Stimulus-Responsive Sequential Release Systems for Drug and Gene Delivery

Abstract

In recent years, a range of studies have been conducted with the aim to design and characterize delivery systems that are able to release multiple therapeutic agents in controlled and programmed temporal sequences, or with spatial resolution inside the body. This sequential release occurs in response to different stimuli, including changes in pH, redox potential, enzyme activity, temperature gradients, light irradiation, and by applying external magnetic and electrical fields. Sequential release (SR)-based delivery systems, are often based on a range of different micro- or nanocarriers and may offer a silver bullet in the battle against various diseases, such as cancer. Their distinctive characteristic is the ability to release one or more drugs (or release drugs along with genes) in a controlled sequence at different times or at different sites. This approach can lengthen gene expression periods, reduce the side effects of drugs, enhance the efficacy of drugs, and induce an anti-proliferative effect on cancer cells due to the synergistic effects of genes and drugs. The key objective of this review is to summarize recent progress in SR-based drug/gene delivery systems for cancer and other diseases.

Keywords: cancer nanomedicine; sequential drug and gene release; stimulus-responsive nanoparticles; synergistic combinations; temporal control.

Fig. 1.

Schematic illustration of the effects of stimulating factors in sensitive carriers mediating sequential drug release in a tumor model.

Fig. 2.

Schematic illustration of the CR multifunctional DOX loaded MSN. As depicted MSNs were decorated in a stepwise manner by HA, gelatin, and PEG. MSN@HA was loaded by DOX. In a bienzymatic responsive process the gelatin layer was hydrolyzed by MMP-2, and after HA receptor-mediated endocytosis the MSN@HA/DOX was trapped in the tumor and underwent HA hydrolysis, DOX released in controlled manner [56]. The figure was adapted from Reference [56] and reproduced under the Creative Commons Attribution License, which permits unrestricted use.

Fig. 3.

Schematic illustration of HPAH-DOX micelles encapsulating LY. In this system, the SR was demonstrated with LY being released faster than DOX, making the tumor cells more sensitive to DOX by inhibiting autophagy. Reprinted (adapted) with permission from [92] Copyright (2020) American Chemical Society.

Fig. 4.

Schematic illustration of sequential drug release (CUR & catechin) from pH-sensitive core-shell chitosan microcapsules. a) Decomposition of chitosan shell with burst release of CUR & catechin in acidic conditions; b) Destruction of PLGA NPs and sustained-release of CUR & catechin in two days degradation of PLGA core in acidic conditions Reprinted (adapted) with permission from [20] Copyright (2020) American Chemical Society.

Fig. 5.

a) Schematic illustration of PEG-PLA NPs containing PTX in the PLA core, and the three-layer structure of the ADENS; b) the simultaneous delivery of PTX and siRNA in tumor cells and effect in tumor growth. Open access from Springer Nature[132], no permission needed.

Fig. 6.

a) Schematic illustration of photolysis MCP and DOC under 405 nm and 365 nm, respectively; b) SR of DOX and shRNA using PMSNs regulated by two wavelength light Reprinted (adapted) with permission from [27] Copyright (2020) American Chemical Society.

Fig. 7.. Schematic illustration of multifunctional magnetoliposomes and the SR of carboxyfluorescein and therapeutic zipper ON.

Carboxyfluorescein was first released after exposure to a 3.22 kHz AMF over a short period of time, subsequently, after the applied of 6.22 kHz AMF, zipper ON (dsDNA hybridized with zipper) was released Reprinted (adapted) with permission from [154] Copyright (2020) American Chemical Society.

Fig. 8.. Schematic illustration of SR DOX releases from rGO-AuNRVe-DOX triggered by both NIR laser irradiation and the acidic environment of cancer cells

Reprinted (adapted) with permission from [168] Copyright (2020) American Chemical Society.

Fig. 9.

Schematic illustration of titania nanotube arrays, polymer micelles, and their role in the SR of multiple hydrophobic and hydrophilic drugs. a) loading of two polymer micelles containing hydrophilic and hydrophobic drugs (indomethacin and itraconazole) in TNT; b) the pattern of sequential drugs release from immiscible layers of carriers; c) and d) showed details of SR [33]. Reprinted with permission from the Royal Society of Chemistry (2020).