Stimuli-responsive nanoparticles for targeting the tumor microenvironment

Abstract

One of the most challenging and clinically important goals in nanomedicine is to deliver imaging and therapeutic agents to solid tumors. Here we discuss the recent design and development of stimuli-responsive smart nanoparticles for targeting the common attributes of solid tumors such as their acidic and hypoxic microenvironments. This class of stimuli-responsive nanoparticles is inactive during blood circulation and under normal physiological conditions, but is activated by acidic pH, enzymatic up-regulation, or hypoxia once they extravasate into the tumor microenvironment. The nanoparticles are often designed to first "navigate" the body's vascular system, "dock" at the tumor sites, and then "activate" for action inside the tumor interstitial space. They combine the favorable biodistribution and pharmacokinetic properties of nanodelivery vehicles and the rapid diffusion and penetration properties of smaller drug cargos. By targeting the broad tumor habitats rather than tumor-specific receptors, this strategy has the potential to overcome the tumor heterogeneity problem and could be used to design diagnostic and therapeutic nanoparticles for a broad range of solid tumors.

Keywords: Hypoxia; Matrix metalloproteinases; Nanomedicine; Tumor heterogeneity; Tumor microenvironment; pH.

Figure 1

Schematic illustration of stimuli-responsive nanoparticles for targeting the tumor microenvironment. Nanoparticle activation can lead to (a) accelerated drug release, (b) enhanced cellular binding and internalization, and / or (c) improved drug diffusion and tumor penetration.

Figure 2

Schematic diagram showing nanoparticle fluorescence activation in the acidic tumor microenvironment (pH 6.5 – 6.8) and inside the more acidic organelles (pH 5.0 – 6.0). Adapted from Ref [41] with permission from Nature Publishing Group.

Figure 3

(a) Schematic illustration of chemical bond cleavage and charge reversal in pH-sensitive nanogels. In the acidic tumor extracellular environment, the nanogel is activated to become positively charged and is efficiently internalized by tumor cells. (b) pH-activated chemical structure and zeta potential change of the nanogel. (c) Confocal fluorescence microscopy image showing the nanogel distribution in the tumor tissue following intratumoral injection. The white arrows indicate the locations of the nanogels. The nanogel was labeled with fluorescein isothiocyanate (FITC; green), while F-actin and nuclei of the cells were stained, respectively, with rhodamine phalloidin (red) and 4’,6-diamidino-2-phenylindole (DAPI; blue). Figure adapted from Ref [46] with permission from Wiley-VCH.

Figure 4

(a) The amino acid sequence of a pH-responsive insertion peptide. (b) A schematic representation of the peptide in solution and interacting with a lipid bilayer at neutral (pH 7.0) and acidic pH (below pH 6.0). State I refers to the peptide in solution at normal and basic pHs. Upon addition of lipid, the unstructured peptide is adsorbed on the membrane surface (State II). The drop of pH leads to the protonation of Asp/Glu residues, increasing peptide hydrophobicity, and resulting in the insertion and formation of a transmembrane α-helix (State III). Adapted from Ref [59] with permission from the National Academy of Sciences.

Figure 5

MMP2-responsive multifunctional liposomal nanocarrier and its drug delivery strategy. The multifunctional liposomal nanocarriers are retained in the tumor site due to the EPR effect as well as the active targeting effect of mAb 2C5. The up-regulated MMP2 in the tumor microenvironment cleaves the MMP2-sensitive linker and removes the protective long-chain PEG, resulting in the exposure of TAT peptides (TATp) for the enhanced cellular internalization. Figure adapted from Ref [83] with permission from the American Chemical Society.

Figure 6

Hypoxia-activated phototriggered nanoparticles specifically release drug to tumor cells. In this design, an electron acceptor, nitroimidazole, was incorporated into the coumarin phototrigger that has an intrinsic property of photo-S N 1-dependent cleavage and a sufficiently high two-photon absorption cross section. In normal tissues, photoexcitation of the coumarin dye relaxes via photoinduced electron transfer (PET) to the adjacent nitroimidazole group, resulting in the inactivation of fluorescence, photocleavage and drug release. In contrast, in the hypoxic environment of the solid tumors, the nitro group of the nitroimidazole is reduced to an amine, which activates the coumarin phototrigger by eliminating the PET process and leads to the recovery of fluorescence and the efficient drug release. Figure adapted from Ref [105] with permission from Wiley-VCH.