Improved antitumor activity and reduced myocardial toxicity of doxorubicin encapsulated in MPEG-PCL nanoparticles

Abstract

Abstract. Doxorubicin (Dox) is a broad-spectrum antitumor drug used for the treatment of many types of malignant tumors. Although it possesses powerful antitumor activity, its clinical application is seriously encumbered by its unselective distribution and systemic toxicities, particularly myocardial toxicity. Thus, it is imperative to modify Dox to decrease its systemic toxicities and improve its therapeutic index. In the present study, we adopted a novel type of monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles to encapsulate Dox to prepare Dox-loaded MPEG-PCL (Dox/MPEG-PCL) nanoparticles by a controllable self-assembly process. The cellular uptake efficiency and cell proliferation inhibition of the Dox/MPEG-PCL nanoparticles were examined. The antitumor activity of the Dox/ MPEG-PCL nanoparticles was tested on a multiple pulmonary metastasis model of melanoma on C57BL/6 mice. Systemic toxicities and survival time were compared between the mice treated with the Dox/MPEG-PCL nanoparticles and free Dox. The potential myocardial toxicity of the Dox/MPEG-PCL nanoparticles was investigated using a prolonged observation period. Encapsulation of Dox in MPEG-PCL nanoparticles significantly improved the cellular uptake and cell proliferation inhibition of Dox in vivo. Intravenous injection of Dox/ MPEG-PCL nanoparticles obtained significant inhibition of the growth and metastasis of melanoma in the lung and prolonged survival time compared with free Dox (P<0.05). The Dox/MPEG-PCL nanoparticles did not show obvious additional systemic toxicities compared with free Dox during the treatment time. During the prolonged observation period, obvious decreased cardiac toxicity was observed in the Dox/ MPEG-PCL nanoparticle-treated mice compared with that observed in the free Dox-treated mice. These results indicated that encapsulating Dox with MPEG-PCL micelles could significantly promote its antitumor activity and reduce its toxicity to the myocardium.

Autocatalytic Delivery of Brain Tumor–Targeting, Size‐Shrinkable Nanoparticles for Treatment of Breast Cancer Brain Metastases

“…Despite its inhibitory effect on tumor growth, treatment with DOX significantly reduced mouse weight (Figure 6g). Histological analysis revealed that this side effect was caused by significant myocardial injury, a well‐known dose‐limiting factor for in vivo used of DOX;23 in contrast, DOX‐LANPs did not induce detectable myocardial toxicity nor damage to normal organs (Figure S7, Supporting Information). Kaplan–Meier survival analysis found that treatment with DOX‐LANPs significantly enhanced the survival of BCBMs‐bearing mice ( p < 0.05).…”

In vitro chemosensitivity of a canine tumor venereal transmissible cancer cell line

“…The effectivity of each drug has been reported at the clinical level in the treatment of several cancers besides CTVT (15)(16)(17)(18)(19)(20)(21)(22)(23). Until now, there were no reports of the use of 5-FU, methotrexate, gemcitabine, temozolomide, panobinostat, and toceranib in CTVT treatment.…”

Zebrafish (Danio rerio) model as an early stage screening tool to study the biodistribution and toxicity profile of doxorubicin-loaded mixed micelles

“…nanotechnological platforms have been recently assayed in zebrafish model to evaluate some of these parameters (Ang et al, 2017;Chen et al, 2017;Gao et al, 2017;Sun et al, 2016).…”