ABSTRACT
Enediyne natural products, including neocarzinostatin and calicheamicin γ1, are used in the form of a copolymer or antibody-drug conjugate to treat hepatomas and leukemia. Tiancimycin (TNM) A is a novel anthraquinone-fused enediyne that can rapidly and completely kill tumor cells. Herein, we encapsulated TNM A in liposomes (Lip-TNM A) and cyclic arginine-glycine-aspartate (cRGD)-functionalized liposomes (cRGD-Lip-TNM A) and demonstrated its antitumor activity using mouse xenografts. Because TNM A causes rapid DNA damage, cell cycle arrest, and apoptosis, these nanoparticles exhibited potent cytotoxicity against multiple tumor cells for 8 h. In B16-F10 and KPL-4 xenografts, both nanoparticles showed superior potency over doxorubicin and trastuzumab. However, cRGD-Lip-TNM A reduced the tumor weight more significantly than Lip-TNM A in B16-F10 xenografts, in which the αvß3-integrin receptors are significantly overexpressed in this melanoma. Lip-TNM A was slightly more active than cRGD-Lip-TNM A against KPL-4 xenografts, which probably reflected the difference of their in vivo fate in this mouse model. In a highly metastatic 4T1 tumor model, cRGD-Lip-TNM A reduced tumor metastasis induced by losartan, a tumor microenvironment-remodeling agent. These findings suggest that targeted delivery of enediynes with unique modes of action may enable more effective translation of anticancer nanomedicines.
Subject(s)
Breast Neoplasms , Melanoma , Animals , Breast Neoplasms/drug therapy , Cell Line, Tumor , Doxorubicin/pharmacology , Enediynes , Female , Humans , Liposomes , Melanoma/drug therapy , Mice , Tumor MicroenvironmentABSTRACT
Metals play essential roles in life by coordination with small molecules, proteins, and nucleic acids. Although the coordination of copper ions in many proteins and methanobactins is known, the coordination chemistry of Cu(II) in natural products and their biological functions remain underexplored. Herein, we report the discovery of a Cu(II)-binding natural product, chalkophomycin (CHM, 1), from Streptomyces sp. CB00271, featuring an asymmetric square-coordination system of a bidentate diazeniumdiolate and a conjugated 1H-pyrrole 1-oxide-oxazoline. The structure of 1 may inspire the synthesis of Cu(II) chelators against neurodegenerative diseases or Cu(II)-based antitumor therapeutics.
Subject(s)
Chelating Agents/chemistry , Coordination Complexes/chemistry , Copper/chemistry , Molecular Structure , Oxazoles/chemistry , Pyrrolidinones/chemistryABSTRACT
Serious bacterial infections by multi-drug-resistant pathogens lead to human losses and endanger public health. The discovery of antibiotics with new modes of action, in combination with nanotechnology, might offer a promising route to combat multi-drug-resistant pathogens. Platensimycin (PTM), a potent inhibitor of FabB/FabF for bacterial fatty acid biosynthesis, is a promising drug lead against many drug-resistant bacteria. However, the clinical development of PTM is hampered by its poor pharmacokinetics. Herein, we report a nanostrategy that encapsulated PTM in two types of nanoparticles (NPs) poly(lactic-co-glycolic acid) (PLGA) and poly(amidoamine) (PAMAM) dendrimer to enhance its antibacterial activity in vitro and in vivo. The PTM-encapsulated NPs were effective to inhibit Staphylococcus aureus biofilm formation, and killed more S. aureus in a macrophage cell infection model over free PTM. The pharmacokinetic studies showed that PTM-loaded PLGA and PAMAM NPs exhibited increased AUC0-t (area under the curve) (â¼4- and 2-fold) over free PTM. In a mouse peritonitis model, treatment of methicillin-resistant S. aureus infected mice using both PTM-loaded NPs (10 mg/kg) by intraperitoneal injection led to their full survival, while all infected mice died when treated by free PTM (10 mg/kg). These results not only suggest that PTM-loaded NPs may hold great potential to improve the poor pharmacokinetic properties of PTM, but support the rationale to develop bacterial fatty acid synthase inhibitors as promising antibiotics against drug-resistant pathogens.
