Supramolecular Self-Assembled Nanoparticle for Organelle Targeting in Cancer

Abstract

Cancer is one of the leading causes of morbidity and mortality worldwide. To understand the characteristics of cancer cells, the hallmarks of cancer are outlined by Hanahan and Weinberg. Resisting cell death, sustaining proliferative signaling and deregulation of cellular energetics are the imperative hallmarks of cancer which are tightly governed by important sub-cellular organelles such as nucleus, mitochondrion and endoplasmic reticulum(ER). Thus specific targeting of the organelles in cancer cells is interesting strategy for future cancer therapy. However, organelle targeting in cellular milieu is highly challenging task. To address this, we have developed self-assembled glycosylated chalcone boronic acid derivatives to target anti-apoptotic Bcl-2 in mitochondria and showed their anticancer activity. ER is involved in protein synthesis/folding and dis-regulation in that mechanism leads to ER-stress. Moreover, ER membrane wraps around another important organelle, nucleus and forms double membrane nuclear envelop leading to ER-nuclear cross-talk. Hence, we hypothesize that simultaneous targeting of ER and nuclear DNA in cancer cells would lead to improved anti-cancer efficacy. To achieve this, we have developed triazine based small molecule which supramolecularly self-assembled into spherical nanoparticle which can induce ER-stress and DNA damage in cancer cells. Interestingly, the ER-targeting self-assembled nanoparticle induced autophagy in cancer cells, leading to combination therapy with autophagy inhibitor for improved therapeutic efficacy. Subsequently, we have engineered lipidic nanoparticle for specific targeting of ER-resident chaperon GRP94 to induce ER stress as interesting strategy in cancer therapy. These ER localizing GRP94 targeting nanoparticle induced improved anti-cancer effect in cancer cells. Finally, we have engineered lipidic nanoparticle to target proteasome which is having cross-talk with ER stress through unfolded protein response (UPR) for disruption of ubiquitin proteasome system (UPS) as novel strategy for cancer treatment. These lipidic proteasome targeted nanoparticles inhibited sub-cellular protein degradation machinery to trigger cancer cell death. We anticipate that, here presented unique approaches will extend the concept of supramolecular self-assembly of small molecules and lipidic nanoparticles to target multiple sub-cellular organelles simultaneously for improved therapeutic effect in anti-cancer therapy in future