of an anticancer drug. J Drug Target 21:54–66.

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Zhang ZQ, Song SC. (2016). Thermosensitive/superparamagnetic iron oxide nanoparticle-loaded nanocapsule hydrogels for multiple cancer hyperthermia. Biomaterials 106:13–23.

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Wei W, Meng C, Wang Y, et al. (2019). The interaction between self - assembling peptides and emodin and the controlled release of emodin from in-situ hydrogel. Artif Cells Nanomed Biotechnol 47:3961–75.

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Meng C, Wei W, Wang Y, et al. (2019). Study on the interaction between self-assembling peptide and mangiferin and in vitro release of mangiferin from in-situ hydrogel. Int J Nanomedicine14:7447–60.

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Wu RS, Lin J, Xing YM, et al. (2019). pH-sensitive black phosphorous incorporated hydrogel as novel implant for cancer treatment. J Pharm Sci 108:2542–51.

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