Synthesis, Characterization and Host-Guest Complexation of Asplatin: Improved In Vitro Cytotoxicity and Biocompatibility as Compared to Cisplatin

Abstract

Para-sulfocalix[n]arenes are promising host molecules that can accommodate various chemotherapeutic drugs. Pt(IV)-based complexes, including satraplatin and asplatin, are promising alternatives that overcome the shortcomings of Pt(II) complexes. In this study, asplatin has been synthesized by fusing acetylsalicylic acid (aspirin) and cisplatin. Furthermore, it has been characterized using 1H NMR, mass spectrometry, elemental analysis, and UHPLC. A host-guest complex of asplatin and p-sulfocalix[4]arene (PSC4) has been developed and characterized using UV, Job’s plot analysis, HPLC, and density functional theory (DFT) calculations. The experimental and computational investigations propose that a 1:1 complex between asplatin and PSC4 is formed. The stability constant of the designed complex has been determined using Job’s plot and UHPLC and computed to be 9.1 × 104 M–1 and 8.7 × 104 M−1, which corresponds to a free energy of complexation of −6.8 kcal mol–1, while the calculated value for the inclusion free energy is −13.2 kcal mol−1. Both experimentally and theoretically estimated complexation free energy show that a stable host-guest complex can be formed in solution. The in vitro drug release study displayed the ability of the complex to release its cargo at a cancerous pH (pH of 5.5). Additionally, the asplatin/PSC4 complex is shown to be biocompatible when tested on human skin fibroblast noncancerous cells, demonstrating the highest in vitro cytotoxic activity against (MCF-7), cervical (HeLa), and lung cancer cells (A-549), with IC50 values of 0.75, 2.15, and 3.60 µg/mL, respectively. This is as compared to either cisplatin (IC50 of 5.47, 5.94 and 9.61 µg/mL, respectively) or asplatin (IC50 of 1.54, 5.05 and 3.91 µg/mL, respectively). On the other hand, the free asplatin exhibited higher cytotoxicity on cancerous cells and lower toxicity on noncancerous cells. The outcomes of the present joint theoretical and experimental investigation reinforce the interest in platinum-based anticancer therapeutics when they are protected from undesired interactions and suggest the use of the PSC4 macromolecule as a promising carrier for Pt(IV) anticancer drugs. The formed asplatin/PSC4 inclusion complex may represent an effective chemotherapeutic agent.

Thermosensitive Liposomes Encapsulating Nedaplatin and Picoplatin Demonstrate Enhanced Cytotoxicity against Breast Cancer Cells

“…Several nanoplatforms have been reported to accommodate chemotherapeutic agents such as polymeric nanocapsules, dendritic nanosystems, macromolecules, and nanovesicles (niosomes and liposomes). , Recently, supramolecular host molecules, including p -sulfonatocalix­[4]­arine ( p -SC4), have exhibited a significant influence on the targeted delivery of chemotherapeutics − Considerable efforts have also been devoted to developing intelligent liposomal nanosystems that selectively release their cargo into cancer cells upon exposure to a particular stimulus, such as hyperthermia, ultrasound, or pH change. − Thermosensitive liposomes (TSL) have been used for the localized temperature-responsive release of chemotherapeutics into solid cancers. ThermoDox is a TSL loaded with doxorubicin (DOX) and comprised of 1,2-dipalmitoyl- sn -glycero-3-phosphocholine (DPPC), 1-stearoyl-2-hydroxy- sn -glycero-3-phosphatidylcholine (MSPC), and N -(carbonylmethoxypolyethylene glycol2000)-1,2-distearoyl- sn -glycero-3-phosphoethanolamine (mPEG 2000 -DSPE) at a molar ratio of 86:10:4.…”

“… 10 P -SC4 is biodegradable, hydrophilic, and at doses up to 10 5 μg/kg is compatible with human cells . 10 − 12 Considerable efforts have also been devoted to developing intelligent liposomal nanosystems that selectively release their cargo into cancer cells upon exposure to a particular stimulus, such as hyperthermia, ultrasound, or pH change. 13 − 15 Thermosensitive liposomes (TSL) have been used for the localized temperature-responsive release of chemotherapeutics into solid cancers.…”

Stimuli-Responsive Cucurbit[n]uril-Based Supramolecular Nanocarriers for Delivery of Chemotherapeutics

“…Supramolecular macrocyclic nanosystems, including calix­[ n ]­arenes, cyclodextrins, pillar­[ n ]­arenes, cucurbit­[ n ]­urils (CBs), etc. , have shown dynamic regulation characteristics and multifunctional properties. − The structure of macrocyclic compounds can be altered in response to various external stimuli (temperature, pH, light, etc. ) thus controlling the release of their loaded guest molecules .…”

“…Figure13. Construction of enzyme-responsive CB[7]-based supramolecular nanosystem (average size of 200 nm) which could deliver chlorambucil (ChBL) anticancer drug.…”

Peganum harmala Alkaloids and Tannic Acid Encapsulated in PAMAM Dendrimers: Improved Anticancer Activities as Compared to Doxorubicin

“…Accordingly, considerable efforts have been exerted to formulate natural products into different nanocarriers to enhance their anticancer activities. These delivery systems include stimuli-responsive supramolecular systems, − liposomes, , PEGylated chitosan nanoparticles, and nanoparticles prepared using algae and other natural products …”