Chimeric Nanoparticle: A Platform for Simultaneous Targeting of Phosphatidylinositol-3-Kinase Signaling and Damaging DNA in Cancer Cells

Abstract

Phosphatidylinositol-3-kinase (PI3K) signaling has been hijacked in different types of cancers. Hence, PI3K inhibitors have emerged as novel targeted therapeutics in cancer treatment as mono and combination therapy along with other DNA damaging drugs. However, targeting PI3K signaling with small molecules leads to the emergence of drug resistance and severe side effects to the cancer patients. To address these, we have developed a biocompatible, biodegradable cholesterol-based chimeric nanoparticle (CNP), which can simultaneously load PI103, doxorubicin, and cisplatin in a controlled ratiometric manner. Size, shape, and morphology of these CNPs were characterized by dynamic light scattering (DLS), field-emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), and transmission electron microscopy (TEM). Increased amounts of PI103, doxorubicin, and cisplatin were released from CNPs through controlled and continuous manner over 120 h at pH = 5.5 compared to neutral pH. The CNPs showed much enhanced in vitro cytotoxicity in HeLa, HL60, MCF7, and MDA-MB-231 cancer cells compared to a free drug cocktail at 24 and 48 h by inducing apoptosis. Confocal laser scanning microscopy (CLSM) imaging revealed that indeed these CNPs were internalized into subcellular lysosomes through endocytosis in a time dependent mode over 6 h and retained inside for 48 h in HeLa, MDA-MB-231, and MCF7 cells. These CNPs showed their efficacy by damaging DNA and inhibiting Akt as a downstream modulator of PI3K signaling in HeLa cervical cancer cells. These CNPs have the potential to open up new directions in next-generation nanomedicine by simultaneous targeting of multiple oncogenic signaling pathways and inducing DNA damage for augmented therapeutic outcome by reducing toxic side effects and overcoming drug resistance.

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…Therefore, selection of specific materials can determine key drug delivery parameters such as ratios and release times. A cholesterol-based, biodegradable, non-toxic chimeric nanoparticle was recently designed to codeliver Doxorubicin (DOX), PI3K inhibitor PI103, and cisplatin in a controlled ratio through chemical conjugation [157]. The nanoparticles demonstrated enhanced in vitro toxicity compared to the coadministration of the free drugs in HL60, MCF7, and MDA-MB-231 cancer cells.…”

“…4. Various nanoformulations for co-delivery of therapeutics with normalized pharmacokinetics and pharmacodynamics, including self-assembled nanoscale coordination polymer [158], cholesterol-based chimeric nanoparticle [157], thermosensitive hydrogel [123], mesoporous silica nanoparticle [125], and liposomes [124].…”

Engineering andIn VitroEvaluation of Acid Labile Cholesterol Tethered MG132 Nanoparticle for Targeting Ubiquitin-Proteasome System in Cancer

“…We have chosen cholesterol as biocompatible/biodegradable vector due to its presence in cell membrane. Moreover, recently, we have shown that cholesterol can be easily functionalized to conjugate multiple anti‐cancer drugs to develop chimeric nanoparticles for next‐generation cancer therapy . In this study, we have first activated the hydroxyl group in cholesterol ( 1 ) by 4‐nitrophenyl chloroformate ( 2 ) in presence of pyridine as base to obtain cholesterol‐4‐nitrophenylcarbonate ( 3 ) in 79 % yield (Figure a).…”

“…We envision that, the nanoparticles will be taken up by the cancer cells through endocytosis mechanism and homing into the acidic lysosomes for the release of active drug . To evaluate the release of active MG132 through the cleavage of acid labile hydrazone linkage from the nanoparticle, we incubated the MG132‐NPs in pH=5.5 and quantified the amount of MG132 released in different time points by dialysis method using concentration versus absorbance graph at λ max =203 nm from UV‐Vis spectroscopy (Figure S14). Indeed, at pH=5.5, MG132‐NPs released 63.1 ± 4.9 % (mean ± SEM, n=3) free MG132 after 120 h (Figure a) slowly.…”

Enhancing Therapeutic Efficacy of Cisplatin by Blocking DNA Damage Repair

“…C ancer remains one of the leading causes of morbidity and mortality around the world, which continues to increase with around 10 million new cases every year. 1,2 Although traditional chemotherapy is quite beneficial in improving survival rate, it has also shown a lot of hindrances including severe toxicity, limited efficiency, and especially unexpected drug resistance. 3−5 It is well-known that drug resistance is mediated by multiple defense mechanisms of cancer cells, such as DNA repair, inhibition of apoptosis, and cell cycle arrest.…”