Nanoparticles Encapsulating Nitrosylated Maytansine To Enhance Radiation Therapy

Abstract

Radiotherapy remains a major treatment modality for cancer types such as non-small cell lung carcinoma (or NSCLC). To enhance treatment efficacy at a given radiation dose, radiosensitizers are often used during radiotherapy. Herein, we report a nanoparticle agent that can selectively sensitize cancer cells to radiotherapy. Specifically, we nitrosylated maytansinoid DM1 and then loaded the resulting prodrug, DM1-NO, onto poly­(lactide-co-glycolic)-block-poly­(ethylene glycol) (PLGA-b-PEG) nanoparticles. The toxicity of DM1 is suppressed by nanoparticle encapsulation and nitrosylation, allowing the drug to be delivered to tumors through the enhanced permeability and retention effect. Under irradiation to tumors, the oxidative stress is elevated, leading to the cleavage of the S–N bond and the release of DM1 and nitric oxide (NO). DM1 inhibits microtubule polymerization and enriches cells at the G2/M phase, which is more radiosensitive. NO under irradiation forms highly toxic radicals such as peroxynitrites, which also contribute to tumor suppression. The two components work synergistically to enhance radiotherapy outcomes, which was confirmed in vitro by clonogenic assays and in vivo with H1299 tumor-bearing mice. Our studies suggest the great promise of DM1-NO PLGA nanoparticles in enhancing radiotherapy against NSCLC and potentially other tumor types.

Photoacoustic Cavitation‐Ignited Reactive Oxygen Species to Amplify Peroxynitrite Burst by Photosensitization‐Free Polymeric Nanocapsules

“…Due to the acid‐responsive dissociation and NIR absorbing properties of NO‐NCPs, in vitro NO release was evaluated against acidic milieu and pulsed laser irradiation [26] . Quantitative detection of NO release from the nanocapsules was indirectly evaluated by a typical Griess assay via the determination of nitrite produced from free NO (Figure 1 E).…”

Nanotechnologies for enhancing cancer immunotherapy

“…A dual sensitization nanocomposite Zr-MOF-QU (quercetin) was developed to inhibit carbonic anhydrase IX (CA IX) so as to alleviate hypoxia-induced resistance and sensitize tumor tissues to improve cell apoptosis from RT [42]. Nitrosylated maytansinoid DM1-NO poly(lactide-co-glycolic)-block-poly (ethylene glycol) (PLGA-b-PEG) nanoparticles synergistically enhanced RT effect via the inhibition of microtubule polymerization and enrichment of cells at the G2/M phase [94]. Improving imaging capability is the third way, taking isotopesealed nanocapsules which are switchable from "cold" to "hot" under neutron radiation as an example [43].…”

Diverse Particle Carriers Prepared by Co‐Precipitation and Phase Separation: Formation and Applications

“…The toxicity of DM1 is suppressed by nitrosylation and encapsulation. Under irradiation at the tumor site, oxidative stress increases, leading to the S−N bond breakage and the release of DM1 and NO, both of which could suppress the tumors [67] …”