RESUMEN
Current clinical treatment of Helicobacter pylori infection, the main etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma, requires a combination of at least two antibiotics and one proton pump inhibitor. However, such triple therapy suffers from progressively decreased therapeutic efficacy due to the drug resistance and undesired killing of the commensal bacteria due to poor selectivity. Here, we report the development of antimicrobial polypeptide-based monotherapy, which can specifically kill H. pylori under acidic pH in the stomach while inducing minimal toxicity to commensal bacteria under physiological pH. Specifically, we designed a class of pH-sensitive, helix-coil conformation transitionable antimicrobial polypeptides (HCT-AMPs) (PGA)m-r-(PHLG-MHH)n, bearing randomly distributed negatively charged glutamic acid and positively charged poly(γ-6-N-(methyldihexylammonium)hexyl-l-glutamate) (PHLG-MHH) residues. The HCT-AMPs showed unappreciable toxicity at physiological pH when they adopted random coiled conformation. Under acidic condition in the stomach, they transformed to the helical structure and exhibited potent antibacterial activity against H. pylori, including clinically isolated drug-resistant strains. After oral gavage, the HCT-AMPs afforded comparable H. pylori killing efficacy to the triple-therapy approach while inducing minimal toxicity against normal tissues and commensal bacteria, in comparison with the remarkable killing of commensal bacteria by 65% and 86% in the ileal contents and feces, respectively, following triple therapy. This strategy renders an effective approach to specifically target and kill H. pylori in the stomach while not harming the commensal bacteria/normal tissues.
Asunto(s)
Aminas/química , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Ácido Glutámico/farmacología , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Péptidos Catiónicos Antimicrobianos/síntesis química , Modelos Animales de Enfermedad , Femenino , Ácido Glutámico/análogos & derivados , Ácido Glutámico/síntesis química , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/patogenicidad , Helicobacter pylori/fisiología , Concentración de Iones de Hidrógeno , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Especificidad de Órganos , Conformación Proteica en Hélice alfa , Electricidad Estática , Estómago/efectos de los fármacos , Estómago/microbiología , Estómago/patologíaRESUMEN
The inherent features of small interfering RNA (siRNA), including a relatively high molecular weight, negative charge, and hydrophilic nature, lead to the widespread use of cationic polymers and lipid-based nanocarriers, which might induce potential cytotoxicity, thus limiting their clinical application. Here, we report a facile strategy for changing the inherent features of siRNA molecules by achieving hydrophobization. We found that the simple mixing of siRNA and doxorubicin hydrochloride (DOX·HCl) could form a hydrophobic complex, which was readily encapsulated into noncationic PEG- b-PLA micelles for systemic delivery. In addition to delivering DOX·HCl, this strategy could be extended to deliver other hydrochloride forms of anticancer drugs with large hydrophobic domains. This facile strategy efficiently avoids the use of cationic nanocarriers, providing a new avenue for siRNA delivery.
Asunto(s)
Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , ARN Interferente Pequeño/farmacología , Antineoplásicos/química , Cationes/química , Doxorrubicina/química , Doxorrubicina/farmacología , Portadores de Fármacos/farmacología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Lactatos/química , Micelas , Nanopartículas/administración & dosificación , Nanopartículas/química , Polietilenglicoles/química , Polímeros/química , ARN Interferente Pequeño/químicaRESUMEN
The cell nucleus-targeted delivery of therapeutic agents plays a critical role in cancer therapy, since the biological target of many anticancer therapeutics is the cell nucleus. However, multiple physiological barriers limit the delivery efficiency of free drugs, resulting in unsatisfactory therapeutic effects. Herein, thioketal crosslinked polyphosphoester-based nanoparticles with a tumor acidity (pHe )-sensitive transactivator of transcription (TAT) peptide (DA-masked TAT-decorating reactive oxygen species (ROS)-sensitive Ce6/DOX-loaded hyperbranched nanoparticles (D TRCD)) are explored for cascade nucleus-targeted drug delivery. Following administration, D TRCD experiences prolonged circulation by masking the targeting effect of its TAT peptide and then achieves enhanced tumor cell uptake and improved translocation into the perinuclear region by reactivating the TAT targeting capability in tumor tissue. Subsequently, ROS generated by D TRCD under 660 nm laser not only disrupts the nuclear membrane to allow entry into the nuclei but also triggers intracellular release of the payload in the nuclei. As evidenced by in vivo experiments, such pHe /photo dual-sensitive polymeric nanocarriers offer remarkable therapeutic effects, efficiently suppressing tumor growth. This multistage cascade nucleus-targeted drug delivery concept provides new avenues to develop nucleus-targeted drug delivery systems.
