PEGylated versus Non-PEGylated pH-Sensitive Liposomes: New Insights from a Comparative Antitumor Activity Study

PEGylated liposomes are largely studied as long-circulating drug delivery systems. Nevertheless, the addition of PEG can result in reduced interactions between liposomes and cells, hindering liposomal internalization into target cells. The presence of PEG on the surface of pH-sensitive liposomes is not advantageous in terms of biodistribution and tumor uptake, raising the question of whether the indiscriminate use of PEG benefits the formulation. In this study, two doxorubicin-loaded pH-sensitive liposomal formulations, PEGylated (Lip2000-DOX) or non-PEGylated (Lip-DOX), were prepared and characterized. Overall, the PEGylated and non-PEGylated liposomes showed no differences in size or morphology in Cryo-TEM image analysis. Specifically, DLS analysis showed a mean diameter of 140 nm, PDI lower than 0.2, and zeta potential close to neutrality. Both formulations showed an EP higher than 90%. With respect to drug delivery, Lip-DOX had better cellular uptake than Lip2000-DOX, suggesting that the presence of PEG reduced the amount of intracellular DOX accumulation. The antitumor activities of free-DOX and both liposomal formulations were evaluated in 4T1 breast tumor-bearing BALB/c mice. The results showed that Lip-DOX was more effective in controlling tumor growth than other groups, inhibiting tumor growth by 60.4%. Histological lung analysis confirmed that none of the animals in the Lip-DOX group had metastatic foci. These results support that pH-sensitive liposomes have interesting antitumor properties and may produce important outcomes without PEG

Toxicological study of a new doxorubicin-loaded pH-sensitive liposome : a preclinical approach.

Doxorubicin (DOX) is widely used in cancer treatment, however, the use of this drug is often limited due to its cardiotoxic side effects. In order to avoid these adverse effects, the encapsulation of DOX into nanosystems has been used in the last decades. In this context, pH-sensitive liposomes have been shown promising for delivering cytotoxic agents into tumor cells, however, the lack of information about in vivo toxicity of this nanocarrier has impaired translational studies. Therefore, the aim of this work was to investigate the acute toxicity and cardiotoxicity of DOX-loading pH-sensitive liposomes (SpHL-DOX). To achieve this, female BALB/c mice, after intravenous administration, were monitored by means of clinical, laboratory, histopathological and electrocardiographic (ECG) analyses. Results indicate that SpHL was able to prevent renal toxicity and the hepatic injury was less extensive than free DOX. In addition, lower body weight loss was associated with less ECG QT interval prolongation to animals receiving SpHL-DOX (14.6???5.2%) compared to animals receiving free DOX (35.7???4.0%) or non-pH-sensitive liposomes (nSpHL-DOX) (47.0???9.8%). These results corroborate with SpHL-DOX biodistribution studies published by our group. In conclusion, the SpHL-DOX showed less toxic effects on mice compared to free DOX or nSpHL-DOX indicating that SpHL-DOX is a promising strategy to reduce the serious cardiotoxic effects of DOX