Hydrogel local drug delivery systems for postsurgical management of tumors: Status Quo and perspectives

Abstract

Surgery is one of the primary treatments for solid tumors. However, the incomplete resection of tumor cells and the immunosuppressive microenvironment make the issue of postsurgical tumor recurrence a great challenge. Furthermore, a wide range of requirements, including ensuring effective hemostasis, implementing prophylactic measures against infection, and promoting wound healing, were also raised in the postsurgical management of tumors. To fulfill these demands, multiple hydrogel local drug delivery systems (HLDDS) were developed recently. These HLDDS are expected to offer numerous advantages in the postsurgical management of tumors, such as achieving high local drug concentrations at the lesion, efficient delivery to surgical microcavities, mitigating systemic side effects, and addressing the diverse demand. Thus, in this review, a detailed discussion of the diverse demands of postsurgical management of tumors is provided. And the current publication trend on HLDDS in the postsurgical management of tumors is analyzed and discussed. Then, the applications of different types of HLDDS, in-situ HLDDS and non-in-situ HLDDS, in postsurgical management of tumors were introduced and summarized. Besides, the current problems and future perspectives are discussed. The review is expected to provide an overview of HLDDS in postsurgical management of tumors and promote their clinical application.

Keywords: Hydrogel local drug delivery systems; Postsurgical management; Stimuli-responsive materials; Tumors recurrence.

Graphical abstract

Fig. 1

Current situation for postsurgical management of tumors. (a) Etiology of postsurgical management of tumors. (b) Treatment strategies for postsurgical management of tumors. (c) Diversec demands for postsurgical management of tumors.

Fig. 2

Bibliometric analysis of HLDDS. (a) Number of publications versus year. (b) Types of publications. (c) Citations of these publications. (d) Numbers of publications from top-10 regions. (e) Number of publications in top-10 periodicals.

Fig. 3

Various types of HLDDS, including implantable HLDDS, injectable HLDDS, responsive in-situ HLDDS and non-responsive in-situ HLDDS.

Fig. 4

The design and mechanism of 3D printed hydrogel scaffolds for bone tumor postoperative treatment. (a) The schematic of function process and mechanism of the 3D printed scaffold regulating macrophage immune microenvironment for postoperative treatment of bone tumors. (b) Schematic of preparation process and related mechanism of the inhibitor-loaded scaffold. (c) Effect of released components from scaffolds on BMMs proliferation after 1 and 3 days of culture. (n = 3, ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001 vs. control by one-way ANOVA). (d) TRAP staining images and (e) related quantification results show the effect of released components on BMMs osteoclastogenesis after 1 and 3 days of culture. (n = 3, ∗∗∗P < 0.001 vs. control; ^###P < 0.001 vs. CPC group; ··P < 0.01 vs. CPC/hydrogel group by one-way ANOVA). (f) Confocal microscope images show morphology of BMMs in scaffold extract medium after 3 days of culture. Reproduced from Ref. [25] with permission from Elsevier.

Fig. 5

Mechanism of immunogenic cell death (ICD) induced by the autolysing Salmonella delivery vehicle (SDV), and ATP-responsive hydrogel design and characterization. (a) Illustration depicting the immunostimulatory autolyzing Salmonella-nanocapsule delivery system (IASNDS) invading GBM cells, triggering cell death, activating antigen-presenting cells, and eliciting an immune response. (b) IASNDS cellular entry, intracellular autocleavage initiation, and tumor cell pyroptosis induction mechanism. (c) Schematic of the ATP-responsive hydrogel used to encapsulate the IASNDS. (d) Representative photographs of hydrogels before and after gel formation. (e) Variation in the hydrogel modulus with time, measured at an angular frequency of 1 rad s⁻¹ (n = 3). (f) Schematic of ATP-induced dehybridization of double-stranded Black-Hole-Quencher 3-modified Apt and Cy5.5-modified CpG structures, with fluorescence spectra showing the fluorescence recovery of Cy5.5 under ATP induction. (n = 3). (g) Cumulative amount of CpG ODN released from the hydrogel under different concentrations of ATP. (n = 3). (h) Visualization of alterations in mouse brain tissues was achieved by applying WGA staining (red), enabling observation of tumor cell dynamics across the different treatment groups in mice (n = 3). (i) The percentage of positive cells was tallied following immunohistochemical staining for Ki-67 in tumor tissues originating from various mouse groups (n = 5). Data are presented as the mean ± S.D. Reproduced from Ref. [27] with permission from Springer Nature.

Fig. 6

The structural formula of (a) chitosan, (b) poloxamer, (c) PLA-PEG-PLA, PDLLA-PEG-PDLLA, (d) PLGA-PEG-PLGA, (e) PECT and (f) PNIPAM.

Fig. 7

Chitosan and Poloxamer-based in-situ HLDDS prevent tumor recurrence. (a) Schematic illustration of the synthesis procedure for DOX@CSSH/HNTs-SH Gel and its application in inhibiting tumor recurrence. (b) The gelation time of DOX@CSSH/HNTs-SH Gel. (c) The G′ values of different hydrogels varied with frequency in frequency sweep mode. (d) Illustration of the preparation process of MA@PDA-F127. (e) Optical photograph depicting the sol-gel transition of MA@PDA-F127 hydrogels in response to temperature changes. (f) Photothermal heating curves of MA@PDA-F127 hydrogels under irradiation by an 808 nm laser with a power density of 1.5 W cm⁻². (g) Quantification of Calreticulin (CRT) expression in 4T1 cells following various treatments. (h) Texture curve of PTX-NCS-gel prepared with 0.1 %, 0.2 %, and 0.3 % carbomer, and the area under the curve is expressed as adhesion. (i) Temperature viscosity curves of PTX-NCS-gel prepared with 0.1 %, 0.2 %, and 0.3 % carbomer. (j) Kaplan–Meier survival curves of 4T1 tumor models after different treatments. Reproduced from Refs. [101,111,119,124] with permission from Elsevier, Wiley and Springer Nature.

