Table 2.

Examples of pH-sensitive hydrogels for cancer therapy. n.a.—not applicable; β-CD—β-cyclodextrin; 5-FU—5-fluorouracil; DOX—doxorubicin; FACS—fluorescence-activated cell sorting; PTX—paclitaxel.

Date	Drug	In vitro model	In vivo model	Hydrogel formulation	Highlights	References
2014	5-FU	HT-29 cells (colorectal adenocarcinoma)	n.a.	β-CD-graft-gelatin crosslinked with oxidized dextran	Presence of β-CD increase drug loading. Swelling and drug release is low at pH 1.2 and high at pH 7.4, being appropriate for drug release at colon. Hydrogels were biocompatible and increase the efficacy of 5-FU.	[38]
2019	Bortezomib	MC3T3E1 (osteoblast) and NIH-3T3 (fibroblast) cells	n.a.	Alginate-conjugated polydopamine	The release mechanism followed non-Fickian diffusion. FACS analysis revealed cell apoptosis defined by loss of cell viability for colon cancer cells.	[39]
2019	Prospidin	HeLa (cervical adenocarcinoma) and HeP-2 (human hepatocellular liver carcinoma) cells	Zajdel hepatoma Mongrel white rats	Dextran phosphate (DP)	At low pH, the swelling of hydrogels is 4.6–12.3 times lower than at pH 7.4. Susceptible to degradation by the simulated physiological conditions. The amount of drug release is dependent on the pH of outer media and decreases with the growth of phosphoric group content in DP hydrogels	[40]
2015	5-FU	n.a.	n.a.	N-N′-dimethylacrylamide monomers polymerized in presence of methacrylic acid or 2-aminoethyl methacrylate hydrochloride containing ferro-nanoparticles	Drug release is always higher in the presence of a magnetic field and generally increases with its intensity.	[41]
2017	DOX	HepG2 cells (human hepatocellular liver carcinoma)	Sprague-Dawley rat	N-carboxyethyl chitosan + PEGDA	Exhibited in vitro pH-dependent gel degradation and doxorubicin release. No hydrogel diffusion after subcutaneous injection.	[33]
2019	PTX	HepG2 (human hepatocellular liver carcinoma), H22 (murine hepatoma)	H22 subcutaneous xenograft BALB/c mice	Self-assembling octapeptides	In vitro controlled release of PTX at pH 5.5 for 6 days. In vivo hydrogel retention at the tumor site. Increased antitumor efficacy compared to free PTX (reduced tumor weight and volume), and reduced toxicity (low weight loss).	[42]
2017	DOX	MDA-MB-231 cells (breast cancer)	n.a.	DNA hairpin conjugated with polyacrylamide	pH-induced separation of the nucleic acid duplex units causing DOX release at pH 5.0. Increase DOX cellular uptake and efficacy.	[43]
2019	DOX	HCT116 cells (colorectal adenocarcinoma)	Kunming Mice	Chitosan-grafted-dihydrocaffeic acid/oxidized pullulan	87% DOX release over 60 h at pH 5.5 over 52% at pH 7.4. In vitro enhancement of DOX therapeutic efficacy. In vivo adhesion in the injection site.	[44]
2019	5-FU and Rutin	MDA-MB-231 and MCF-7 cells (breast cancer)	n.a.	Zein, acrylic acid, N, N-methylene bisacrylamide, and ammonium persulphate	Improved release at pH 7.4 over pH 1.2. Improved in vitro pharmacological activity by apoptosis induction by oxidative stress.	[45]
2020	Triaryl-(Z)-olefin	n.a.	Ehrlich carcinoma cell subcutaneous xenograft Swiss albino mice	Cholesterol and span 60 niosomes in chitosan and glyceryl monooleate-based hydrogels	Controlled release of drug and improved tumor regression	[46]
2020	DOX	HeLa cells (cervical adenocarcinoma)	n.a.	Zein nanoparticle crosslinked pectin	Improved DOX cellular internalization and cytotoxicity	[47]
2020	PTX	A549 (lung cancer) and HepG2 (human hepatocellular liver carcinoma) cells	n.a.	Long-chain hexadecyl amine modified nanocellulose	Improved release at pH < 6.8. Improved PTX internalization by cells and therapeutic efficacy.	[48]
2020	DOX	HepG2 cells (human hepatocellular liver carcinoma)	HepG2 xenograft BALB/c nude mouse model	4armPEG-benzaldehyde and N-carboxyethyl chitosan	Degradation occurs at pH 5.6 which contributes for controlled DOX release. In vivo biocompatibility, degradation over 5 days, and improved tumor inhibition	[49]
2019	DOX	HeLa cells (cervical adenocarcinoma)	n.a.	Carboxyethyl modified chitosan and aldehyde modified hyaluronic acid	Improved drug release at pH < 6.8. Biocompatibility and biodegradability. In vitro pharmacological efficacy	[50]