Enhanced penetration of pro-apoptotic and anti-angiogenic micellar nanoprobe in 3D multicellular spheroids for chemophototherapy

Anbu Mozhi, Vishnu Sunil, Wenbo Zhan, Pramila Baban Ghode, Nitish V Thakor, Chi-Hwa Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)
7 Downloads (Pure)


Light irradiation is considered an ideal non-invasive stimulus that enables precise tumour treatment with flexible, facile, and spatiotemporal control. Photodynamic therapy (PDT) is an important clinically relevant therapeutic modality that has proven to compensate for the reduced therapeutic efficacy of conventional chemotherapy. However, oxygen consumption during PDT can result in an inadequate oxygen supply which reduces photodynamic efficacy. In our quest to circumvent the limitations of chemotherapy and photodynamic therapy, we have engineered a robust and smart “all-in-one” nanoparticle-based drug delivery system capable of overcoming biological barriers and leveraging on several synergistic cancer cell killing mechanisms. The fabricated Targeted Micellar Nanoprobe (TMNP) had exceptionally high encapsulation efficiencies of a hydrophobic drug simvastatin (SV) and a photosensitizer protoporphyrin IX (PpIX) due to the ℼ-ℼ stacking of the aromatic groups of SV and PpIX and strong hydrophobic interactions with the alkyl chains of the carrier. In-vitro results demonstrated that TMNP exhibited excellent colloidal stability, biocompatibility and drug retaining capability in physiological condition. Under light irradiation, TMNP causes the accelerated generation of reactive oxygen species (ROS) which subsequently damages the mitochondria. On further evaluation of the mechanisms behind the superior anti-cancer effect of TMNP, we concluded that TMNP causes synergistic apoptosis and necrosis along with cell cycle arrest at the G1-S phase and elicits anti-angiogenic effects. Taking into consideration that these promising results on 2D monolayer cell cultures might not translate into similar results in animal models, we developed 3D multicellular tumour spheroids (MCs) as an intermediate step to bridge the gap between 2-D cell experiments and in-vivo studies. TMNPs showed enhanced penetration and growth inhibition on MCs. In addition, the modelling of the transport of TMNP in the tumour exhibited the improved effective delivery volume. Overall, TMNPs could potentially be used for image-guided delivery of the therapeutic payloads for precise cancer treatment.

Original languageEnglish
Pages (from-to)502-518
Number of pages17
JournalJournal of Controlled Release
Early online date5 May 2020
Publication statusPublished - 10 Jul 2020

Bibliographical note

Chi-Hwa Wang is supported by National Additive Manufacturing Innovation Cluster @ National University of Singapore. Nitish V. Thakor is supported by Singapore National Research Foundation, Award No.: NRF-CRP15- 201 5-04. Vishnu Sunil greatly appreciates the National University of Singapore Research Scholarship for the funding of his Ph.D. studies in the National University of Singapore.


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