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Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: A review
Abstract
As the mainstay in the treatment of various cancers, chemotherapy plays a vital role, but still faces many challenges, such as poor tumour selectivity and multidrug resistance (MDR). Targeted drug delivery using nanotechnology has provided a new strategy for addressing the limitations of the conventional chemotherapy. In the last decade, the volume of research published in this area has increased tremendously, especially with functional nano drug delivery systems (nanocarriers). Coupling a specific stimuli-triggered drug release mechanism with these delivery systems is one of the most prevalent approaches for improving therapeutic outcomes. Among the various stimuli, pH triggered delivery is regarded as the most general strategy, targeting the acidic extracellular microenvironment and intracellular organelles of solid tumours. In this review, we discuss recent advances in the development of pH-sensitive nanocarriers for tumour-targeted drug delivery. The review focuses on the chemical design of pH-sensitive biomaterials, which are used to fabricate nanocarriers for extracellular and/or intracellular tumour site-specific drug release. The pH-responsive biomaterials bring forth conformational changes in these nanocarriers through various mechanisms such as protonation, charge reversal or cleavage of a chemical bond, facilitating tumour specific cell uptake or drug release. A greater understanding of these mechanisms will help to design more efficient drug delivery systems to address the challenges encountered in conventional chemotherapy.
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“Acidic pH caused protonation leads to hydrophilic-hydrophobic phase transition for the anionic polymers, and hydrophobic- hydrophilic phase transition for cationic polymers, inducing deformation of amphiphilic structures leading to drug release [136].”
From Recent Advances in Nanomicelles Delivery Systems. (2020) · cites this paper as [136]
In the citing paper
“Generally, two basic perceptions define the mechanism of the pH-responsive nanoparticles, such as the cleavage of chemical bonds and nanocarrier protonation.138”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [138]
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Anis, T., Hassan, S. M. U., Khurshid, A., Fakhar-e-alam, M., Shahzad, F., Ali, A., Ahmad, J., & Hossain, N. (2022) · Journal of Cluster Science · doi:10.1007/s10876-022-02272-z · Cited by 6
pH-Responsive Natural Polymers as Versatile Carriers for Drug Delivery in Breast Cancer: A Review
Velapure, P. D., Chakote, S. R., Kansal, D., Barooah, A., Pawde, D. M., & Bobade, C. D. (2026) · Biomedical Materials & Devices · doi:10.1007/s44174-025-00427-w · Cited by 5
Naeini, S. M. A., Faramarzi, M., & Heydarinasab, A. (2025) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-025-04166-z · Cited by 5
“Compared to physical encapsulation, covalent drug conjugation via hydrazone linkages enhances drug retention in circulation and ensures precise, tumor-responsive release, thereby reducing systemic toxicity and improving therapeutic efficacy (Kanamala et al. 2016; Rad et al. 2024).”
Wu, W., Chen, Z., Zhe, M., Yu, P., Shakya, S., Xing, F., & Ritz, U. (2025) · Chinese Chemical Letters · doi:10.1016/j.cclet.2025.111448 · Cited by 5
pH-responsive polymers: classification, response mode, properties and biomedical applications
Wang, D., Yao, H., Ye, J., Wang, Z., Cong, H., & Yu, B. (2025) · Chemical Engineering Journal · doi:10.1016/j.cej.2025.168589 · Cited by 5
Nawaz, A., Ahmad, Z., Taj, M. B., Ihsan, A., & Tasleem, M. (2025) · Materials Research Bulletin · doi:10.1016/j.materresbull.2025.113930 · Cited by 6
Click chemistry-based drug delivery systems for targeted cancer therapy
Liu, Y., Zhang, W. E., Wu, Y., Wan, D., & Pan, J. (2026) · Materials Today Bio · doi:10.1016/j.mtbio.2026.102912 · Cited by 5
“In the drug release stage, traditional responsive carriers mostly trigger release by responding to microenvironmental signals such as pH changes or enzyme concentration differences [33,34].”
