Hydrogels for localized chemotherapy of liver cancer: a possible strategy for improved and safe liver cancer treatment

Figures & data

Figure 1. Advantages of localized chemotherapy over conventional systemic chemotherapy for the treatment of solid tumors.

Table 1. Hydrogel-based drug delivery systems for cancer treatment.

Delivery route	Drug	Hydrogel	Cell model (in vitro)	Cancer model (in vivo)	Feature	Ref.
In situ injection	Temozolomide and paclitaxel	PEG-DMA	U87MG	Glioblastoma	Codelivery of temozolomide and paclitaxel	Zhao et al. (2019)
	PTX	GC-β-CD	SKOV3	Ovarian cancer	Conjugated β-CD for photocuring	Hyun et al. (2019)
Intratumoral injection	DOX and MBP	Chitosan	HT29	Colon cancer	Chemotherapy and hyperthermia combined	Zheng et al. (2019)
	Paclitaxel	FER-8 peptide	HepG2	Liver cancer	High drug-loading, sustained release, and higher degradation	Raza et al. (2019)
Intravenous administration	DOX	Dextrin	4T1 and U2OS	Breast cancer	Effectively targeting and inhibiting cancer progression	Zhang et al. (2017)
	Doxorubicin	PAA	SMCC-7721	Liver cancer	Stabilized amorphous CaCO3 and tunable pH-responsiveness	Xu et al. (2019)
	DOX and ICG	NIPAM, SBMA, MAA, and BAC	HepG2	Liver cancer	Near-infrared light-triggered and temperature/redox-sensitive	Li et al. (2017)
Subcutaneous injection	DOX/IL-2/IFN-γ	PELG-PEG-PELG	B16F10	Melanoma	Localized codelivery of anticancer drugs	Lv et al. (2018)
	AD-DOX	Poly(NIPAM-co-MPCD)	MCF-7 and HeLa	Sarcoma	pH/NIR dual-sensitive for chemo-photothermal treatment	Xu et al. (2017)
Transdermal delivery	Silibinin	PCBCL-b-PEG-b-PCBCL	B16F10	Melanoma	Patch loaded with silibinin for the treatment of melanoma	Makhmalzadeh et al. (2018)
Peritumoral injection	Cisplatin and CA4P	mPEG-b-PELG	CT26 and MCF-7	Colorectal cancer	CDDP and CA4P coloaded polypeptide gel	Yu et al. (2019)
Intraperitoneal injection	Oxaliplatin and tannic acid	PCL-10R5-PCL	CT26	Colorectal cancer	Oxaliplatin coloaded with tannic acid	Ren et al. (2019)

PEG-DMA: polyethylene glycol dimethacrylate; GC: glycol CTS; CD: cyclodextrin; PF127: Pluronic F127; DOX: doxorubicin; PAA: poly(acrylic acid); ICG: indocyanine green; NIPAM: n-isopropylacrylamide; SBMA: sulfobetaine methacrylate; MAA: methylallyl amine; BAC: N,N′-bis(acryloyl)cystamine; PELG: poly(γ-ethyl-l-glutamate); PCBCL: poly[(α-benzyl carboxylate-ε-caprolactone)-co-(α-carboxyl-ε-caprolactone)]; PCL: poly(3-caprolactone).

Figure 2. Classification of hydrogels based on the different properties. Reproduced with permission from reference Ullah et al. (2015).

Figure 3. Various physical and chemical approaches for the synthesis of the hydrogel. Reproduced with permission from reference Sinha & Chakma (2019).

Figure 4. D-PNAx hydrogels for i.t. injection of targeted chemotherapy using DOX-induced co-assembling nanoparticles are shown schematically. Reproduced with permission from Wan et al. (2016).

Figure 5. Schematic diagram depicting the concept of Gal-CS-g-PNIPAM nanogels. Reproduced with permission from American Chemical Society 2011 (Duan et al., 2011).

Figure 6. (A) Mechanism of visible light initiated mixed-mode step-chain-growth thiol-acrylate photopolymerization. (B–E) Physical properties of visible light-cured PEGDA thiol-acrylate hydrogels formed with 0.025, 0.05, or 0.1 mM of eosin-Y. (B) Photographs; (C) gel points; (D) elastic (G′) and viscous (G″) modulus, and (E) equilibrium mass swelling ratio (Qm). Reproduced with permission from Wiley Online Library (Hao & Lin, 2014).

Figure 7. (I) Schematic illustration of MSN-GII@PFH&DOX includes (a) the MSNs surface modification with amino groups and (b, c) carboxyl groups activation, (d) in situ amidation-initiated self-assembled supramolecular nanogels on the interface of MSNs (MSN-GI), (e) ternary inorganic-supramolecular-polymeric nanogels (MSN-GII) by laccase-mediated polymerization, (3) co-loading of guest molecules PFH and DOX, and (4) ultrasound imaging and imaging-guided HIFU ablation of tumors. (II) Schematic illustration of the mechanism of in situ amidation-fueled self-assembly. Reproduced with permission from American Chemical Society 2019 (Wang et al., 2019).

Figure 8. (a) Schematic illustration of the preparation of ferrimagnetic silk fibroin hydrogel (FSH); (b) injectable FSH guided magnetic hyperthermia therapy of tumor under alternating magnetic field (AMF). Reproduced with permission from reference (Qian et al., 2020).

Table 2. List of stimuli-responsive hydrogel for liver cancer therapy.

