Codelivery of π–π Stacked Dual Anticancer Drugs Based on Aloe-Derived Nanovesicles for Breast Cancer Therapy

Abstract

To overcome the low efficacy of conventional monotherapeutic approaches that use a single drug, functional nanocarriers loaded with an amalgamation of anticancer drugs have been promising in cancer therapy. Herein, aloe-derived nanovesicles (gADNVs) are modified with an active integrin-targeted peptide (Arg-Gly-Asp, RGD) by the postinsertion technique to deliver indocyanine green (ICG) and doxorubicin (DOX) for efficient breast cancer therapy. We presented for the first time that the π−π stacking interaction can turn the "competitive" relationship of ICG and DOX inside gADNVs into a "cooperative" relationship and enhance their loading efficiency. The dual-drug codelivery nanosystem, denoted as DIARs, was well stable and leakproof, exhibiting high tumor-targeting capability both in vitro and in vivo. Meanwhile, this nanosystem showed significant inhibition of cell growth and migration and induced cell apoptosis with the combination of phototherapy and chemotherapy. Intravenous administration of DIARs exhibited high therapeutic efficacy in a 4T1 tumor-bearing mouse model and exhibited no obvious damage to other organs. Overall, our DIAR nanosystem constitutively integrated the natural and economical gADNVs, π−π stacking interaction based on efficient drug loading, and tumor-targeted RGD modification to achieve an effective combination therapy for breast cancer.

Emerging Drug Delivery Vectors: Engineering of Plant-Derived Nanovesicles and Their Applications in Biomedicine

“… 14 , 58 , 87 For example, Zeng et al used vesicles extracted from Aloe vera to encapsulate both the photosensitizer indocyanine green (ICG) and the small molecule chemotherapeutic agent doxorubicin (DOX), and this delivery system combined with phototherapy and chemotherapy showed effective inhibition of breast cancer cells. 88 Del Pozo-Acebo et al isolated EVs from broccoli, loaded them with exogenous miRNAs with biological effector capabilities, and then co-incubated them with Caco-2 cells. The results showed that the miRNA was taken up by this intestinal cell line and produced cytotoxicity, indicating that broccoli EVs have the potential to improve the biostability of therapeutic RNA and resist RNase degradation and gastrointestinal digestion.…”

Engineered Plant-Derived Nanovesicles Facilitate Tumor Therapy: Natural Bioactivity Plus Drug Controlled Release Platform

“… [ 85 ] Aleo Target and Loading Indocyanine green and DOX ICG and DOX were premixed and incubated with NVs in PBS for 30 min at 37 °C, then pre-dissolved DSPE-PEG-RGD (using a 2:1 mixture of PBS and methanol) was added and incubated for 30 min, and the solution was centrifuged at 100000 g for 40 min. [ 95 ] Broccoli Loading miRNA The solution containing miRNAs was diluted with siRNA 1× buffer and incubated with Lipo2000 reagent at room temperature for 15 min. The filtered NVs was then incubated with the resulting mixture for 30 min at room temperature and kept at 4°C.…”

“… 85 When multiple drugs are loaded, there may be a “competitive” relationship between the drugs, and Zeng et al proposed using π-π stacking interactions to turn DOX and ICG into “friends”, making the relationship “cooperative” and improving drug delivery efficiency. 95 However, loading of large molecules remains the bottleneck, and techniques such as electroporation may damage the membrane structure of PDNVs. Further studies are needed to resolve the impact of recipient cell type, drug delivery method, molecular weight size, source of plant cells, loading co-incubation time, and drug solubility on loading efficiency.…”

“… 17 In addition, studies have also shown that external forces such as photothermal can enhance the release of PDNVs drugs at the tumor site. 95 , 118 …”

A mini-review: Advances in plant-derived extracellular vesicles as nano-delivery systems for tumour therapy

“…Zeng et al ( Zeng et al, 2022 ) argue that to overcome the drawbacks of traditional treatment methods, a functional nanocarrier loaded with mixed anticancer drugs has favourable prospects in breast cancer treatment. They found that aloe vera gel-derived nanovesicles (gADNV) is an example of an excellent nanocarrier in this regard.…”