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Artigo em Inglês | MEDLINE | ID: mdl-30479120


The mitochondria have emerged as a novel target for cancer chemotherapy primarily due to their central roles in energy metabolism and apoptosis regulation. Here we report a new molecular approach to achieve high levels of tumor- and mitochondria-selective delivery of the anticancer drug doxorubicin. This is achieved by molecular engineering which functionalizes doxorubicin with a hydrophobic lipid tail conju-gated by a solubility-promoting polyethylene glycol polymer (amphiphilic Doxorubicin or amph-DOX). In vivo, the amphiphile conjugated to doxorubicin exhibits a dual function: i) it binds avidly to serum albumin and hijacks albumin's circulating and transporting pathways, resulting in prolonged circulation in blood, increased accumulation in tumor, and reduced exposure to the heart; ii) it also redirects doxorubicin to mi-tochondria by altering the drug molecule's intracellular sorting and transportation routes. Efficient mito-chondrial targeting with amph-DOX causes a significant increase of reactive oxygen species (ROS) levels in tumor cells, resulting in markedly improved antitumor efficacy than the unmodified doxorubicin. Am-phiphilic modification provides a simple strategy to simultaneously increase the efficacy and safety of doxorubicin in cancer chemotherapy.

Nanoscale ; 10(19): 9311-9319, 2018 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-29737353


Nanotechnology has demonstrated tremendous clinical utility, with potential applications in cancer immunotherapy. Although nanoparticles with intrinsic cytotoxicity are often considered unsuitable for clinical applications, such toxicity may be harnessed in the fight against cancer. Nanoparticle-associated toxicity can induce acute necrotic cell death, releasing tumor-associated antigens which may be captured by antigen-presenting cells to initiate or amplify tumor immunity. To test this hypothesis, cytotoxic cationic silica nanoparticles (CSiNPs) were directly administered into B16F10 melanoma implanted in C57BL/6 mice. CSiNPs caused plasma membrane rupture and oxidative stress of tumor cells, inducing local inflammation, tumor cell death and the release of tumor-associated antigens. The CSiNPs were further complexed with bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP), a molecular adjuvant which activates the stimulator of interferon genes (STING) in antigen-presenting cells. Compared with unformulated c-di-GMP, the delivery of c-di-GMP with CSiNPs markedly prolonged its local retention within the tumor microenvironment and activated tumor-infiltrating antigen-presenting cells. The combination of CSiNPs and a STING agonist showed dramatically increased expansion of antigen-specific CD8+ T cells, and potent tumor growth inhibition in murine melanoma. These results demonstrate that cationic nanoparticles can be used as an effective in situ vaccine platform which simultaneously causes tumor destruction and immune activation.

Bioconjug Chem ; 29(3): 719-732, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29165988


Antigen-specific immunotherapy (ASI) holds great promise for the treatment of autoimmune diseases. In mice, administration of major histocompatibility complex (MHC) binding synthetic peptides which modulate T cell receptor (TCR) signaling under subimmunogenic conditions induces selective tolerance without suppressing the global immune responses. However, clinical translation has yielded limited success. It has become apparent that the TCR signaling pathway via synthetic peptide antigen alone is inadequate to induce an effective tolerogenic immunity in autoimmune diseases. Bioconjugate strategies combining additional immunomodulatory functions with TCR signaling can amplify the antigen-specific immune tolerance and possibly lead to the development of new treatments in autoimmune diseases. In this review, we provide a summary of recent advances in the development of bioconjugates to achieve antigen-specific immune tolerance in vivo, with the discussion focused on the underlying design principles and challenges that must be overcome to target these therapies to patients suffering from autoimmune diseases.

ACS Appl Mater Interfaces ; 9(28): 23466-23475, 2017 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-28640587


Nanoparticles have emerged as the platform of choice to improve the efficacy and safety of subunit vaccines. A major challenge underlying the use of nanomaterials in vaccines lies in the particle designs that can efficiently target and activate the antigen-presenting cells, especially dendritic cells. Here we show a toll-like receptor 9 (TLR-9) agonist and antigen coloaded, silica nanoparticles (SiNPs) are able to accumulate in antigen presenting cells in the draining lymph nodes after injection. Vaccine loaded SiNPs led to dramatically enhanced induction of antigen-specific B and T cell responses as compared to soluble vaccines, which in turn drove a protective antitumoral immunity in a murine tumor model. Additionally, SiNP vaccines greatly reduced the production of systemic proinflammatory cytokines and completely abrogated splenomegaly, key systemic toxicities of TLR-9 agonists that limit their advances in clinical applications. Our results demonstrate that structure-optimized silica nanocarriers can be used as an effective and safe platform for targeted delivery of subunit vaccines.

Bioconjug Chem ; 28(7): 1993-2000, 2017 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-28644608


Nucleic acid based adjuvants recognized by Toll-like receptors (TLR) are potent immune system stimulants that can augment the antitumor immune responses in an antigen-specific manner. However, their clinical uses as vaccine adjuvants are limited primarily due to lack of accumulation in the lymph nodes, the anatomic sites where the immune responses are initiated. Here, we showed that chemical conjugation of type B CpG DNA, a TLR9 agonist to dextran polymer dramatically enhanced CpG's lymph node accumulation in mice. Dextran conjugation did not alter CpG ODN's uptake, internalization, and bioactivity in vitro. Delivery of Dextran-CpG conjugate markedly increased the uptake by antigen presenting cells in the lymph nodes and enhanced CD8+ T cell responses primed by protein vaccines, leading to improved therapeutic antitumor immunity. Furthermore, immunization with Dextran-CpG mixed with necrotic whole tumor cells induced a protective antitumor response in a murine model, suggesting that this approach was not limited to molecularly defined antigens. This simple method might also be applicable for the delivery of many other nucleic acid based adjuvants in cancer vaccines.

Adjuvantes Imunológicos/farmacocinética , Vacinas Anticâncer/imunologia , Dextranos/química , Imunoterapia/métodos , Linfonodos/metabolismo , Oligodesoxirribonucleotídeos/uso terapêutico , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/uso terapêutico , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos de Neoplasias , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Camundongos , Camundongos Endogâmicos C57BL , Receptor Toll-Like 9/agonistas , Receptores Toll-Like/imunologia