Asunto(s)
Núcleo Celular/metabolismo , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Polímeros/química , Animales , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/uso terapéutico , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Humanos , Concentración de Iones de Hidrógeno , Especies Reactivas de OxígenoRESUMEN
α-Helical antimicrobial peptides (AMPs) generally have facially amphiphilic structures that may lead to undesired peptide interactions with blood proteins and self-aggregation due to exposed hydrophobic surfaces. Here we report the design of a class of cationic, helical homo-polypeptide antimicrobials with a hydrophobic internal helical core and a charged exterior shell, possessing unprecedented radial amphiphilicity. The radially amphiphilic structure enables the polypeptide to bind effectively to the negatively charged bacterial surface and exhibit high antimicrobial activity against both gram-positive and gram-negative bacteria. Moreover, the shielding of the hydrophobic core by the charged exterior shell decreases nonspecific interactions with eukaryotic cells, as evidenced by low hemolytic activity, and protects the polypeptide backbone from proteolytic degradation. The radially amphiphilic polypeptides can also be used as effective adjuvants, allowing improved permeation of commercial antibiotics in bacteria and enhanced antimicrobial activity by one to two orders of magnitude. Designing AMPs bearing this unprecedented, unique radially amphiphilic structure represents an alternative direction of AMP development; radially amphiphilic polypeptides may become a general platform for developing AMPs to treat drug-resistant bacteria.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad MicrobianaRESUMEN
Mannose receptor (MR) is a highly effective endocytic receptor. It is closely related to tumour immune escape and metastasis. We found that MR was highly expressed in some colon cancer cell lines such as CT26 and HCT116 cells. Therefore, MR might be a potential target in colon cancer therapy. In this study, we aimed to develop mannosylated liposomes containing anticancer drug paclitaxel and investigate the potential effects on targeted therapy for colon cancer. Mannosylated liposomes were prepared by film dispersion method. Characterisation, drug release behaviour, cytotoxicity, cellular uptake, anti-tumour efficacy and safety profiles of liposomes were investigated. The results showed that mannosylated liposomes had a higher CT26 cells uptake efficiency and tumour inhibition rate, which might be due to the target effect to MR. And no notable toxicity was observed. Taken together, these data demonstrated that mannosylated liposomes could target colon cancer and improve the efficacy of chemotherapy.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Lectinas Tipo C/metabolismo , Liposomas/química , Lectinas de Unión a Manosa/metabolismo , Manosa/metabolismo , Paclitaxel/administración & dosificación , Receptores de Superficie Celular/metabolismo , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Receptor de Manosa , Ratones , Ratones Endogámicos BALB CRESUMEN
The application of antimicrobial peptides (AMPs) is largely hindered by their non-specific toxicity against mammalian cells, which is usually associated with helical structure, hydrophobicity, and charge density. A random coil-to-helix transition mechanism has now been introduced into the design of AMPs, minimizing the toxicity against mammalian cells while maintaining high antimicrobial activity. By incorporating anionic phosphorylated tyrosine into the cationic polypeptide, the helical structure of AMPs was distorted owing to the side-chain charge interaction. Together with the decreased charge density, the AMPs exhibited inhibited toxicity against mammalian cells. At the infectious site, the AMPs can be activated by bacterial phosphatase to restore the helical structure, thus contributing to strong membrane disruptive capability and potent antimicrobial activity. This bacteria-activated system is an effective strategy to enhance the therapeutic selectivity of AMPs.
