pH-Sensitive stimulus-responsive nanocarriers for targeted delivery of therapeutic agents

Abstract

In recent years miscellaneous smart micro/nanosystems that respond to various exogenous/endogenous stimuli including temperature, magnetic/electric field, mechanical force, ultrasound/light irradiation, redox potentials, and biomolecule concentration have been developed for targeted delivery and release of encapsulated therapeutic agents such as drugs, genes, proteins, and metal ions specifically at their required site of action. Owing to physiological differences between malignant and normal cells, or between tumors and normal tissues, pH-sensitive nanosystems represent promising smart delivery vehicles for transport and delivery of anticancer agents. Furthermore, pH-sensitive systems possess applications in delivery of metal ions and biomolecules such as proteins, insulin, etc., as well as co-delivery of cargos, dual pH-sensitive nanocarriers, dual/multi stimuli-responsive nanosystems, and even in the search for new solutions for therapy of diseases such as Alzheimer's. In order to design an optimized system, it is necessary to understand the various pH-responsive micro/nanoparticles and the different mechanisms of pH-sensitive drug release. This should be accompanied by an assessment of the theoretical and practical challenges in the design and use of these carriers. WIREs Nanomed Nanobiotechnol 2016, 8:696-716. doi: 10.1002/wnan.1389 For further resources related to this article, please visit the WIREs website.

FIGURE 1

(a) Hypoxia and the resultant decreased pH_e induced by different routes including production and export of H⁺ and lactate (through up-regulation of NHE1, MCT4), conversion of CO₂ to carbonic acid, influx of the dissociated weak base HCO₃⁻ while H⁺ is left outside, etc., (b); glucose metabolism in mammalian cells involving aerobic glycolysis metabolism (i.e., Warburg effect). ((a) Reprinted with permission from Ref. Copyright 2012 Elsevier. (b) Reprinted with permission from Ref. Copyright 2004 Nature)

FIGURE 2

Several examples of pH-sensitive nanocarrier platforms.

FIGURE 3

Schematic illustration of drug loading and release of drug in a pH-sensitive micelle.

FIGURE 4

(a) Schematic illustration of the LBL-coated LNPs fabrication process, and (b) cell viability of LNPs, LBL-LNPs, and free DOX. (Reprinted with permission from Ref. Copyright 2014 Elsevier)

FIGURE 5

(a) Schematic of fabrication of PDA coated MSNs and pH-dependent drug release, (b) DOX release profile from MSN-DOX@PDA at various pH values. (Reprinted with permission from Ref. Copyright 2014 Elsevier)

FIGURE 6

Dissolution of micelles based on pH changes.

FIGURE 7

Schematic representation of drug delivery and release by using liposomes.

FIGURE 8

The swelling mechanism for different kinds of nanocarriers.

FIGURE 9

Cumulative release of DOX from polymer-drug conjugate NPs through cleavage of acid-labile hydrazonelinker. (Reprinted with permission from Ref. Copyright 2011 American Chemical Society)