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Reexamining the effects of drug loading on the in vivo performance of PEGylated liposomal doxorubicin

Acta Pharmacologica Sinica volume 45, pages 646–659 (2024)Cite this article

Abstract

Higher drug loading employed in nanoscale delivery platforms is a goal that researchers have long sought after. But such viewpoint remains controversial because the impacts that nanocarriers bring about on bodies have been seriously overlooked. In the present study we investigated the effects of drug loading on the in vivo performance of PEGylated liposomal doxorubicin (PLD). We prepared PLDs with two different drug loading rates: high drug loading rate, H-Dox, 12.9% w/w Dox/HSPC; low drug loading rate, L-Dox, 2.4% w/w Dox/HSPC (L-Dox had about 5 folds drug carriers of H-Dox at the same Dox dose). The pharmaceutical properties and biological effects of H-Dox and L-Dox were compared in mice, rats or 4T1 subcutaneous tumor-bearing mice. We showed that the lowering of doxorubicin loading did not cause substantial shifts to the pharmaceutical properties of PLDs such as in vitro and in vivo stability (stable), anti-tumor effect (equivalent effective), as well as tissue and cellular distribution. Moreover, it was even more beneficial for mitigating the undesired biological effects caused by PLDs, through prolonging blood circulation and alleviating cutaneous accumulation in the presence of pre-existing anti-PEG Abs due to less opsonins (e.g. IgM and C3) deposition on per particle. Our results warn that the effects of drug loading would be much more convoluted than expected due to the complex intermediation between nanocarriers and bodies, urging independent investigation for each individual delivery platform to facilitate clinical translation and application.

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Fig. 1: Characterization of H-Dox and L-Dox.
Fig. 2: Pharmacokinetic profiles of PEGylated liposomes (sLips) with or without Dox administered to SD rats.
Fig. 3: Pharmacokinetic profiles and protein coronas of H-Dox and L-Dox in SD rats with or without the presence of anti-PEG antibodies (Abs).
Fig. 4: Cutaneous accumulation of H-Dox and L-Dox in BALB/c mice with or without prestimulation with anti-PEG Abs.
Fig. 5: Immunogenicity of H-Dox and L-Dox in SD rats.
Fig. 6: Pharmacodynamics and biosafety of H-Dox and L-Dox in 4T1 subcutaneous tumor-bearing BALB/c mice.
Fig. 7: Pharmacokinetic profiles and tissue distribution of H-Dox and L-Dox in 4T1 subcutaneous tumor-bearing BALB/c mice.
Fig. 8: In vivo cellular uptake of carriers with different lipid concentrations in BALB/c mice.
Fig. 9

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Data availability

The data that support the findings of this study are available within the paper and the supplementary information. All other data are available from the authors upon reasonable request.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (82273866, 82125035, 81973245) and Shanghai Education Commission Major Project (2021-01-07-00-07-E00081).

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Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences & Department of Pharmacy, Shanghai Pudong Hospital & State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 200032, China

    Yi-fei Yu, Shi-qi Lin, Yu-xiu Chu, Yang Yang, Tian-hao Ding, Kuan Jiang & Chang-you Zhan

  2. School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai, 201203, China

    Er-can Wu, Feng Pan, Jun Qian & Chang-you Zhan

  3. Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, 200031, China

    Kuan Jiang

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Yu, Yf., Wu, Ec., Lin, Sq. et al. Reexamining the effects of drug loading on the in vivo performance of PEGylated liposomal doxorubicin. Acta Pharmacol Sin 45, 646–659 (2024). https://doi.org/10.1038/s41401-023-01169-5

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