Nanoscale Coordination Polymers Codeliver Chemotherapeutics and siRNAs to Eradicate Tumors of Cisplatin-Resistant Ovarian Cancer

Abstract

Drug resistance impedes the successful treatment of many types of cancers, especially ovarian cancer (OCa). To counter this problem, we developed novel long-circulating, self-assembled core–shell nanoscale coordination polymer (NCP) nanoparticles that efficiently deliver multiple therapeutics with different mechanisms of action to enhance synergistic therapeutic effects. These NCP particles contain high payloads of chemotherapeutics cisplatin or cisplatin plus gemcitabine in the core and pooled siRNAs that target multidrug resistant (MDR) genes in the shell. The NCP particles possess efficient endosomal escape via a novel carbon dioxide release mechanism without compromising the neutral surface charge required for long blood circulation and effectively downregulate MDR gene expression in vivo to enhance chemotherapeutic efficacy by several orders of magnitude. Even at low doses, intraperitoneal injections of nanoparticles led to effective and long-lasting tumor regression/eradication in subcutaneous and intraperitoneal xenograft mouse models of cisplatin-resistant OCa. By silencing MDR genes in tumors, self-assembled core–shell nanoparticles promise a more effective chemotherapeutic treatment for many challenging cancers.

Nanoscale Metal–Organic Frameworks for Therapeutic, Imaging, and Sensing Applications

“…A majority of drugs or prodrugs do not possess coordination geometry or molecular rigidity needed to construct crystalline MOFs, but they can be used to form amorphous nanoscale coordination polymer (NCPs). Since their first report of a NCP formed from lanthanide metal ions and a cisplatin prodrug in 2008, Lin and co‐workers have refined this strategy to prepare a series of surface‐modified NCPs for chemotherapy, gene silencing, PDT, combined chemotherapy and PDT, and immunotherapy . Significant progress has also been made to translate NCPs into clinic, but such amorphous nanoparticles are beyond the scope of this review.…”

Organosilica Nanoparticles for Gemcitabine Monophosphate Delivery in Cancer Cells

“…In order to extend the scope of stimuli-triggered GMP delivery, we decided to study methyl amine and methylammonium-based organosilica nanoparticles as gemcitabine monophosphate carriers. Indeed the encapsulation of GMP is still very challenging and covalent systems such as squalenization, [13,14] formulations with metal ions (MOF, [15,16] Zn 2 + [17][18][19] or Gd 3 + [20] -based coordination systems), calcium phosphate-based nanoparticles [21][22][23][24][25] have been reported. Here, we describe two innovative strategies for GMP transport and release, based on different types of organosilica materials: i) the use of new amine-based organosilica nanoparticles (POR-organosilica) obtained from bis(3-trimethoxysilylpropyl)-N-methylamine, incorporating a porphyrin derivative in the structure for near-infrared (NIR) imaging, and ii) the use of ammonium based mesoporous ionosilica nanoparticles, which we already described for dichlofenac delivery, [26] obtained from a tris-trialkoxysilylated ammonium precursor.…”

Overcoming multidrug resistance in cancer: Recent progress in nanotechnology and new horizons

“…Therefore, this approach is used as an adjunct treatment to enhance the delivery of numerous nanocarriers . Accumulating studies have reported that hyperthermia exerts multiple effects including direct killing of tumor cells via protein denaturation, DNA aggregation and cross‐linking, activating apoptotic pathways, changes in cell cycle regulatory signaling pathways, alterations in the tumor microenvironment, activation of heat shock proteins, induction of the immune response, alterations in blood flow, and oxygen and nutrient distribution at the tumor site . When BT‐474 cells are treated with magnetic nanoparticles and mitomycin‐C in the presence or absence of hyperthermia, it is reported that hyperthermia intensifies inhibitory effects of nanoparticles and mitomycin‐C on the expression levels of MDR‐associated proteins .…”

“…81 Accumulating studies have reported that hyperthermia exerts multiple effects including direct killing of tumor cells via protein denaturation, DNA aggregation and cross-linking, activating apoptotic pathways, changes in cell cycle regulatory signaling pathways, alterations in the tumor microenvironment, activation of heat shock proteins, induction of the immune response, alterations in blood flow, and oxygen and nutrient distribution at the tumor site. 81,82 When BT-474 cells are treated with magnetic nanoparticles and mitomycin-C in the presence or absence of hyperthermia, it is reported that hyperthermia intensifies inhibitory effects of nanoparticles and mitomycin-C on the expression levels of MDR-associated proteins. 83 Inactivation of drug detoxification mechanisms, increase in the drug uptake, induction of apoptosis, enhancement of drug cytotoxicity, and reduction in cell membrane localization of MDR proteins are other effects mediated by hyperthermia, which circumvent MDR in various cancers.…”