Evaluation of paclitaxel-loaded polymeric nanoparticles in 3D tumor model: impact of tumor stroma on penetration and efficacy

Dwi L. Priwitaningrum, Kunal Pednekar, Alexandros V. Gabriël, Aida A. Varela-Moreira, Severine Le Gac, Ivo Vellekoop, Gert Storm, Wim E. Hennink, Jai Prakash*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Since tumor stroma poses as a barrier to achieve efficacy of nanomedicines, it is essential to evaluate nano-chemotherapeutics in stroma-mimicking 3D models that reliably predict their behavior regarding these hurdles limiting efficacy. In this study, we evaluated the effect of paclitaxel-loaded polymeric micelles (PTX-PMCs) and polymeric nanoparticles (PTX-PNPs) in a tumor stroma–mimicking 3D in vitro model. PTX-PMCs (77 nm) based on a amphiphilic block copolymer of mPEG-b-p(HPMAm-Bz) and PTX-PNPs (159 nm) based on poly(lactic-co-glycolic acid) were prepared, which had an encapsulation efficiency (EE%) of 81 ± 15% and 45 ± 8%, respectively. 3D homospheroids of mouse 4T1 breast cancer cells and heterospheroids of NIH3T3 fibroblasts and 4T1 (5:1 ratio) were prepared and characterized with high content two-photon microscopy and immunostaining. Data showed an induction of epithelial-mesenchymal transition (α-SMA) in both homo- and heterospheroids, while ECM (collagen) deposition only in heterospheroids. Two-photon imaging revealed that both fluorescently labeled PMCs and PNPs penetrated into the core of homospheroids and only PMCs penetrated into heterospheroids. Furthermore, PTX-PMCs, PTX-PNPs, and free PTX induced cytotoxicity in tumor cells and fibroblasts grown as monolayer, but these effects were substantially reduced in 3D models, in particular in heterospheroids. Gene expression analysis showed that heterospheroids had a significant increase of drug resistance markers (Bcl2, Abgc2) compared to 2D or 3D monocultures. Altogether, this study shows that the efficacy of nanotherapeutics is challenged by stroma-induced poor penetration and development of resistant phenotype. Therefore, this tumor stroma–mimicking 3D model can provide an excellent platform to study penetration and effects of nanotherapeutics before in vivo studies. Graphical Abstract: [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)1470-1483
Number of pages14
JournalDrug Delivery and Translational Research
Volume13
Issue number5
DOIs
Publication statusPublished - May 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Funding

The project was supported by Directorate General of Higher Education (DIKTI) of Indonesia.

FundersFunder number
Direktorat Jenderal Pendidikan Tinggi

    Keywords

    • 3D spheroids
    • Nanomedicine
    • Polymeric nanoparticles
    • Therapeutic efficacy
    • Tumor penetration
    • Tumor stroma

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