ABSTRACT
Drug resistant cancers like pancreatic ductal adenocarcinoma (PDAC) are difficult to treat, and nanoparticle drug delivery systems can overcome some of the limitations of conventional systemic chemotherapy. In this study, we demonstrate that FdUMP and dFdCMP, the bioactive, phosphorylated metabolites of the chemotherapy drugs 5-FU and gemcitabine, can be encapsulated into calcium phosphosilicate nanoparticles (CPSNPs). The non-phosphorylated drug analogs were not well encapsulated by CPSNPs, suggesting the phosphate modification is essential for effective encapsulation. In vitro proliferation assays, cell cycle analyses and/or thymidylate synthase inhibition assays verified that CPSNP-encapsulated phospho-drugs retained biological activity. Analysis of orthotopic tumors from mice treated systemically with tumor-targeted FdUMP-CPSNPs confirmed the in vivo up take of these particles by PDAC tumor cells and release of active drug cargos intracellularly. These findings demonstrate a novel methodology to efficiently encapsulate chemotherapeutic agents into the CPSNPs and to effectively deliver them to pancreatic tumor cells.
Subject(s)
Antineoplastic Agents/administration & dosage , Calcium Compounds/chemistry , Carcinoma, Pancreatic Ductal/drug therapy , Deoxycytidine/analogs & derivatives , Fluorouracil/administration & dosage , Nanoparticles/chemistry , Pancreatic Neoplasms/drug therapy , Silicates/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Deoxycytidine/administration & dosage , Deoxycytidine/chemistry , Deoxycytidine/therapeutic use , Drug Carriers/chemistry , Drug Delivery Systems , Fluorouracil/analogs & derivatives , Fluorouracil/therapeutic use , Humans , Male , Mice , Mice, Nude , Nanoparticles/ultrastructure , Phosphorylation , Xenograft Model Antitumor Assays , GemcitabineABSTRACT
Bioimaging and therapeutic delivery applications are areas of biomedicine where nanoparticles have had significant impact, but the use of a nanomaterial in these applications can be limited by its physicochemical properties. Calcium phosphate-based composite nanoparticles are nontoxic and biodegradable, and are therefore considered attractive candidates for bioimaging and therapeutic drug delivery applications. Also, the pH-dependent solubility profiles of calcium phosphate materials make this class of nanoparticles especially useful for in vitro and in vivo delivery of dyes, oligonucleotides, and drugs. In this article, we discuss how calcium phosphate-based composite nanoparticles fulfill some of the requirements typically made for nanoparticles in biomedical applications. We also highlight recent studies in bioimaging and therapeutic delivery applications focusing on how these studies have addressed some of the challenges associated with using these nanoparticles in bioimaging and delivery of therapeutics.
Subject(s)
Calcium Phosphates/chemistry , Drug Delivery Systems/methods , Molecular Imaging/methods , Nanocomposites/chemistry , Animals , Humans , MiceABSTRACT
Encapsulation of imaging agents and drugs in calcium phosphate nanoparticles (CPNPs) has potential as a nontoxic, bioresorbable vehicle for drug delivery to cells and tumors. The objectives of this study were to develop a calcium phosphate nanoparticle encapsulation system for organic dyes and therapeutic drugs so that advanced fluoresence methods could be used to assess the efficiency of drug delivery and possible mechanisms of nanoparticle bioabsorption. Highly concentrated CPNPs encapsulating a variety of organic fluorophores were successfully synthesized. Well-dispersed CPNPs encapsulating Cy3 amidite exhibited nearly a 5-fold increase in fluorescence quantum yield when compared to the free dye in PBS. FCS diffusion data and cell staining were used to show pH-dependent dissolution of the particles and cellular uptake, respectively. Furthermore, an experimental hydrophobic cell growth inhibitor, ceramide, was successfully delivered in vitro to human vascular smooth muscle cells via encapsulation in CPNPs. These studies demonstrate that CPNPs are effective carriers of dyes and drugs for bioimaging and, potentially, for therapeutic intervention.
Subject(s)
Calcium Phosphates/chemistry , Drug Carriers , Nanocomposites , Organic Chemicals/chemistry , Animals , Cattle , Microscopy, Electron, TransmissionABSTRACT
Paradigm-shifting modalities to more efficiently deliver drugs to cancerous lesions require the following attributes: nanoscale-size, targetability, and stability under physiological conditions. Often, these nanoscale drug delivery vehicles are limited due to agglomeration, poor solubility, or cytotoxicity. Thus, we have designed a methodology to encapsulate hydrophobic antineoplastic chemotherapeutics within a 20-30 nm diameter, pH-responsive, nonagglomerating, nontoxic calcium phosphate nanoparticle matrix. In the present study, we report on calcium phosphate nanocomposite particles (CPNPs) that encapsulate both fluorophores and chemotherapeutics, are colloidally stable in physiological solution for an extended time at 37 degrees C and can efficaciously deliver hydrophobic antineoplastic agents, such as ceramide, in several cell model systems.
