Endogenous pH-responsive nanoparticles with programmable size changes for targeted tumor therapy and imaging applications

Abstract

Nanotechnology-based antitumor drug delivery systems, known as nanocarriers, have demonstrated their efficacy in recent years. Typically, the size of the nanocarriers is around 100 nm. It is imperative to achieve an optimum size of these nanocarriers which must be designed uniquely for each type of delivery process. For pH-responsive nanocarriers with programmable size, changes in pH (~6.5 for tumor tissue, ~5.5 for endosomes, and ~5.0 for lysosomes) may serve as an endogenous stimulus improving the safety and therapeutic efficacy of antitumor drugs. This review focuses on current advanced pH-responsive nanocarriers with programmable size changes for anticancer drug delivery. In particular, pH-responsive mechanisms for nanocarrier retention at tumor sites, size reduction for penetrating into tumor parenchyma, escaping from endo/lysosomes, and swelling or disassembly for drug release will be highlighted. Additional trends and challenges of employing these nanocarriers in future clinical applications are also addressed.

Keywords: endogenous pH-responsive; nanocarriers; size change; targeted drug delivery; tumor therapy.

Figure 1

Illustration of size-dependent antitumor drug delivery. stage 1: extravasation based on the tumor vascular pore size selection (Three arrows indicate that less phagocytosis by MPS, longer circulation time in bloodstream, and higher extraversion at tumor vasculature are beneficial for enhancing passive targeting of tumor by EPR effect); stage 2: antitumor drug delivery in the highly permeable tumor tissue; stage 3: antitumor drug delivery in the poorly permeable tumor tissue; stage 4: tumor cell uptake and subsequent intracellular drug release. pH ~7.4 for normal tumor tissue and blood stream, ~6.5 for tumor tissue, ~5.5 for endosome, ~5.0 for lysosome.

Figure 2

(A) Schematic illustration of pH-responsive aggregation of gold nanoparticlesenhancing targeted retention and cellular uptake in response to the tumor extracellular acidic stimuli. (B) Illustration of the size-dependent prolonging of blood circulation time and targeted tumor retention. (C) TEM images of pH-responsive aggregation. Reproduced with permission from , copyright 2013 American Chemical Society.

Figure 3

(A) Scheme and (B) Digital image of the tumor-targeted aggregation of pH-responsive polymeric nanomicelles for enhanced retention at tumor tissue and rapid intracellular drug release in tumor cells. Reproduced with permission from , copyright 2014 Royal Society of Chemistry.

Figure 4

(A) Schematic of the ultrasensitive pH-triggered charge/size dual-rebound gene delivery system for efficient antitumor applications. (B) Fast hydrodynamic charge/size dual-rebound property and (C) TEM of the gene delivery system. (GP)D and P[(GP)D] represent (PLG/PEI)/DNA and PEG[(PLG/PEI)/DNA], respectively. Reproduced with permission from , copyright 2016 American Chemical Society.

Figure 5

Schematic illustration of a multistage pH-responsive stepwise size reduction and charge-reversal polymeric nanocarrier. (A) negatively charged nanocarrier at neutral pH to enhance blood retention, (B) passive accumulation of larger size nanocarriers in the tumor via EPR effect, (C) the first-stage size reduction into smaller linear copolymers for tumor tissue deep penetration, (D) increased nanocarrier uptake by tumor cells mediated by concomitant R8NLS, (E) the second-stage size reduction into therapeutic drug for intracellular release in the endo/lysosomal compartment, (F) endo/lysosome escape and nuclear targeted delivery. Reproduced with permission from , copyright 2015 Wiley-VCH.

Figure 6

(A) Structure of polymer-drug conjugate. (B) Schematic illustration of the pH-sensitive cluster nanobomb at neutral pH and the disintegration into small particles at tumor due to its acidic pH. (C) Schematic illustration of cluster nanobomb for in vivo drug delivery in the poorly permeable pancreatic tumor model. (I) large superstructure for prolonged blood circulation, (II) targeted tumor accumulation via EPR, (III) pH-responsive disintegration into small particles for deep tumor parenchyma penetration. Hydrodynamic diameter and TEM of polymer-drug conjugate at (D) pH 7.4 and (E) pH 6.7. (F) pH-dependent size change detected by DLS. Reproduced with permission from . Copyright 2016, American Chemical Society.

Figure 7

pH-responsive size-shifting cross-linked micelle nanoclusters for enhanced tumor targeting and deep penetration. Reproduced with permission from , copyright 2016 American Chemical Society.

Figure 8

Illustration of the large compound nanoparticles with pH-activated size reduction property for in vivo nucleus-targeted gene delivery.

Figure 9

Illustration of DOX-loaded micelles for rapid intracellular drug release in response to the acidic stimulus of endo/lysosome in anti-cancer therapy. Reproduced with permission from , copyright 2014 Royal Society of Chemistry.

Figure 10

Highly packed interlayer-crosslinked nanomicelles for reduction- and pH-responsive collectively triggered burst drug release. Reproduced with permission from , copyright 2011 Wiley-VCH.

Figure 11

Acid-labile polycarbonate-modified pH-responsive degradable polymeric nanocarriers showing swelling and eventual disassembly for controlling intracellular drug release.

Figure 12

(A) Illustration of the dual tailor-made pH-responsive polymer-drug conjugate to inhibit drug-resistant cancer stem cells. (B) Acid-labile breakage of the polymer-drug conjugate. (C) In vitro pH-sensitive drug release profiles. Reproduced with permission from , copyright 2011 American Chemical Society.

Figure 13

Illustration of the transformable liquid-metal nanomedicine for the antitumor application. (A) Preparation and (B) Main components of liquid-metal nanomedicine. (C) pH-responsive delivery of the DOX-loaded liquid-metal nanomedicine for targeted antitumor therapy. (D) Acid-triggered fusion and degradation process of liquid-metal nanomedicine. (E) Chemical structures of the main components. Reproduced with permission from , copyright 2015 Nature Publishing Group.

Figure 14

(A) Schematic illustration of pH-responsive aggregation-induced amplification of the photoacoustic signal from Melanin-like nanoparticles and (B) Surface modification of the bare Melanin-like nanoparticles and their aggregation under mildly acidic condition. Reproduced with permission from , copyright 2016 Royal Society of Chemistry.

Figure 15

(A) Schematic of the ultra-pH-responsive hybrid nanotransistor to digitize organelle pH after receptor-mediated endocytosis in tumor cells. (B) The count rates and normalized fluorescence intensity of the hybrid nanotransistor are plotted at different pH values. (C) Representative fluorescence images of multispectral ultra-pH-responsive hybrid nanotransistor at different pH values. Yellow is the merged color of green and red signals. White is the merged color of blue, green, and red signals. Reproduced with permission from , copyright 2017 Wiley-VCH.