ABSTRACT
Single-nanoparticle (NP) combination chemotherapeutics are quickly emerging as attractive alternatives to traditional chemotherapy due to their ability to increase drug solubility, reduce off-target toxicity, enhance blood circulation lifetime, and increase the amount of drug delivered to tumors. In the case of NP-bound drugs, that is, NP-prodrugs, the current standard of practice is to assume that the subcellular mechanism of action for each drug released from the NP mirrors that of the unbound, free-drug. Here, we use an RNAi signature assay for the first time to examine the mechanism of action of multidrug-conjugated NP prodrugs relative to their small molecule prodrugs and native drug mechanisms of action. Additionally, the effective additive contribution of three different drugs in a single-NP platform is characterized. The results indicate that some platinum(IV) cisplatin prodrugs, although cytotoxic, may not have the expected mechanism of action for cisplatin. This insight was utilized to develop a novel platinum(IV) oxaliplatin prodrug and incorporate it into a three-drug-conjugated NP, where each drug's mechanism of action is preserved, to treat tumor-bearing mice with otherwise lethal levels of chemotherapy.
Subject(s)
Camptothecin/therapeutic use , Doxorubicin/therapeutic use , Nanoparticles/chemistry , Organoplatinum Compounds/therapeutic use , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Camptothecin/administration & dosage , Carcinoma/drug therapy , Cell Line, Tumor , Doxorubicin/administration & dosage , Drug Delivery Systems , Mice , Molecular Structure , Neoplasms, Experimental/drug therapy , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Prodrugs/administration & dosage , RNA InterferenceABSTRACT
A panel of acid-labile bis-norbornene cross-linkers was synthesized and evaluated for the formation of acid-degradable brush-arm star polymers (BASPs) via the brush-first ring-opening metathesis polymerization (ROMP) method. An acetal-based cross-linker was identified that, when employed in conjunction with a poly(ethylene glycol) (PEG) macromonomer, provided highly controlled BASP formation reactions. A combination of this new cross-linker with a novel doxorubicin (DOX)-branch-PEG macromonomer provided BASPs that simultaneously degrade and release cytotoxic DOX in vitro.
ABSTRACT
A palladium-catalyzed intermolecular vicinal diarylation of terminal 1,3-dienes using aryldiazonium tetrafluoroborates and arylboronic acids is reported. Using this technology, two different arenes are regioselectively introduced in a vicinal fashion across the terminal alkene of a variety of terminal 1,3-dienes at ambient temperature. Through the action of a chiral bicyclo[2.2.2]octadienyl ligand at -20 °C, good enantioselectivity has also been achieved.
Subject(s)
Alkadienes/chemistry , Alkenes/chemical synthesis , Boronic Acids/chemistry , Palladium/chemistry , Alkenes/chemistry , Catalysis , Ligands , Molecular Structure , StereoisomerismABSTRACT
The synthesis of polymer therapeutics capable of controlled loading and synchronized release of multiple therapeutic agents remains a formidable challenge in drug delivery and synthetic polymer chemistry. Herein, we report the synthesis of polymer nanoparticles (NPs) that carry precise molar ratios of doxorubicin, camptothecin, and cisplatin. To our knowledge, this work provides the first example of orthogonally triggered release of three drugs from single NPs. The highly convergent synthetic approach opens the door to new NP-based combination therapies for cancer.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Carriers/chemistry , Nanoparticles/chemistry , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols , Camptothecin/administration & dosage , Camptothecin/chemistry , Camptothecin/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cisplatin/administration & dosage , Cisplatin/chemistry , Cisplatin/pharmacology , Delayed-Action Preparations , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Doxorubicin/pharmacology , HumansABSTRACT
New strategies for the synthesis of multifunctional particles that respond to external stimuli and release biologically relevant agents will enable the discovery of new formulations for drug delivery. In this article, we combine two powerful methods: brush-first ring-opening metathesis polymerization and copper-catalyzed azide-alkyne cycloaddition click chemistry, for the synthesis of a novel class of brush-arm star polymers (BASPs) that simultaneously degrade and release the anticancer drug doxorubicin (DOX) in response to 365 nm light. In vitro cell viability studies were performed to study the toxicity of azide- and DOX-loaded BASPs. The former were completely nontoxic. The latter showed minimal toxicity in the absence of light; UV-triggered DOX release led to IC50 values that were similar to that of free DOX.
Subject(s)
Antibiotics, Antineoplastic/chemistry , Doxorubicin/chemistry , Light , Nanoparticles , Cell Line, Tumor , Humans , Magnetic Resonance Spectroscopy , Spectroscopy, Fourier Transform InfraredABSTRACT
An efficient protocol for the one-step synthesis of biologically relevant 1,1-diarylalkanes has been described. This reaction introduces two different aryl groups across the terminal end of simple feedstock alkenes such as ethylene and allylic carbonates. The propensity to generate π-benzylpalladium intermediates dictates the exclusive 1,1-regioselectivity observed in the product.
Subject(s)
Allyl Compounds/chemical synthesis , Carbonates/chemical synthesis , Ethylenes/chemistry , Allyl Compounds/chemistry , Carbonates/chemistry , Catalysis , Molecular Structure , Palladium , StereoisomerismABSTRACT
A palladium-catalyzed 1,4-addition across the commodity chemical 1,3-butadiene to afford skipped polyene products is reported. Through a palladium σ â π â σ allyl isomerization, two new carbon-carbon bonds are formed with high regioselectivity and trans stereoselectivity of the newly formed alkene. The utility of this method is highlighted by the successful synthesis of the ripostatin A skipped triene core.
Subject(s)
Butadienes/chemistry , Lactones/chemical synthesis , Palladium/chemistry , Polyenes/chemical synthesis , Butadienes/chemical synthesis , Catalysis , DNA-Directed RNA Polymerases/antagonists & inhibitors , Lactones/chemistry , Polyenes/chemistry , StereoisomerismABSTRACT
A three-component coupling of vinyl triflates and boronic acids to alkenes catalyzed by palladium is reported. Using 1,3-dienes, selective 1,2-alkene difunction-alization is observed, whereas the use of terminal alkenes results in 1,1-alkene difunctionalization. The reaction outcome is attributed to the formation of stabilized, cationic Pd-π-allyl intermediates to regulate ß-hydride elimination.
Subject(s)
Alkenes/chemistry , Boronic Acids/chemistry , Mesylates/chemistry , Vinyl Compounds/chemistry , Catalysis , Palladium/chemistryABSTRACT
A palladium-catalyzed reductive cross-coupling of 1,3-dienes with boronic esters in which a pi-allyl Pd species is generated directly from a 1,3-diene via a Pd-catalyzed aerobic alcohol oxidation is reported. Both the scope of the process and the origin of a highly selective 1,2-addition are discussed.