Gene/Protein Disease Symptom Drug Enzyme Compound
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Clinical cancer treatments nowadays still face the challenge of recurrence due to the residual cancer cells and minute lesions in surgeries or chemotherapies. To effectively address the problem, we introduce a strategy for constructing cancer cell nuclear-targeted copper sulfide nanoparticles (NPs) with a significant photothermal effect to completely kill residual cancer cells and prevent local cancer recurrence. The NPs could directly target the tumor cells and further enter the nucleus by the surface modification of RGD and TAT peptides. Under the irradiation of 980 nm near-infrared laser, the NPs rapidly increase the temperature of the nucleus, destroy the genetic substances, and ultimately lead to an exhaustive apoptosis of the cancer cells. In vivo experiments show that the designed NPs could effectively treat cancer and prevent the return of cancer with a single laser irradiation for 5 min. The photothermal therapy strategy with nuclear targeting for cancer therapy and anti-recurrence will provide more possibilities to develop efficient platforms for treating cancer.
ACS Nano 2018 06 26
PMID:Nuclear-Targeted Photothermal Therapy Prevents Cancer Recurrence with Near-Infrared Triggered Copper Sulfide Nanoparticles. 2989 62

Following surgical resection for primary treatment of solid tumors, systemic chemotherapy is commonly used to eliminate residual cancer cells to prevent tumor recurrence. However, its clinical outcome is often limited due to insufficient local accumulation and the systemic toxicity of anticancer drugs. Here, we propose a sprayable adhesive nanoparticle (NP)-based drug delivery system using a bioengineered mussel adhesive protein (MAP) for effective locoregional cancer therapy. The MAP NPs could be administered to target surfaces in a surface-independent manner through a simple and easy spray process by virtue of their unique adhesion ability and sufficient dispersion property. Doxorubicin (DOX)-loaded MAP NPs (MAP@DOX NPs) exhibited efficient cellular uptake, endolysosomal trafficking, and subsequent low pH microenvironment-induced DOX release in cancer cells. The locally sprayed MAP@DOX NPs showed a significant inhibition of tumor growth in vivo, resulting from the prolonged retention of the MAP@DOX NPs on the tumor surface. Thus, this adhesive MAP NP-based spray therapeutic system provides a promising approach for topical drug delivery in adjuvant cancer therapy.
ACS Nano 2018 09 25
PMID:Sprayable Adhesive Nanotherapeutics: Mussel-Protein-Based Nanoparticles for Highly Efficient Locoregional Cancer Therapy. 3005 23

Complete tumor eradication is the ultimate goal of cancer therapy. However, the majority of anticancer drugs cause nonimmunogenic cell death and only exert on-site anticancer activities. The intrinsic genomic instability of cancer allows for the persistence and later expansion of treatment-resistant clones after surviving a sort of Darwinian selection of chemotherapy. Additional incorporation of immunotherapy, which is robust and individualized could be game-changing. Herein, we report a combination strategy that delivers nonimmunogenic cell death inducer Cisplatin to treat primary tumors and converts the tumor cells into vaccines that spurs a long-lasting immune response against residual tumors to prevent tumor recurrence and metastasis. Cisplatin(IV) prodrug was linked to the N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer (P-Cis) and coadministered with digoxin (Dig), which eventually launched two attacks to cancer cells. First, P-Cis exhibited superior tumor retention and cytotoxicity over free Cisplatin (to inhibit the primary tumor growth). Then, Dig reversed the inability of Cisplatin to trigger calreticulin exposure, and HPMA copolymer-amplified Cisplatin-induced ATP release. These complementary mechanisms induced potent immunogenic cell death that promotes dendritic cell maturation and activates CD8+ T cell responses. In established tumor models, P-Cis + Dig combination completely eradicate tumors with no residual cancer cells remaining. Cancer cells succumbing to P-Cis + Dig could protect syngeneic mice against the subsequent challenge with living cells of the same type and stimulated robust abscopal and antimetastatic effects. Such a strategy might be promising to restore the immunogenicity of nonimmunogenic drugs and generate vaccine-like functions for improved immunochemotherapy.
ACS Appl Mater Interfaces 2020 Jan 08
PMID:Restoration and Enhancement of Immunogenic Cell Death of Cisplatin by Coadministration with Digoxin and Conjugation to HPMA Copolymer. 3180 65

Considering the high rate of postsurgical tumor recurrence due to the possible residual cancer cells and the non-negligible toxicity of postsurgical systemic chemotherapy, we designed an injectable DNA hydrogel assembled by chemodrug-grafted DNA strands for localized chemotherapy. First, a multitude of camptothecin was successfully grafted on backbones of the phosphorothioate DNAs, which could be assembled into two types of Y-shaped building blocks and then hierarchically associated together to form drug-containing hydrogels. The injectable feature of drug-containing DNA hydrogels enables a minimally invasive approach for local drug administration. Owing to the enzymatic degradation, the hydrogel can gradually disassemble into nanosized particles, allowing its good permeation into the residual tumor tissue and efficient uptake by cells. Together with its sustained and responsive drug release behaviors, the drug-containing DNA hydrogel can significantly inhibit the regrowth of tumor cells and prevent cancer recurrence. Compared to the control groups, mice treated with our drug-containing DNA hydrogel show the lowest tumor relapse rate (1/3) and substantial slow tumor progression. Despite the long-term local embedding, negligible systemic toxicity and organ damages are observed after the treatment with our drug-grafted DNA hydrogel. With excellent antitumor efficacy and low side effects in vivo, our DNA-drug conjugate (DDC)-based hydrogel represents a promising candidate for local adjuvant therapy in cancer treatment.
ACS Appl Mater Interfaces 2020 May 13
PMID:Injectable Drug-Conjugated DNA Hydrogel for Local Chemotherapy to Prevent Tumor Recurrence. 3231 1