Stimulus	Hydrogel	Therapeutic agent	Delivery rout	Cell line (in vitro)	Tumor model (in vivo)	Ref.
Temperature	Hydrogels of DOX-induced co-assembling nanoparticles (D-PNAx)	Doxorubicin	Intratumoral delivery	–	H22 tumor-bearing mice	Wan et al. (2016)
Temperature	Pluronic F127 (PF127) based hydrogel	Doxorubicin	Intratumoral delivery	HepG2 cells	H22 tumor-bearing mice	Gao et al. (2021)
Temperature	Embelin/PECT^gel	Embelin	Peritumoral injection	H22 cells	Hepatic cancer mouse models	Peng et al. (2014)
Temperature	Hydrogel composed of block copolymer	Doxorubicin	Interventional injection	–	Rabbit with VX2 tumor	Lee et al. (2013)
pH	FER-8 peptide hydrogel	Paclitaxel	Intratumoral injection	–	H22 tumor-bearing mice	Raza et al. (2019)
pH	DOX@ACC/PAA NP	Doxorubicin	Intravenous injection	SMCC-7721 cells	SMCC-7721 xenografts zebrafish, tumor-bearing mice	Xu et al. (2019)
pH	Hydrogels based on CEC and PEGDA	Doxorubicin	Subcutaneous injection	HepG2 cell	–	Qu et al. (2017)
Light	Hydrogel of PEGDA	Eosin-Y	–	Huh7 cells	–	Hao & Lin (2014)
Light	Hydrogel of PEGDA, PEG 400, and phosphotungstic acid	Phthalocyanine zinc	–	HeLa cell	–	Wang et al. (2013)
Ultrasound	Supramolecular hybrid nanogels (MSN-GI)	Doxorubicin	Postintravenous injection	SMMC-7721 cells	Rabbits bearing a VX2 liver tumor	Wang et al. (2019)
Magnet	[P(NIPAM-co-DMA)/Fe3O4]	Cisplatin	–	HepG2 cells	–	Salimi et al. (2018)
Magnet	Magnetic-/pH-responsive hydrogel beads	Methotrexate	–	HepG2 cells	–	Wu et al. (2016)
Magnet	NDP-FG hydrogel	–	Locally administrated at the surgical site	–	Balb/c nude mice	Yan et al. (2022)
Magnet	Magnetic hydrogel based on silk fibroin and iron oxide nanocubes	–	Intratumoral injection	–	VX2 liver tumor-bearing rabbits and Balb/c mouse bearing subcutaneous tumor	Qian et al. (2020)

Figure 9. (a) In this schematic, we show the steps involved in developing PC₁₀A/DOX/HAuNS hydrogels and nanoparticles, as well as the steps involved in dissolving the nanoparticles in the PC10A hydrogel. (b) The sequential drug release of PC₁₀A/DOX/HAuNS hydrogels was used for long-term chemotherapy and photothermal therapy in vivo (Jin et al., 2019).

Table 3. Hydrogel-based active targeting and combination therapy for liver cancer therapy.

Strategy	Hydrogel	Therapeutic agent	Delivery rout	Cell line (in vitro)	Tumor model (in vivo)	Ref.
Active targeting	Glycyrrhetinic acid (GA) modified curcumin supramolecular pro-gelator (GA-Cur)	Curcumin	–	HepG2 cells	–	Chen et al. (2017)
Active targeting	The hydrogel of lactobionic acid conjugated carboxymethylated (CM)-curdlan	Retinoic acid	–	HepG2	–	Na et al. (2000)
Combination therapy	The hydrogel of PEGylated gold nanorods (GNRs) and paclitaxel-loaded chitosan polymeric micelles (PTX-M)	Paclitaxel	Intratumorally injected	HepG2 cells	Heps-bearing mice	Zhang et al. (2016)
Combination therapy	PCL-PEG-PCL hydrogel combined with multiwalled carbon nanotubes (CNTs)	Doxorubicin and rhodamine B	Subcutaneous injection	BEL-7402	Mice	Wei et al. (2018)
Combination therapy	The hydrogel of genetically engineered polypeptide and hollow gold nanoshells (HAuNS)	Doxorubicin	Intratumoral injection	HepG2 cells	HepG2 tumor-bearing mice	Jin et al. (2019)
Combination therapy	The hydrogel of PCL-PEG-PCL copolymer	Doxorubicin	Intratumoral injection	BNL-Luc cell line	BNL-Luc tumor-bearing mice	Peng et al. (2013)

Table 4. Advantages and shortcomings of different hydrogel delivery routes for cancer treatment.

Delivery route	Advantages	Shortcomings	Ref.
Oral delivery	Convenient administration	Harsh gastrointestinal tract environment, first-pass elimination	Minhas et al. (2018)
Transdermal delivery	No first-pass elimination, accurate delivery, convenient administration	Unknown pharmacokinetics	Zhao et al. (2018)
Intravenous injection	High absorption	Rapid renal clearance	Wu et al. (2019)
Pulmonary delivery	No first-pass elimination, high absorption	Strict size requirements	Zhu et al. (2017)
In situ implantation	No first-pass elimination, accurate delivery, cell therapy	Surgery needed	Smith et al. (2017)
In situ injection	No first-pass elimination, accurate delivery, self-assemble	Unknown pharmacokinetics	Yu et al. (2018)
Transarterial chemoembolization	Low systemic toxicity, selective administration	Complex preparation, X-ray needed	Ashrafi et al. (2017)

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