Doxorubicin-Based Ionic Nanomedicines for Combined Chemo-Phototherapy of Cancer

Abstract

Synergistic combination therapy approach offers lots of options for delivery of materials with anticancer properties, which is a very promising strategy to treat a variety of malignant lesions with enhanced therapeutic efficacy. The current study involves a detailed investigation of combination ionic nanomedicines where a chemotherapeutic drug is coupled with a photothermal agent to attain dual mechanisms (chemotherapy (chemo) and photothermal therapy (PTT)) to improve the drug's efficacy. An FDA-approved Doxorubicin hydrochloride (DOX• HCl) is electrostatically attached with a near-infrared cyanine dye (ICG, IR783, and IR820), which serves as a PTT drug using ionic liquid chemistry to develop three ionic material (IM)-based chemo-PTT drugs. Carrier-free ionic nanomedicines (INMs) are derived from ionic materials (IMs). The photophysical properties of the developed combination IMs and their INMs were studied in depth. The phototherapeutic efficiency of the combination drugs was evaluated by measuring the photothermal conversion efficiency and singlet-oxygen quantum yield. The improved photophysical properties of the combination nanomedicines in comparison to their parent compounds significantly enhanced INMs' photothermal efficiency. Cellular uptake, dark and light toxicity studies, and cell death mechanisms of the chemo-PTT nanoparticles were also studied in vitro. The combination INMs exhibited enhanced cytotoxicity compared to their respective parent compounds. Moreover, the apoptosis cell death mechanism was almost doubled for combination nanomedicine than the free DOX, which is attributed to enhanced cellular uptake. Examination of the combination index and improved in vitro cytotoxicity results revealed a great synergy between chemo and PTT drugs in the developed combination nanomedicines.

Interrogating the Role of Endocytosis Pathway and Organelle Trafficking for Doxorubicin-Based Combination Ionic Nanomedicines

“…Three chemotherapeutic-photothermal (chemo-PTT) combination drugs (IMs) were synthesized using a simplistic, rapid, economical, one-step ion exchange method according to previously reported protocol . Briefly, for synthesis of [DOX][IR820] IM, 1:1 mole ratio of DOX and NaIR820 were separately dissolved in water.…”

“…INMs were prepared by facile reprecipitation method in cell media from IMs for in vitro study . Briefly, a stock solution of the chemo-PTT combination IMs was initially prepared at a 1 mM concentration in DMSO.…”

“…Nanoparticles have been widely explored for the treatment, immunization, and bioimaging-based diagnosis of diseases. , Most importantly, the enhanced permeability and retention effect (EPR) exhibited by nanoparticles within tumoral sites makes them suitable to treat cancer . Several studies have demonstrated the loading of active pharmaceutical ingredients (APIs) into nanovehicles such as liposomes, dendrimers, and quantum dots due to their tunable structure, which permits a range of interactions with the cell membrane and efficient encapsulation. , Even though these nanovehicles are intended to deliver APIs to specific targets, these carriers have little to no therapeutic effect and can also change the absorption, distribution, metabolism, and excretion profile (ADME) of the main APIs. , Recent research has reported that liposomal formulation of API exhibited reduced therapeutic activity compared to free APIs . This study emphasizes the impact of liposome synthesis method on the particle sizes, drug loading efficiency, and drug release which can alter overall therapeutic activity, − and thus the importance of carrier-free nanoparticles offering a promising alternative with simple design and straightforward synthesis method that can potentially overcome the limitations associated with traditional nanocarrier systems. , Carrier-free nanoparticles developed using various methodologies have been utilized to deliver drugs effectively to target organelles owing to the EPR effect within the tumoral site .…”

“…Researchers have employed different carrier approaches such as poly(ethylene glycol) (PEG) or liposomes to enhance the drug’s concentration in the cells. Unfortunately, these carrier strategies would not provide enhanced toxicity as compared to free DOX. ,, Recently, our group utilized a very simple ionic nanomaterial (INM) approach to develop DOX-based combination nanomedicine with high toxicity . These DOX-near-infrared (NIR) INMs were developed and thoroughly characterized.…”

“…These DOX-near-infrared (NIR) INMs were developed and thoroughly characterized. The resulting combination nanomedicines demonstrated improved chemotherapeutic behavior compared to the DOX parent compound . Thus, this study is designed to investigate the possible alterations in the internalization mechanism as well as subcellular localization of DOX-based nanomedicine which provides additional information about the drug’s potency, and aid the guidelines necessary for the development of future medications.…”