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1.
Sci Transl Med ; 12(556)2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32801144

RESUMO

Activation of the stimulator of interferon gene (STING) pathway within the tumor microenvironment has been shown to generate a strong antitumor response. Although local administration of STING agonists has promise for cancer immunotherapy, the dosing regimen needed to achieve efficacy requires frequent intratumoral injections over months. Frequent dosing for cancer treatment is associated with poor patient adherence, with as high as 48% of patients failing to comply. Multiple intratumoral injections also disrupt the tumor microenvironment and vascular networks and therefore increase the risk of metastasis. Here, we developed microfabricated polylactic-co-glycolic acid (PLGA) particles that remain at the site of injection and release encapsulated STING agonist as a programmable sequence of pulses at predetermined time points that mimic multiple injections over days to weeks. A single intratumoral injection of STING agonist-loaded microparticles triggered potent local and systemic antitumor immune responses, inhibited tumor growth, and prolonged survival as effectively as multiple soluble doses, but with reduced metastasis in several mouse tumor models. STING agonist-loaded microparticles improved the response to immune checkpoint blockade therapy and substantially decreased the tumor recurrence rate from 100 to 25% in mouse models of melanoma when administered during surgical resection. In addition, we demonstrated the therapeutic efficacy of STING microparticles on an orthotopic pancreatic cancer model in mice that does not allow multiple intratumoral injections. These findings could directly benefit current STING agonist therapy by decreasing the number of injections, reducing risk of metastasis, and expanding its applicability to hard-to-reach cancers.

2.
J Am Chem Soc ; 142(23): 10297-10301, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32453555

RESUMO

Herein, we report the DNA-mediated self-assembly of bivalent bottlebrush polymers, a process akin to the step-growth polymerization of small molecule monomers. In these "condensation reactions", the polymer serves as a steric guide to limit DNA hybridization in a fixed direction, while the DNA serves as a functional group equivalent, connecting complementary brushes to form well-defined, one-dimensional nanostructures. The polymerization was studied using spectroscopy, microscopy, and scattering techniques and was modeled numerically. The model made predictions of the degree of polymerization and size distribution of the assembled products, and suggested the potential for branching at hybridization junctions, all of which were confirmed experimentally. This study serves as a theoretical basis for the polymer-assembly approach which has the potential to open up new possibilities for suprapolymers with controlled architecture, macromonomer sequence, and end-group functionalities.

3.
Chem ; 5(6): 1584-1596, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31903440

RESUMO

Herein, we develop a facile route to bring DNA to the organic phase, which greatly expands the types of structures accessible using DNA macromonomers. Phosphotriester- and exocyclic amine-protected DNA was synthesized and further modified with a norbornene moiety, which enables homopolymerization via ring-opening metathesis to produce brush-type DNA graft polymers in high yields. Subsequent deprotection cleanly reveals the natural phosphodiester DNA. The method not only achieves high molecular weight DNA graft polymers but when carried out at low monomer:catalyst ratios, yields oligomers that can be further fractionated to molecularly pure, monodisperse entities with one through ten DNA strands per molecule. In addition, we demonstrate substantial simplification in the preparation of traditionally difficult DNA-containing structures, such as DNA/poly(ethylene glycol) diblock graft copolymers and DNA amphiphiles. We envision that the marriage of oligonucleotides with the vast range of organic-phase polymerizations will result in many new classes of materials with yet unknown properties.

4.
J Am Chem Soc ; 138(34): 10834-7, 2016 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-27522867

RESUMO

Nucleic acids are generally regarded as the payload in gene therapy, often requiring a carrier for intracellular delivery. With the recent discovery that spherical nucleic acids enter cells rapidly, we demonstrate that nucleic acids also have the potential to act as a delivery vehicle. Herein, we report an amphiphilic DNA-paclitaxel conjugate, which forms stable micellar nanoparticles in solution. The nucleic acid component acts as both a therapeutic payload for intracellular gene regulation and the delivery vehicle for the drug component. A bioreductively activated, self-immolative disulfide linker is used to tether the drug, allowing free drug to be released upon cell uptake. We found that the DNA-paclitaxel nanostructures enter cells ∼100 times faster than free DNA, exhibit increased stability against nuclease, and show nearly identical cytotoxicity as free drug. These nanostructures allow one to access a gene target and a drug target using only the payloads themselves, bypassing the need for a cocarrier system.


Assuntos
DNA/química , Portadores de Fármacos/química , Oligonucleotídeos/química , Dissulfetos/química , Micelas , Modelos Moleculares , Nanopartículas/química , Conformação de Ácido Nucleico , Paclitaxel/química
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