ABSTRACT
Liposomal formulations have been developed for a highly cytotoxic platinum-acridine agent, [PtCl(pn)(C18 H21 N4 )](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.
Subject(s)
Acridines/pharmacology , Adenocarcinoma of Lung/drug therapy , Antineoplastic Agents/pharmacology , Lung Neoplasms/drug therapy , Models, Biological , Organoplatinum Compounds/pharmacology , Platinum/pharmacology , A549 Cells , Acridines/chemistry , Adenocarcinoma of Lung/pathology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Drug Compounding , Drug Screening Assays, Antitumor , Female , Humans , Liposomes/chemistry , Lung Neoplasms/pathology , Mice , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Platinum/chemistryABSTRACT
Integral components of the examination of the oral and maxillofacial region include the early detection of benign and malignant lesions and recognition of manifestations of systemic disorders. The gold standard for establishing a diagnosis has entailed excision of tissue and submission to a laboratory for histopathologic review or, to a lesser extent, microcollection of cells via a fine-needle aspiration biopsy. A revolutionary technology in the medical and dental fields, referred to as a liquid biopsy, involves the harvesting of fragments of DNA or RNA for surveillance of an array of pathological processes from various body fluids, such as blood, plasma, and saliva. This article provides an overview of this developing diagnostic field.
Subject(s)
Dentistry , Liquid Biopsy , Biopsy, Fine-Needle , HumansABSTRACT
Large-pore mesoporous silica nanoparticles (MSN) were prepared and functionalized to serve as a highly robust and biocompatible delivery platform for platinum-acridine (PA) anticancer agents. The material showed a high loading capacity for the dicationic, hydrophilic hybrid agent [PtCl(en)(N-[acridin-9-ylaminoethyl]-N-methylpropionamidine)] dinitrate salt (P1A1) and virtually complete retention of payload at neutral pH in a high-chloride buffer. In acidic media mimicking the pH inside the cell lysosomes, rapid, burst-like release of P1A1 from the nanoparticles is observed. Coating of the materials in phospholipid bilayers resulted in nanoparticles with greatly improved colloidal stability. The lipid and carboxylate-modified nanoparticles containing 40â wt % drug caused S-phase arrest and inhibited cell proliferation in pancreatic cancer cells at submicromolar concentrations similar to carrier-free P1A1. The most striking feature of nanoparticle-delivered P1A1 was that the payload did not escape from the acidified lysosomal vesicles into the cytoplasm, but was shuttled to the nuclear membrane and released into the nucleus.