Evaluation of a Platinum–Acridine Anticancer Agent and Its Liposomal Formulation in an in vivo Model of Lung Adenocarcinoma

Abstract

Liposomal formulations have been developed for a highly cytotoxic platinum–acridine agent, [PtCl(pn)(C18H21N4)](NO3)2 (PA, pn=propane‐1,3‐diamine), and fully characterized. Nanoliposomes consisting of hydrogenated soybean phosphatidylcholine (HSPC), 1,2‐dihexadecanoyl‐sn‐glycero‐3‐phospho‐(1'‐rac‐glycerol) (DPPG), and polyethylene glycol‐2000‐distearoylphosphatidylethanolamine (DSPE‐mPEG2k) were able to stably encapsulate PA at payload‐to‐lipid ratios of 2–20 %. The fusogenic properties of the liposomes promote efficient cellular uptake of PA across the plasma membrane, which results in vesicular transport of payload to the nucleus in cultured lung cancer cells. Unencapsulated PA and one of the newly designed liposomal formulations show promising tumor growth inhibition in tumor xenografts derived from A549 lung adenocarcinoma cells of 76 % and 72 %, respectively. Cisplatin showed no significant efficacy at a 10‐fold higher dose. These findings underscore the utility of platinum‐acridine agents for treating aggressive, chemoresistant forms of cancer and validate nanoliposomes as a biocompatible, expandable platform for their intravenous delivery and other potential routes of administration.

Development of Prodrug–Payloads for Targeted Therapeutic Applications of Platinum–Acridine Anticancer Agents

“…DNA-targeted platinum–acridine hybrid agents (PAs) represented by compound 1 (Figure ) have demonstrated a unique mechanism of action and high potency in several models of solid tumors, − which translates into promising efficacy in xenograft models in vivo. , As in other cases of highly cytotoxic drugs, the suboptimal drug-like properties of PAs have prompted the evaluation of more efficient and safer forms of delivery of these agents to tumor tissue, including passively targeted nanoliposomes . Unlike the classical platinum-based drug cisplatin, which typically kills cancer cells at micromolar concentrations, PAs have demonstrated up to 3 orders of magnitude higher activity at single-digit nanomolar concentrations.…”

“…10,11 As in other cases of highly cytotoxic drugs, the suboptimal drug-like properties of PAs have prompted the evaluation of more efficient and safer forms of delivery of these agents to tumor tissue, including passively targeted nanoliposomes. 11 Unlike the classical platinum-based drug cisplatin, which typically kills cancer cells at micromolar concentrations, PAs have demonstrated up to 3 orders of magnitude higher activity at single-digit nanomolar concentrations. This is significant since major advantages are observed for PAs in several solid tumors that do not respond well to current clinical treatments.…”

Development of Prodrug–Payloads for Targeted Therapeutic Applications of Platinum–Acridine Anticancer Agents

“…3,6 DNA-targeted platinum-acridine hybrid agents (PAs) represented by compound 1 (Figure 1) have demonstrated a unique mechanism of action and high potency in several models of solid tumors, [7][8][9][10] which translates into promising efficacy in xenograft models in vivo. [10][11] As in other cases of highly cytotoxic drugs, the suboptimal drug-like properties of PAs have prompted the evaluation of more efficient and safer forms of delivery of these agents to tumor tissue, including passively targeted nanoliposomes. 11 Unlike the classical platinum-based drug cisplatin, which typically kills cancer cells at micromolar concentrations, PAs have demonstrated up to three orders of magnitude higher activity at single-digit nanomolar concentrations.…”

“…[10][11] As in other cases of highly cytotoxic drugs, the suboptimal drug-like properties of PAs have prompted the evaluation of more efficient and safer forms of delivery of these agents to tumor tissue, including passively targeted nanoliposomes. 11 Unlike the classical platinum-based drug cisplatin, which typically kills cancer cells at micromolar concentrations, PAs have demonstrated up to three orders of magnitude higher activity at single-digit nanomolar concentrations. This is significant since major advantages are observed for PAs in several solid tumors that do not respond well to current clinical treatments.…”

Square-Planar vs. Trigonal Bipyramidal Geometry in Pt(II) Complexes Containing Triazole-Based Glucose Ligands as Potential Anticancer Agents

“…Platinum compounds play a prevalent role in metal-based anticancer therapies, with cisplatin, carboplatin, and oxaliplatin used all over the world in clinics despite general low selectivity and drug resistance often limiting their efficacy [4,5]. To date, the efforts of the scientific community have multiplied to prepare increasingly effective agents, aimed at reducing the numerous and unpleasant side effects of cisplatin and its close derivatives [6][7][8][9][10][11][12][13][14][15][16]. One of the most successful strategies is the introduction of bio-active molecules in the coordination environment of the metal, capable of increasing its versatility and selectivity [17,18].…”