Subject(s)
Adamantane/chemistry , Adamantane/pharmacology , Aminobenzoates/chemistry , Aminobenzoates/pharmacology , Anilides/chemistry , Anilides/pharmacology , Dendrimers/chemistry , Methicillin-Resistant Staphylococcus aureus/drug effects , Nanoparticles/chemistry , Polyamines/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Adamantane/pharmacokinetics , Aminobenzoates/pharmacokinetics , Anilides/pharmacokinetics , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Drug Carriers/chemistry , Methicillin-Resistant Staphylococcus aureus/physiology , MiceABSTRACT
The cationic glycopeptide bleomycin (BLM) is a broad-spectrum chemotherapy drug clinically applied to treat various malignant tumors. The poor cell membrane permeability of BLM, which is prone to high dose usage and may consequently induce dose-dependent lung toxicity, is a sticking point to limit clinical applications of BLM. As a commercial biosurfactant, the anionic lipopeptide surfactin (SF) is well known for its potent ability to disturb membranes and widely applied in cosmetic area as a permeabilization synergist. In this work, our in vitro investigations showed that SF could ameliorate the cell internalization of BLM, and the combined usage of SF notably improved the antitumor activity of BLM or its analogues while having no obvious effects on normal cells. Subsequent in vivo assessments on the subcutaneous treatment of A375 melanoma in mice demonstrated that SF could also enhance the therapeutic effects of BLM family compounds in subeffective doses, with no obvious toxicities on lungs and skin. Also, our preliminary results suggested the formation of complex micelles at the nanoscale by the self-assembly of BLM and SF, which may contribute to the ameliorated internalization and the antitumor effect of BLM. Therefore, SF could be applied as a potential synergist for BLM to reduce its treatment dose while maintaining the therapeutic effect on treatment of skin carcinoma, which provides us an alternative way to minimize the side effects of clinical BLM and facilitate the development of new BLM-type drugs.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Bleomycin/pharmacology , Bleomycin/therapeutic use , Lipopeptides/pharmacology , Lipopeptides/therapeutic use , Melanoma/drug therapy , Peptides, Cyclic/pharmacology , Peptides, Cyclic/therapeutic use , A549 Cells , Animals , Female , Humans , Male , Melanoma/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Neoplasms/drug therapy , Neoplasms/metabolism , Reactive Oxygen Species/metabolismABSTRACT
Staphylococcus aureus is one of the most common pathogens causing hospital-acquired and community-acquired infections. Methicillin-resistant S. aureus (MRSA)-formed biofilms in wounds are difficult to treat with conventional antibiotics. By targeting FabB/FabF of bacterial fatty acid synthases, platensimycin (PTM) was discovered to act as a promising natural antibiotic against MRSA infections. In this study, PTM and its previously synthesized sulfur-Michael derivative PTM-2t could reduce over 95% biofilm formation by S. aureus ATCC 29213 when used at 2 µg/mL in vitro. Topical application of ointments containing PTM or PTM-2t (2 × 4 mg/day/mouse) was successfully used to treat MRSA infections in a BABL/c mouse burn wound model. As a potential prodrug lead, PTM-2t showed improved in vivo efficacy in a mouse peritonitis model compared with PTM. Our study suggests that PTM and its analogue may be used topically or locally to treat bacterial infections. In addition, the use of prodrug strategies might be instrumental to improve the poor pharmacokinetic properties of PTM.
