Application of Nano-Drug Delivery System Based on Cascade Technology in Cancer Treatment

Abstract

In the current cancer treatment, various combination therapies have been widely used, such as photodynamic therapy (PDT) combined with chemokinetic therapy (CDT). However, due to the complexity of the tumor microenvironment (TME) and the limitations of treatment, the efficacy of current treatment options for some cancers is unsatisfactory. Nowadays, cascade technology has been used in cancer treatment and achieved good therapeutic effect. Cascade technology based on nanotechnology can trigger cascade reactions under specific tumor conditions to achieve precise positioning and controlled release, or amplify the efficacy of each drug to improve anticancer efficacy and reduce side effects. Compared with the traditional treatment, the application of cascade technology has achieved the controllability, specificity, and effectiveness of cancer treatment. This paper reviews the application of cascade technology in drug delivery, targeting, and release via nano-drug delivery systems in recent years, and introduces their application in reactive oxygen species (ROS)-induced cancer treatment. Finally, we briefly describe the current challenges and prospects of cascade technology in cancer treatment in the future.

Keywords: cascade technology; combination therapy; multidrug resistance; tumor microenvironment response.

Figure 1

(A) Schematic showing the synthetic procedure of the sequentially responsive nanosystem (DOX@RCMSNs). (B) Schematic illustration of DOX@RCMSNs overcoming the cascaded bio-barriers and the mechanism of action in tumor cells. Adapted from [30].

Figure 2

(A) Schematic diagram of the construction of HACT NPs with the cascade of two targeting agents (HA and peptide) and two cancer therapeutic agents (siRNA and Dox). (B) Schematic illustration of HACT NPs for the treatment of CTGF-overexpressing breast cancer. Adapted from [36].

Figure 3

(A) Schematic diagram of the pHe/photosensitive decomposition of DTRCD. (B) Schematic illustration of the cascade nucleus-targeted drug delivery strategy of DTRCD. Adapted from [45].

Figure 4

(A) Schematic illustration of cascade self-amplifiable drug release and charge reversal PPDC system for tumor therapy. (B) Intracellular ATP level in MCF-7 ADR cells treated with different formulations for 4 h. (C) Quantitative analysis of P-gp expression after incubation of different formulations for 48 h. (D) Western blotting images of P-gp expression in MCF-7 ADR cells after incubation of different formulations for 48 h. β-actin was used as control. (E) Volume of tumor treated with different dosage forms after 21 days. (** p < 0.01 (t-test)) Adapted from [52].

Figure 5

(A) Schematic representation of NQO1-responsive drug delivery system and drug release. (B) TEM images of the micelles after enzyme-mediated disassembly (scale bar: 200 nm) and time-dependent DLS size distribution of QPA-P micelles upon incubation with NQO1 enzymes. (C) Intracellular DOX release from QPA-PM-DOX and Bz-PMDOX in A549 (NQO1 positive) and H596 (NQO1 negative) observed by CLSM (scale bar: 50 μm). Adapted from [62].

Figure 6

(A) Schematic of the cascade reaction of self-destructive polymeric nanomicelles. (B) zeta-potential of Ce6-loaded PEG-PBCTKDOX nanomicelles. (C) Penetration of DOX in MCF7/ADR 3D cell spheroids. (D) Tumor images of H&E staining, Ki67 immunohistochemistry, and TUNEL assay after the treatment depicting morphology, proliferation, and apoptosis, respectively. (E) Final tumor volume images after different drug treatment. Adapted from [4].

Figure 7

(A) Synthetic procedure of CPT@MOF(Fe)-GOX. (B) Schematic illustration of CPT@MOF(Fe)-GOX via a cascade reaction (1–3) in cancer cells. Adapted from [76].

Figure 8

(A) Synthetic procedure of mCMSNs. (B) Schematic illustration of therapeutic mechanism of mCMSNs for PDT under Laser. (C) Chemical mechanism of GSH-triggered CDT and MRI. Adapted from [86].

Figure 9

Formulation of nanoparticles and the ROS-enhanced chemotherapy mechanism. (A) Schematic of the DPPF NPs self-assembly process. (B) Schematic illustration of the DPPF NPs treating cancer mechanism. Adapted from [87].

Figure 10

The scheme of fabrication process and therapeutic mechanism of thermo-responsive (MSNs@CaO₂-ICG)@LA NPs for synergistic CDT/PDT with H₂O₂/O₂ self-supply and GSH depletion. Adapted from [96].