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Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Bacillus cereus/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Péptidos Catiónicos Antimicrobianos/química , Péptidos Catiónicos Antimicrobianos/metabolismo , Bacillus cereus/metabolismo , Línea Celular , Células HEK293 , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Tamaño de la Partícula , Células RAW 264.7 , Staphylococcus aureus/metabolismoRESUMEN
The KRAS mutation is present in ~20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Quinasa 4 Dependiente de la Ciclina/genética , Terapia Genética , Proteínas Proto-Oncogénicas/genética , ARN Interferente Pequeño/genética , Proteínas ras/genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/terapia , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica , Técnicas de Transferencia de Gen , Humanos , Ratones , Nanopartículas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras) , ARN Interferente Pequeño/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Renal ischemia/reperfusion (I/R) injury causes high mortality and morbidity during renal procedures, yet current drugs should be used at high doses or for long periods due to lack of tissue specificity. In previous work we described a novel mycophenolic acid-glucosamine conjugate (MGC) that targets the proximal tubule epithelium, where it efficiently reduces renal I/R injury in rats and promotes recovery from reperfusion. Here we perform mechanistic studies of MGC in rats that suggest that the conjugate works by repressing the activation of renal inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), thereby inhibiting the proliferation and accumulation of lympholeukocytes in the proximal tubules. In addition, MGC appears to inhibit inflammation through various pathways, including inhibition of free oxygen radical production, upregulation of bone morphogenetic protein-7, and downregulation of complement protein 3, TLR 4, intracellular adhesion molecules in the endothelium, proinflammatory cytokines (e.g., TNF-α, IL-6, IL-1, TGF-ß), and chemotactic cytokines [e.g., monocyte chemoattractant protein-1 (MCP-1) and IL-8]. These findings suggest that MGC specifically targets the proximal tubules and acts through numerous mechanisms to substantially mitigate I/R injury in rats; this conjugate may provide a more effective alternative to current combination therapy.
Asunto(s)
Antiinflamatorios/uso terapéutico , Glucosamina/química , Glucosamina/uso terapéutico , Ácido Micofenólico/química , Ácido Micofenólico/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Animales , Antiinflamatorios/química , IMP Deshidrogenasa/metabolismo , Interleucina-6/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Oncolytic peptides (OLPs) with membranolytic activity show great potential to combat multidrug-resistant cancer cells. Herein, we report a cationic helical oncolytic polypeptide (OLPP) with potent membranolytic activity for cancer therapy. The OLPP was synthesized by ring-opening polymerization of N-carboxyanhydrides (NCAs) and thiol-ene reaction. The OLPP was resistant to protease, showed high cytotoxicity to a series of cancer cells and caused cancer cell necrosis by quickly lysing cancer cell membrane independent of classic death-related intracellular pathways. Intra-tumoral injection of the OLPP effectively suppressed tumor growth in mice through the direct oncolytic effect. The OLPP represents a potential oncolytic chemotherapeutics for cancer therapy.
Asunto(s)
Neoplasias , Viroterapia Oncolítica , Animales , Ratones , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Péptidos , Neoplasias/terapia , Necrosis , Línea Celular TumoralRESUMEN
OBJECTIVE: We aimed to evaluate the clinical performance of expanded noninvasive prenatal testing (NIPT-Plus) for the detection of aneuploidies and microdeletion/microduplication syndromes. METHODS: A total of 7177 pregnant women were enrolled in the study from June 2020 to March 2022 at Xijing Hospital, China. Cases with NIPT-Plus-positive results were further confirmed by chromosomal karyotyping and a chromosomal microarray analysis. RESULTS: A total of 112 positive cases (1.56%) were identified by NIPT-Plus, including 60 chromosome aneuploidies and 52 microdeletion/microduplication syndromes. Ninety-five cases were validated by amniocentesis, and 57 were confirmed with true-positive results, comprising 18 trisomy 21, 4 trisomy 18, 1 trisomy 13, 17 sex chromosome aneuploidies, 1 other aneuploidy, and 16 microdeletion/microduplication syndromes. The positive predictive value of total chromosomal abnormalities was 60% (57/95). For trisomy 21, trisomy 18, trisomy 13, sex chromosome aneuploidies, other aneuploidies and microdeletion/microduplication syndromes, the sensitivity was all 100%, the specificity was 100, 99.986, 100, 99.888, 99.958, and 99.636%, and the positive predictive value was 100, 80, 100, 68, 25, and 38.10%, respectively. For all clinical characteristics, the abnormal maternal serum screening group was found to have the highest prevalence of chromosomal abnormalities (1.54%), and the ultrasound abnormality group presented the highest positive predictive value (73.33%). CONCLUSIONS: NIPT-Plus has great potential for the detection of aneuploidies and microdeletion/microduplication syndromes owing to its high sensitivity, safety, and specificity, which greatly reduces unnecessary invasive procedures and the risk of miscarriage and allows informed maternal choice.