Fig. 8

PEG/polyester triblock polymer and PNIPAM-based in-situ HLDDS for preventing tumor recurrence. (a) Schematic illustration of O₃/PFTBA@LIP Gel for the Postsurgical Treatment of HCC. (b) Variations in the complex viscosity (η∗), G′ and G″ of PFTBA@LIP@Gel were plotted as a function of temperature (30–42 °C). (c) Western blot analysis of the expression of GPX4 and ACSL4 in HuH-7 cells 12 h after indicated treatments. (d) Sol–gel transition images of OL-M/Gel, sol at 4 °C and gel at 37 °C. (e) The drug release of OL-M and OL-M/Gel. (f) Schematic illustration of the synthesis procedure for PLGA-PEG-PLGA hydrogel by mixing two PLGA-PEG-PLGA triblock copolymers with different PEG/PLGA proportion. (g) The G′ and G″ of the two copolymer mixtures as a function of temperature. (h) SEM images of the PDNPs-gel. (i) Survival rates of mice treated with different formulations after resection of tumor. (j) Schematic diagram of the device for simulating an embolized vessel with different materials flushed by a blood flow in vitro. (k) Minimum pressure required to push the various plug forward by normal saline (control) or normal saline containing H₂O₂ at 37 °C. (l) DSA images of kidneys of all five experimental rabbits in each group. (m) The gelation of hydrogel–GNR by 808 nm irradiation. (n) Schematic representation of in vivo extravascular gelation shrinkage-induced internal stress to constrict blood vessels upon exposure to an 808 nm laser. (o) CDFI images of the PANC-1 tumor and its periphery before and after the special treatment. Reproduced from Refs. [141,142,144,152,157,158] with permission from American Chemical Society, American Chemical Society, Ivyspring International, American Chemical Society, Wiley, and Springer Nature.

Fig. 9

Ion sensitive in-situ HLDDS prevents tumor recurrence. (a) Schematic diagram to show the construction of ALG-Aapt/CpG hydrogel and the release of CpG from the hydrogel in response to ATP. (b) Distal tumor growth curves and (c) percentage of CD8+T cells in distal tumors under various treatment modalities. (d) Chemical structures of the designed CPT prodrug, subsequently self-assembling into supramolecular filaments which upon addition of counterions form a hydrogel. (e) Cumulative release profile of CPT prodrugs from their composed hydrogel in DPBS at 37 °C over 30 days. (f) Effective conversion of CPT-HKD prodrug into active free CPT in DPBS. (g) Schematic illustration of TT6 SP hydrogel for local delivery of aPD1 against malignant tumors. (h) Pictures of the aPD1/TT6 SP solution before and after the addition of PBS. (i) G′ and G″ of TT6 solution from time sweep rheology measurements at 37 °C. The addition of PBS to TT6 solution at 180 s resulted in a rapid increase in G′, indicating the formation of a supramolecular hydrogel. (j) Kaplan-Meier survival curves for rechallenged mice corresponding to the indicated treatments. (k) Schematic illustration of DOCA-PLGLAG-iRGD supramolecular hydrogel. (l) Ratios of the CD8⁺ T cells to regulatory T cells in tumors corresponding to different treatment groups. Reproduced from Refs. [161,[168], [169], [170]] with permission from Wiley, Elsevier and ACS Publications.

Fig. 10

Photocuring in-situ HLDDS prevents tumor recurrence. (a) Schematic diagram illustrating the fabrication process of GPDF hydrogel and (b) its potential application in inhibiting tumor recurrence with various properties. (c) SEM images of GelMA, GPD, and GPDF hydrogels. (d) The antioxidant ability of the various hydrogels. (e) Photographs of the wounds treated with various hydrogels on day 3, 7, and 14. (f) Photothermal images of different samples at various time points under 808 nm laser (1 W/cm₂, 10 min). (g) Relative tumor volume in various treatments after resection of tumor. (h) G′ and G″ of the three hydrogels. (i) The proportion of iNOS (M1) and CD206 (M2) and levels of (j)TNF-α and (k) IL-1β in sera of mice bearing B16F10 tumor after 2 days post PDT. Reproduced from Refs. [[179], [180], [181]] with permission from Elsevier and Wiley.

Fig. 11

The design of an instant protection spray (IPS), provides burn with an antibacterial and physical barrier. IPS was designed based on a novel crossed-angle layout. Unlike the conventional step-by-step spray, IPS owned a faster and more convenient one-step use mode and can form a complete hydrogel film instantly within 30 s to provide a physical barrier for burn. Reproduced from Ref. [189] with permission from Wiley.

Fig. 12

Conclusion and perspectives of HLDDS in postsurgical tumor management. (a)The advantages of HLDDS for postsurgical tumor management. (b)The reasons for the hindered clinical application of HLDDS. (c) The development direction and potential of HLDDS in postsurgical tumor management.