Cholesterol-Inulin Conjugates for Efficient SN38 Nuclear Delivery: Nanomedicines for Precision Cancer Therapy.

Abstract

Simple SummarySevere limitations of conventional chemotherapy including unspecific biodistribution both at the tissue and cell organelle level have led to the necessity of developing precise and personalized therapeutic strategies. Accordingly, nanomedicine has aroused increased attention due to the versatility and precision of nano-sized drug delivery systems. One of the main advantage offered by well-designed nanoplatforms is the possibility to load, stabilize, and deliver (also at intracellular level) hydrophobic anticancer drugs, whose clinical use is strongly affected by their lower bioavailability. In this overview, the synthesis of polymeric nano-sized core-shell micelle-like nanostructures is a promising delivery strategy for hydrophobic drugs due to their excellent drug loading efficacy, stability in aqueous media, and versatile design. On these grounds, we developed stable and biodegradable inulin-based micelles for the delivery of SN38, chosen as a powerful poorly water-soluble anticancer drug. We designed an amphiphilic polysaccharide hydrophobized by partial functionalization with thiocholesterol moieties (INU-Cys-TC) via disulfide redox-sensitive bridges. We demonstrated that INU-Cys-TC can self-assemble into micelles at low concentration, encapsulating a high amount of SN38 (INU-Cys-TC@SN38) to be released in a sustained fashion. INU-Cys-TC@SN38 has proven to be capable of entering cancer and normal cells, releasing their payload, especially inside cell nuclei, where SN38 can act, providing the maximum inhibition of its molecular target. However, due to a different cell localization, INU-Cys-TC@SN38 was much more toxic for cancer cells, improving the SN38 selectivity, precision, and enhancing its anticancer effect not only toward colorectal cells, but also for breast cancer cells. This is a good example of drug repurposing due to innovative environment-sensitive delivery strategies. An amphiphilic inulin-thiocholesterol conjugate (INU-Cys-TC) was strategically designed as a biodegradable core-shell nanocarrier of 7-ethyl-10-hydroxy-camptothecin (SN38) to enhance its solubility and stability in aqueous media, thus exploiting its brilliant anticancer effect. INU-Cys-TC was designed to have the hydrophilic inulin backbone (external shell) partially functionalized with hydrophobic thiocholesterol moieties (internal core) through a biodegradable disulfide bond due to cysteamine bridges. Thiocholesterol moieties impair redox-sensitive self-assembling abilities, yielding to nano-sized micelles in aqueous media capable of efficiently encapsulating a high amount of SN38 (DL = 8.1%). Micelles (INU-Cys-TC@SN38) were widely characterized, demonstrating an effective and stable delivery strategy to overcome the poor water-solubility of SN38. SN38-loaded micelles showed a gradual and prolonged release of SN38 over time, and a cell- and time-dependent cytotoxicity. In particular, we show that micelles efficiently deliver SN38 inside cell nuclei, and, compared to normal cell lines, they can also enter cancer cells by endo-lysosomes, where a complete degradation can occur releasing the drug payload. Overall, the proposed micelles appear potentially effective as nanomedicines for precision cancer therapies of colorectal and breast cancer, thus improving the SN38 therapeutic index and extending its use in a huge plethora of cancers.