Tailored Design of an ROS-Responsive Drug Release Platform for Enhanced Tumor Therapy via “Sequential Induced Activation Processes”

Abstract

The reactive oxygen species (ROS)-responsive intelligent drug delivery system has developed rapidly in recent years. However, because of the low concentration of ROS in most types of tumor cells, it is not possible to rapidly and effectively stimulate the drug delivery system to release the active drug. Here, we introduced “sequential induced activation processes” for efficient tumor therapy by designing a new ROS-responsive drug release platform. β-Lapachone, a positively charged nitrogen mustard (NM) prodrug, and two diblock molecules (mPEG-AcMH and PAsp-AcMH) are self-assembled to form prodrug primary micelles, which are further aggregated into nanoparticles that facilitate drug codelivery. When administered by intravenous injection, the nanoparticles reach the tumor site and enter the tumor cells by endocytosis. The β-lapachone released in the tumor cells induces a large amount of H2O2, and the ROS-responsive NM prodrug is activated to form activated NM, quinone methide, and boric acid under the induction of H2O2. The activated NM leads to tumor cell apoptosis.

pH and ROS sequentially responsive podophyllotoxin prodrug micelles with surface charge-switchable and self-amplification drug release for combating multidrug resistance cancer

“…3.1. PPT prodrug designed and self-assembly (Lv et al, 2014;Luan et al, 2019;Xu et al, 2020). The polyamine acid chain can be decomposed by enzymatic hydrolysis of the peptide bond, and the degradation product can be applied to the life cycle of the organism (Guo et al, 2020).…”

Smart Nanoparticles for Chemo-Based Combinational Therapy

“…Some studies reported that the ROS in tumors was insufficent to rapidly and effectively stimulate the drug delivery. To address this issue, Luan et al introduced "sequential induced activation process" to the ROS-responsive nanoplatform [83], where β-lapachone (a ROSsensitive nitrogen mustard prodrug) and two diblock polymers were self-assembled to form nanoparticles favorable for drug delivery. At tumor sites, the release of β-lapachone induced the generation of H 2 O 2 , which triggered the ROS-sensitive nitrogen mustard prodrug to form the active nitrogen mustard, leading to the cellular apoptosis.…”

Recent Advances and Challenges in Controlling the Spatiotemporal Release of Combinatorial Anticancer Drugs from Nanoparticles

“…In contrast, polyamino acid chains are characterized by remarkable biocompatibility, perfect biodegradability, and low toxicity [144,145]. Therefore, Luan et al formed nanoparticle(P-NM-Lapa) with polyaspartic acid-acetylated maltoheptaose (PAsp-AcMH) composed of (AcMH) and (PAsp), mPEG-AcMH composed of AcMH and nontoxic PEG, and β-lapachone and positively charged nitrogen mustard (NM) prodrug [36]. P-NM-Lapa decomposes AcMH in an acidic environment, releasing β-lapachone and NM prodrugs.…”

“…Therefore, this means that P-NM-Lapa is more stable in the body and has no toxic side effects compared to when DOX was administered. In addition, by using β-lapachone together with a NM prodrug that reacts with H 2 O 2 and has less toxicity, a synergistic effect and selective expression in cancer cells can be realized [36].…”