Esmaeilpour, D., Sivakumar, P. M., Khosravi, A., Zarepour, A., Taj, M. B., Zare, E. N., Sillanpää, M. E. T., & Karimi-Maleh, H. (2026) · Materials Today Bio · doi:10.1016/j.mtbio.2026.102981 · Cited by 7
“For example, in acidic tumor environments or lysosomal compartments, pH-responsiveness coatings like CS, or ALG can be triggered to disassemble, releasing siRNA [139,140].”
pH-Sensitive Macromolecular Carriers: Targeted Therapeutics for Cancer and Inflammation
Singh, D., Kurmi, B. D., Singh, A., & Bhattacharya, S. (2025) · Journal of Macromolecular Science Part B · doi:10.1080/00222348.2025.2466325 · Cited by 5
Stimulus-responsive antibacterial strategies for construction of anti-infection bone implants
Fu, Y., Zhu, M. C., Shi, A., Zhang, B., & Xu, P. (2025) · Next Materials · doi:10.1016/j.nxmate.2025.100554 · Cited by 5
Anticancer Nanoparticle Carriers of the Proapoptotic Protein Cytochrome c
Zhivkov, A. M., Hristova, S. H., & Popov, T. T. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17030305 · Cited by 5
“…the action of triggers such as pH change (the tumor tissue is slightly acidified because of lactate generation), enzymes (some enzymes such as metal-proteinases are highly expressed in the tumor cells), reactive oxygen species, temperature, magnetic field, ultrasound, electric field, etc. [10–12].”
Feng, H., Wang, C., Zhou, J., Liu, J., Zhang, J., Guo, R., Liu, J., Dong, A., & Deng, L. (2018) · Macromolecular Chemistry and Physics · doi:10.1002/macp.201800062 · Cited by 5
Lebedevа, N. S., Yurina, E. S., & Gubarev, Y. A. (2019) · Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy · doi:10.1016/j.saa.2019.02.047 · Cited by 5
Chakraborty, S., Berač, C. M., Urschbach, M., Spitzer, D., Mezger, M., Besenius, P., & Speck, T. (2022) · ACS Applied Polymer Materials · doi:10.1021/acsapm.1c01208 · Cited by 5
Recyclable cell-surface chemical tags for repetitive cancer targeting
Bhatta, R., Han, J., Zhou, J., Li, H., & Wang, H. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.05.007 · Cited by 5
Luo, M., Lin, J., Zhou, X., & Pu, X. (2022) · Scientific Reports · doi:10.1038/s41598-022-26317-5 · Cited by 5
Qin, D., Wang, F., Sheng, W., Chang, S., Duan, H., & Wang, L. (2022) · Journal of the Iranian Chemical Society · doi:10.1007/s13738-022-02727-0 · Cited by 5
“As a tumor-targeted drug delivery carrier, the small particle size of nanogels allows them to enter and remain in cancer tissue through enhanced permeability and retention (EPR) effect [12, 13].”
BackgroundSheng, L., Zhu, X., Sun, M., Lan, Z., Yang, Y., Xin, Y., & Li, Y. (2023) · Pharmaceuticals · doi:10.3390/ph16020166 · Cited by 5
“According to the property of an anionic polymer, its hydrophilic–hydrophobic phase transition can be triggered under a certain pH value, which is usually lower than the pKa of anionic polymer [11].”
Background
Metadata
- Authors
- Kanamala, M., Wilson, W. R., Yang, M., Palmer, B. D., & Wu, Z.
- Affiliations
- University of Auckland (NZ)
- Corresponding author
- Wu, Zimei
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 85
- Pages
- 152-167
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W2288119981
- Cited by
- 1,004
- References
- 213
- Citations by year
- 2026: 65 · 2025: 96 · 2024: 78 · 2023: 85 · 2022: 99 · 2021: 117 · 2020: 129 · 2019: 113 · 2018: 108 · 2017: 77 · 2016: 37
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- ResearchSpace (University of Auckland) (submittedVersion)
- Funders
- Royal Society of New Zealand (UOA1201)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
- Keywords
- pH-responsive nanocarriers, tumour-targeted drug delivery, stimuli-responsive drug release, intracellular drug release, protonation, charge reversal, bond cleavage, tumor selectivity, multidrug resistance, chemotherapy
- MeSH terms
- Animals, Biocompatible Materials, Clinical Trials as Topic, Disease Models, Animal, Humans, Hydrogen-Ion Concentration, Neoplasms, Drug Delivery Systems, Nanotechnology, Nanostructures, Drug Liberation
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