Enzyme/pH-sensitive dendritic polymer-DOX conjugate for cancer treatment

Abstract

It is in a great demand to design a biodegradable, tumor microenvironment-sensitive drug delivery system to achieve safe and highly efficacious treatment of cancer. Herein, a novel pH/enzyme sensitive dendritic pdiHPMA-DOX conjugate was designed. diHPMA dendritic copolymer with GFLG segments in the branches which are sensitive to the intracellular enzyme of the tumor was prepared through RAFT polymerization. DOX was attached to dendritic diHP-MA polymer through a pH-sensitive hydrazone bond. The dendritic pdiHPMA-DOX conjugate self-assembled into nanoparticles with an ideal spherical shape at a mean size of 103 nm. The DOX attached to the polymeric carrier was released in an acidic environment, and the GFLG linker for synthesizing the dendritic vehicle with a high molecular weight (M W , 220 kDa) was cleaved to release low M W segments (<40 kDa) in the presence of cathepsin B. The dendritic polymeric conjugate was internalized via an endocytic pathway, and then released the anticancer drug, which led to significant cytotoxicity for tumors. The blood circulation time was profoundly prolonged, resulting in high accumulation of DOX into tumors. In vivo anti-tumor experiments with 4T1 tumor bearing mice demonstrated that the conjugate had a better antitumor efficacy in comparison with free DOX. Additionally, body weight measurements and histological examinations indicated that the conjugate showed low toxicities to normal tissues. This dendritic polymeric drug carrier in a response to intracellular enzyme and acidic pH of tumor tissue or cells holds great promise in tumor-targeted therapy.

Triggering the Antitumor Activity of Acyclic Enediyne through Maleimide-Assisted Rearrangement and Cycloaromatization

“…On the other hand, taking advantage of the MARACA mechanism, all of the maleimide-based enediynes exhibit significant cytotoxicity toward all three kinds of cancer cells. The IC 50 values range from micromolar to submicromolar levels, comparable to or even higher than many commercial antitumor agents like cisplatin , and doxorubicin . As essential properties for small molecular drugs, solubility and permeability are measured by log P and topological polar surface area (tPSA) values .…”

A novel GSH responsive poly(alpha-lipoic acid) nanocarrier bonding with the honokiol-DMXAA conjugate for combination therapy

“…Considering that both cytotoxic drugs and VDAs need to reach the tumor site to produce a marked effect, we can use the tumor-microenvironment-responsive nanocarriers to enhance the selective release of cytotoxic drugs and VDAs at the tumor sites. According to the characteristics of tumor microenvironment, such as enzymes [12] and pH [13][14][15] differences, high reactive oxygen species (ROS) [16][17][18] and L-glutathione (GSH) [19] level, various stimuli-responsive nanocarriers have been designed. Of these aspects, as the GSH concentration of the malignant tissues is at least four-fold higher than that of the normal tissues [20][21][22], and the intracellular concentration of GSH is much higher than that in most extracellular fluids [23,24], many new GSH responsive nanoparticles achieved selective release of drugs at tumors [25].…”

Recent advances in development of dendritic polymer‐based nanomedicines for cancer diagnosis

“…Fourier transform infrared and titrimetry have been used to characterize their surface chemistry (Gorzkiewicz et al, 2019; Nguyen et al, 2019). Basic properties and structures of dendritic polymers, such as multiple functional groups, excellent water‐solubility, low viscosity, biocompatibility, biodegradability, and stimuli‐responsiveness, endow them with great potential in various applications in the bio‐related field, including but not limited to drug/gene delivery, cancer diagnosis, tissue regeneration, and theranostics (K. Chen, Liao, Guo, Zhang, et al, 2018; Dai et al, 2018; L. Li, Wang, C., Huang, et al, 2018; Pan, Guo, Luo, Yi, & Gu, 2014).…”