Smart pH-responsive nanomedicines for disease therapy

Abstract

Background Currently nanomedicines are the focus of attention from researchers and clinicians because of the successes of lipid-nanoparticles-based COVID-19 vaccines. Nanoparticles improve existing treatments by providing a number of advantages including protection of cargo molecules from external stresses, delivery of drugs to target tissues, and sustained drug release. To prevent premature release-related side effects, stable drug loading in nanoformulations is required, but the increased stability of the formulation could also lead to a poor drug-release profile at the target sites. Thus, researchers have exploited differences in a range of properties (e.g., enzyme levels, pH, levels of reduced glutathione, and reactive oxygen species) between non-target and target sites for site-specific release of drugs. Among these environmental stimuli, pH gradients have been widely used to design novel, responsive nanoparticles. Area covered In this review, we assess drug delivery based on pH-responsive nanoparticles at the levels of tissues (tumor microenvironment, pH ~ 6.5) and of intracellular compartments (endosome and lysosome, pH 4.5–6.5). Upon exposure to these pH stimuli, pH-responsive nanoparticles respond with physicochemical changes to their material structure and surface characteristics. These changes include swelling, dissociation, or surface charge switching, in a manner that favors drug release at the target site (the tumor microenvironment region and the cytosol followed by endosomal escape) rather than the surrounding tissues. Expert opinion Lastly, we consider the challenges involved in the development of pH-responsive nanomedicines.

The Future of Tissue-Targeted Lipid Nanoparticle-Mediated Nucleic Acid Delivery

“…Another potentially impactful application of LNP technology is modification to exploit stimuli-responsive properties. Internal (e.g., pH, enzyme and redox) and external (e.g., temperature, light, ultrasound and magnetic fields) stimuli have been explored for a variety of nanoparticle platforms [ 80 , 81 , 82 , 83 , 84 ], with Celsion Corporation’s ThermoDox arguably the most well-known example [ 85 , 86 , 87 ]. There are several reports in the literature using internal and external stimuli to afford the release of nucleic acid cargos.…”

Nanoparticles targeting hematopoietic stem and progenitor cells: Multimodal carriers for the treatment of hematological diseases

“…Entrapment in endosomes/lysosomes leads to payload degradation and is a potential failure point of NP systems carrying gene editing tools. Incorporation of pH-sensitive compounds or cleavable chemical linkers between the PEG moiety and the NP surface can overcome entrapment in lysosomes ( Schmaljohann, 2006 ; Zerrillo et al, 2019 ; Shinn et al, 2022 ). Upon reduction in pH during the endosomal/lysosomal routing, the linkers can be cleaved to expose a positively charged surface to trigger endosomal escape and translocation to the cytoplasm.…”

“…Different mechanisms, including membrane fusion, osmotic or mechanic rupture due to NP swelling, and membrane destabilization by pH-responsive NPs have been proposed to underlie endosomal escape and subsequent release of encapsulated payload into the cytosol ( Smith et al, 2019 ). As the endosomal escape of NPs is crucial for the efficacy of cargo delivery, positively charged or pH-sensitive functional groups can be incorporated into NPs to enhance this process ( Schmaljohann, 2006 ; Shinn et al, 2022 ).…”

Stimuli‐accelerated polymeric drug delivery systems

“…35 Besides the intracellular delivery of drugs, pHdependent release can be used in tumor therapy for targeting the TME, which is weakly acidic (pH 6.5). 36 For this reason, smart DDS are a very interesting approach for optimizing tumor therapy and, therefore, pH-dependent systems are described in a multitude of studies and reviews. 37,38 Most of the published research regarding pH-responsiveness deals either with an acid-induced polarity switch, 39,40 e.g.…”

“…These lipids switch their charge from neutral to cationic based on the neutral pH in the blood and the acidic pH in endosomes 35 . Besides the intracellular delivery of drugs, pH‐dependent release can be used in tumor therapy for targeting the TME, which is weakly acidic (pH 6.5) 36 . For this reason, smart DDS are a very interesting approach for optimizing tumor therapy and, therefore, pH‐dependent systems are described in a multitude of studies and reviews 37, 38 …”