Injectable and Self-Healable pH-Responsive Gelatin–PEG/Laponite Hybrid Hydrogels as Long-Acting Implants for Local Cancer Treatment

Abstract

Injectable, self-healable, and pH-responsive hybrid hydrogels are highly promising biomaterials for controlled and long-term therapeutic agent release in cancer treatment. Herein, we fabricated an injectable, self-healable, and pH-responsive hybrid hydrogel through the formation of the hydrazone bond between hydrazide-functionalized gelatin (Gel-ADH) and aldehyde-functionalized PEG (diBA-PEG) polymers. During gelation, the resulting pregels were also integrated with laponite (LAP) nanodisks loaded with an anticancer drug, doxorubicin (DOX), yielding to hybrid Gel-ADH/diBA-PEG/LAP@DOX hydrogels. The gelation time of the hybrid hydrogel was observed to be 80 s and the resulting hybrid hydrogels demonstrated excellent injectability and rapid self-healing capability. The gel−sol transition behaviors of hybrid hydrogels indicated an outstanding gelation stability, which is a highly desirable feature in controlled drug delivery application. The injectable hybrid Gel-ADH/diBA-PEG/LAP@DOX hydrogels exhibited a very efficient pHdependent long-term drug release profile. Biocompatibility of the hydrogel components (Gel-ADH, diBA-PEG, and LAP) was also tested using the human breast cell line (SVCT) and endothelial cell line (HUVEC). All components of the hybrid hydrogel possess excellent biocompatibility and even support cell proliferation. Moreover, the cytotoxicity of the hydrogels was investigated on the human breast cancer cell line (MCF-7) and triple-negative breast cancer cell line (MDA-MB-231). Our results clearly suggested that this injectable, self-healable, and pH-responsive hybrid Gel-ADH/diBA-PEG/LAP@DOX hydrogel offers a promising potential as a drug carrier for long-term and controlled release application.

Drug Delivery Based on Stimuli-Responsive Injectable Hydrogels for Breast Cancer Therapy: A Review

“…In addition to the hydrogels undergoing sol to gel transition around physiological temperature, there is another type of injectability which is realized by the change of hydrogel viscosity in response to the increase in shearing rate and shearing strain. These hydrogels demonstrate shear thinning behaviors and can be injected into the human body and stay at the tumor site after the injection for controlled drug release [ 19 , 23 , 26 , 40 ]. In the meantime, some hydrogels of this type also demonstrate self-recovery.…”

“…In the meantime, some hydrogels of this type also demonstrate self-recovery. Both storage modulus (G′) and loss modulus (G″) show reproducibility in accordance with cyclic increase and decrease in shearing strains [ 19 , 23 , 26 ].…”

“…With regard to injectable hydrogels used for breast cancer treatment, the pH values play crucial roles in determining the drug release profiles [ 23 , 43 ]. More details and discussion are given below.…”

“…The obtained hydrogels remain at the disease site to achieve a sustainable and targeted drug delivery [ 20 , 21 ]. Recently, many works have attempted to incorporate a diverse range of nanoparticles and other functional molecules into the hydrogel depots to fabricate more sophisticated drug delivery platforms that implement combined cancer therapies [ 22 , 23 , 24 ]. Thus, the modern focus of the injectable hydrogel-based drug delivery system for breast cancer treatment is on creating an integrated system.…”

Hydrogel, Electrospun and Composite Materials for Bone/Cartilage and Neural Tissue Engineering

“…The cellulose and its derivatives, carrageenan, sodium alginate, agarose, chitosan, dextran, hyaluronic acid (HA), fibrin, collagen and gelatin [79,80], are just a few important examples of natural representatives of hydrogels, while poly(methyl methacrylate) (PMMA), polyethylene glycol (PEG) and poly(2-hydroxyethyl methacrylate) (poly(HEMA))-based polymers [81] belong to the synthetic sort. The examples of hybrid hydrogels are gelatin-PEG [82] and chitosan/acrylamide [83]. Hydrogels also might be divided in terms of ionic charge to cationic (e.g., chitosan) [84], anionic (e.g., HA) [85], amphiphilic (e.g., collagen) non-ionic hydrogels (e.g., dextran) [86].…”