pH stimuli-responsive hydrogels from non-cellulosic biopolymers for drug delivery

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TL;DR

This review summarizes the properties and applications of pH-responsive hydrogels derived from non-cellulosic biopolymers such as chitosan, alginate, hyaluronic acid, dextran, xanthan, and guar gum for drug delivery. These hydrogels exploit physiological pH gradients (e.g., gastrointestinal tract, tumor microenvironment) to achieve site-specific, controlled drug release. The clinical significance lies in their potential to improve therapeutic efficacy and reduce side effects in oral, parenteral, and transdermal drug delivery, particularly for cancer therapy, insulin delivery, and colon-targeted treatments.

Full summary

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**Background:** Stimuli-responsive hydrogels are smart biomaterials that release drugs in response to external triggers such as pH, temperature, or light. pH-responsive hydrogels are particularly valuable because pH varies across physiological compartments (e.g., stomach pH 1.2, intestine pH 7.4, tumor microenvironment acidic). Non-cellulosic biopolymers (e.g., chitosan, alginate, hyaluronic acid, dextran, xanthan, guar gum, carrageenan, chondroitin sulfate, fucoidan) offer advantages like biocompatibility, biodegradability, and low immunogenicity. This review focuses on their properties, mechanisms, and applications in drug delivery, excluding cellulose-based systems which have been reviewed elsewhere.

**Methods:** This is a narrative review that synthesizes existing literature on pH-sensitive hydrogels from non-cellulosic biopolymers. It discusses the physicochemical properties of each polymer (e.g., pKa, ionic nature, source), mechanisms of pH responsiveness (swelling/deswelling due to ionization of acidic or basic groups), and applications in oral, parenteral, and transdermal drug delivery. The review also covers biological fate, commercial products, and future opportunities.

**Key Results:** The review highlights several key findings: - Chitosan (pKa 6.5) is cationic and swells at acidic pH, making it suitable for gastric drug delivery. In one study, chitosan-based hydrogels loaded with metronidazole remained in a dog's stomach for over 48 hours, showing prolonged residence time. - Alginate (pKa 3.2) is anionic and swells at basic pH, ideal for colon delivery. Alginate gels form in the presence of divalent cations (Ca2+, Ba2+, Sr2+, Zn2+). - Hyaluronic acid (pKa 3–4) swells up to 1000-fold at neutral pH due to its anionic nature. - Dextran (pKa 7.4) is degraded by dextranase produced by colon bacteria, enabling colon-specific release. - Guar gum succinate microparticles showed faster swelling and drug release at pH 7.4 (simulated intestinal fluid) compared to pH 1.2 (simulated gastric fluid). - Carrageenan-based hydrogels increased drug release from 15% at pH 1.2 to 80% at pH 7.4. - For oral insulin delivery, N-succinyl chitosan hydrogels released negligible insulin in stomach but quantitative release in alkaline environment, achieving 4.43% relative bioavailability in diabetic mice with no adverse effects. - Injectable hydrogels using multialdehyde guar gum and N,O-carboxymethyl chitosan released more doxorubicin at acidic pH (tumor environment) than neutral pH, killing 72% of MCF-7 cells. - A chitosan/fenugreek-g-poly(MAA) hydrogel for capecitabine showed 93% release over 30 hours at pH 7.4, with plasma half-life of 13 hours and AUC of 42.88 μg·h/mL.

**Clinical Implications:** pH-responsive hydrogels from non-cellulosic biopolymers offer a promising platform for targeted and controlled drug delivery, addressing challenges such as drug degradation in the stomach, poor intestinal absorption, and tumor acidity. They can improve therapeutic outcomes for gastric disorders, colon diseases (e.g., ulcerative colitis, colorectal cancer), diabetes (oral insulin), and cancer (localized chemotherapy). Commercial products already exist (e.g., hyaluronic acid-based Juvederm, alginate-based Ocusert), indicating clinical translation potential. However, limitations include batch-to-batch variability, weak mechanical properties, rapid biodegradation, and high production costs. Future research should focus on semi-synthetic modifications, grafting, and integration with imaging technologies to enhance performance and sustainability.