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Síndrome de Down , Pruebas Prenatales no Invasivas , Femenino , Embarazo , Humanos , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Síndrome de la Trisomía 18/diagnóstico , Síndrome de la Trisomía 18/genética , Diagnóstico Prenatal/métodos , Síndrome de la Trisomía 13/diagnóstico , Síndrome de la Trisomía 13/genética , Aneuploidia , Aberraciones CromosómicasRESUMEN
Rationale: Broad-spectrum oncolytic peptides (Olps) constitute potential therapeutic options for treating heterogeneous triple-negative breast cancer (TNBC); however, their clinical application is limited owing to high toxicity. Methods: A nanoblock-mediated strategy was developed to induce selective anticancer activity of synthetic Olps. A synthetic Olp, C12-PButLG-CA, was conjugated to the hydrophobic or hydrophilic terminal of a poly(ethylene oxide)-b-poly(propylene oxide) nanoparticle or a hydrophilic poly(ethylene oxide) polymer. A nanoblocker, that can significantly reduce the toxicity of Olp, was screened out through hemolytic assay, and then Olps were conjugated to the nanoblock via a tumor acidity-cleavable bond to obtain the selective RNolp ((mPEO-PPO-CDM)2-Olp). The tumor acidity responsive membranolytic activity, in vivo toxicity and anti-tumor efficacy of RNolp were determined. Results: We found that the conjugation of Olps to the hydrophobic core of a nanoparticle but not the hydrophilic terminal or a hydrophilic polymer restricts their motion and drastically reduces their hemolytic activity. We then covalently conjugated Olps to such a nanoblock via a cleavable bond that can be hydrolyzed in the acidic tumor environment, yielding a selective RNolp molecule. At physiological pH (pH 7.4), RNolp remained stable with the Olps shielded by nanoblocks and exhibited low membranolytic activity. At the acidic tumor environment (pH 6.8), Olps could be released from the nanoparticles via the hydrolysis of the tumor acidity-cleavable bonds and exerted membranolytic activity against TNBC cells. RNolp is well tolerated in mice and demonstrated high antitumor efficacy in orthotopic and metastatic mouse models of TNBC. Conclusion: We developed a simple nanoblock-mediated strategy to induce a selective cancer therapy of Olps for TNBC.
Asunto(s)
Nanopartículas , Neoplasias de la Mama Triple Negativas , Humanos , Ratones , Animales , Neoplasias de la Mama Triple Negativas/patología , Línea Celular Tumoral , Óxido de Etileno/uso terapéutico , Péptidos/química , Nanopartículas/química , Polímeros/químicaRESUMEN
Antimicrobial polymers exhibit great potential for treating drug-resistant bacteria; however, designing antimicrobial polymers that can selectively kill bacteria and cause relatively low toxicity to normal tissues/cells remains a key challenge. Here, we report a pH window for ionizable polymers that exhibit high selectivity toward bacteria. Ionizable polymer PC6A showed the greatest selectivity (131.6) at pH 7.4, exhibiting low hemolytic activity and high antimicrobial activity against bacteria, whereas a very high or low protonation degree (PD) produced relatively low selectivity (≤35.6). Bactericidal mechanism of PC6A primarily comprised membrane lysis without inducing drug resistance even after consecutive incubation for 32 passages. Furthermore, PC6A demonstrated synergistic effects in combination with antibiotics at pH 7.4. Hence, this study provides a strategy for designing selective antimicrobial polymers.
