pH-Responsive Drug Delivery Systems for Cancer Therapy

pH-responsive drug delivery systems exploit the acidic milieu of solid tumours and intracellular compartments to achieve selective release of therapeutic agents. Tumour extracellular pH typically ranges from 6.5 to 6.9, compared with about 7.4 in normal tissues, while endosomal and lysosomal compartments can reach pH values as low as 5.0. Carriers are engineered to undergo protonation, bond cleavage or structural collapse under these acidic conditions, triggering payload release. Common strategies include acid-labile linkages (for example hydrazone or imine bonds), protonation-induced polymer swelling or disassembly, and pH-sensitive shielding of targeting ligands. Such systems improve drug accumulation at the tumour site, enhance cellular uptake and facilitate endosomal escape, thereby reducing systemic toxicity and overcoming drug resistance mechanisms. Recent advances span liposomes, polymeric and polypeptide micelles, dendrimers and hybrid nanoparticles, many of which combine chemotherapy with immunomodulation or imaging capabilities. These technologies hold global significance by offering more effective, tailored cancer therapies with the potential to improve patient outcomes and reduce adverse effects.

Research from Nature Portfolio

A dual-functional liposomal platform has been developed by co-modifying liposomes with an integrin-targeting peptide and a pH-responsive antimicrobial peptide. Under mildly acidic conditions, this system achieves enhanced uptake by integrin‐positive tumour cells, efficient lysosomal escape and controlled paclitaxel release, culminating in marked tumour inhibition in animal models. In a separate study, histidine-modified polysaccharide nano-micelles were formulated to self-assemble around paclitaxel. These micelles display pH-triggered swelling and drug release at pH values characteristic of tumour interstitium and endosomal compartments, resulting in increased cytotoxicity against cancer cells and significant suppression of tumour growth in vivo.

pH-Responsive Drug Delivery Systems for Cancer Therapy publication trend

The graph below shows the total number of articles in ph-responsive drug delivery systems for cancer therapy across all publications each year (not limited to Nature Index journals).

Technical terms

pH-responsive: Describes materials that alter their chemical bonds or structure in response to changes in acidity, enabling controlled release of drugs under specific pH conditions.

Extracellular matrix (ECM): The network of proteins and polysaccharides surrounding cells; in tumours, the ECM is often mildly acidic and can trigger pH-sensitive carriers.

Endosome: A membrane-bound intracellular compartment where internalised materials are sorted; acidification within endosomes can serve as a stimulus for drug release.

Lysosomal escape: The process by which delivery systems avoid degradation in lysosomes and release therapeutic cargo into the cytosol.

Encapsulation efficiency: The percentage of a drug successfully loaded into a carrier during formulation, reflecting payload incorporation.

References

1. Delivery of Chemotherapy Agents and Nucleic Acids with pH-Dependent Nanoparticles. Pharmaceutics (2023).
2. Dual-functionalized liposomal delivery system for solid tumors based on RGD and a pH-responsive antimicrobial peptide. Scientific Reports (2016).
3. A novel pH-sensitive carrier for the delivery of antitumor drugs: histidine-modified auricularia auricular polysaccharide nano-micelles. Scientific Reports (2017).
4. Precise delivery of doxorubicin and imiquimod through pH-responsive tumor microenvironment-active targeting micelles for chemo- and immunotherapy. Materials Today Bio (2022).