Subject(s)
Adamantane/therapeutic use , Aminobenzoates/therapeutic use , Anilides/therapeutic use , Anti-Bacterial Agents/therapeutic use , Burns/drug therapy , Fatty Acid Synthesis Inhibitors/therapeutic use , Methicillin-Resistant Staphylococcus aureus/drug effects , Peritonitis/drug therapy , Prodrugs/therapeutic use , Staphylococcal Skin Infections/drug therapy , Adamantane/administration & dosage , Aminobenzoates/administration & dosage , Anilides/administration & dosage , Animals , Anti-Bacterial Agents/administration & dosage , Biofilms/drug effects , Burns/microbiology , Disease Models, Animal , Drug Resistance, Bacterial/drug effects , Drug Stability , Fatty Acid Synthase, Type II/antagonists & inhibitors , Fatty Acid Synthesis Inhibitors/administration & dosage , Female , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Microsomes/drug effects , Peritonitis/microbiology , Prodrugs/administration & dosage , Staphylococcal Skin Infections/microbiology , Sulfides , Treatment OutcomeABSTRACT
Although natural products are essential sources of small-molecule antitumor drugs, some can exert substantial toxicities, limiting their clinical utility. Anthraquinone-fused enediyne natural products are remarkably potent antitumor drug candidates, and uncialamycin and tiancimycin (TNM) A are under development as antibody-drug conjugates. Herein, a novel drug delivery system is introduced for TNM A using anti-human epidermal growth factor receptor 2 (HER2) immunoliposomes (ILs). Trastuzumab-coated TNM A-loaded ILs (HER2-TNM A-ILs) is engineered with an average particle size of 182.8 ± 2.1 nm and a zeta potential of 1.75 ± 0.12 mV. Compared with liposomes lacking trastuzumab, HER2-TNM A-ILs exhibited selective toxicity against HER2-positive KPL-4 and SKBR3 cells. Coumarin-6, a fluorescent TNM A surrogate, is encapsulated within anti-HER2 ILs; the resultant ILs have enhanced cellular uptake in KPL-4 and SKBR3 cells when compared with control liposomes. Furthermore, ILs loaded with more Cy5.5 accumulated in KPL-4 mouse tumors. A single HER2-TNM A-IL dose (0.02 mg kg-1) suppressed the growth of HER2-positive KPL-4 mouse tumors without apparent toxicity. This study not only provides a straightforward method for the effective delivery of TNM A against HER2-positive breast tumors but also underscores the potential of IL-based drug delivery systems when employing highly potent cytotoxins as payloads.
Subject(s)
Anthraquinones , Antineoplastic Agents , Drug Delivery Systems , Enediynes , Liposomes , Receptor, ErbB-2 , Animals , Mice , Enediynes/chemistry , Enediynes/pharmacology , Receptor, ErbB-2/immunology , Anthraquinones/pharmacology , Anthraquinones/administration & dosage , Humans , Drug Delivery Systems/methods , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/administration & dosage , Female , Disease Models, Animal , Trastuzumab/administration & dosage , Breast Neoplasms/drug therapy , Breast Neoplasms/immunologyABSTRACT
Dynemicin A has been the sole prototypical anthraquinone-fused enediyne (AFE) explored since its discovery in 1989. This study investigates the distinct DNA binding and cleavage mechanisms of emerging AFEs, represented by tiancimycins and yangpumicins, along with semisynthetic analogues. Our findings reveal their potent cytotoxicity against various tumor cell lines, while 18-methoxy tiancimycin A treatment could significantly suppress breast tumor growth with minimal toxicity. One of the most potent AFEs, i.e., tiancimycin A, preferentially targets DNA sequences 5'-ATT, 5'-CTT, 5'-GAA, 5'-GAT, and 5'-TTA. Molecular dynamics simulations suggest that emerging AFEs intercalate deeper into AT-rich DNA base pairs compared to dynemicin A. Importantly, tiancimycin A may equilibrate between insertional and intercalative modes without deintercalation, enabling selective cleavage of T and A bases. This study underscores how subtle structural variations among AFEs significantly influence their DNA recognition and cleavage, facilitating future design of novel AFEs as potent and selective payloads for antibody-drug conjugates.