Asunto(s)
Antibacterianos , Concentración de Iones de Hidrógeno , Antibacterianos/química , Antibacterianos/farmacología , Polímeros/química , Pruebas de Sensibilidad Microbiana , Bacterias/efectos de los fármacosRESUMEN
We report a new strategy for differential delivery of antimicrobials to bacterial infection sites with a lipase-sensitive polymeric triple-layered nanogel (TLN) as the drug carrier. The TLN was synthesized by a convenient arm-first procedure using an amphiphilic diblock copolymer, namely, monomethoxy poly(ethylene glycol)-b-poly(ε-caprolactone), to initiate the ring-opening polymerization of the difunctional monomer 3-oxapentane-1,5-diyl bis(ethylene phosphate). The hydrophobic poly(ε-caprolactone) (PCL) segments collapsed and surrounded the polyphosphoester core, forming a hydrophobic and compact molecular fence in aqueous solution which prevented antibiotic release from the polyphosphoester core prior to reaching bacterial infection sites. However, once the TLN sensed the lipase-secreting bacteria, the PCL fence of the TLN degraded to release the antibiotic. Using Staphylococcus aureus (S. aureus) as the model bacterium and vancomycin as the model antimicrobial, we demonstrated that the TLN released almost all the encapsulated vancomycin within 24 h only in the presence of S. aureus, significantly inhibiting S. aureus growth. The TLN further delivered the drug into bacteria-infected cells and efficiently released the drug to kill intracellular bacteria. This technique can be generalized to selectively deliver a variety of antibiotics for the treatment of various infections caused by lipase-secreting bacteria and thus provides a new, safe, effective, and universal approach for the treatment of extracellular and intracellular bacterial infections.
Asunto(s)
Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Lipasa/metabolismo , Polietilenglicoles/química , Polietileneimina/química , Polímeros/química , Antibacterianos/farmacología , Portadores de Fármacos/metabolismo , Lipasa/química , Pruebas de Sensibilidad Microbiana , Nanogeles , Polietilenglicoles/metabolismo , Polietileneimina/metabolismo , Polímeros/metabolismo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Relación Estructura-Actividad , Vancomicina/farmacologíaRESUMEN
The particular characteristics of the tumor microenvironment have the potential to strongly promote tumor growth, metastasis and angiogenesis and induce drug resistance. Therefore, the development of effective, systemic therapeutic approaches specifically based on the tumor microenvironment is highly desirable. Hypoxia-inducible factor-1α (HIF-1α) is an attractive therapeutic target because it is a key transcription factor in tumor development and only accumulates in hypoxic tumors. We report here that a cationic mixed micellar nanoparticle (MNP) consisting of amphiphilic block copolymers poly(ε-caprolactone)-block-poly(2-aminoethylethylene phosphate) (PCL(29)-b-PPEEA(21)) and poly(ε-caprolactone)-block-poly(ethylene glycol) (PCL(40)-b-PEG(45)) was a suitable carrier for HIF-1α siRNA to treat hypoxic tumors, which showed an average diameter of 58.0 ± 3.4 nm. The complex MNP(siRNA), formed by the interaction of MNP and siRNA, was transfected into PC3 prostate cancer cells efficiently, while the inhibition of HIF-1α expression by MNP loaded with HIF-1α siRNA (MNP(siHIF)) blocked PC3 cell proliferation, suppressed cell migration and disturbed angiogenesis under in vitro hypoxic mimicking conditions. It was further demonstrated that systemic delivery of MNP(siHIF) effectively inhibited tumor growth in a PC3 prostate cancer xenograft murine model without activating innate immune responses. Moreover, delivery of MNP(siHIF) sensitized PC3 tumor cells to doxorubicin chemotherapy in vitro and in vivo by downregulating MDR1 gene expression which was induced by hypoxia. The underlying concept of use of MNP(siHIF) to block HIF-1α holds promise as an example of a clinical approach using specific siRNA therapy for cancer treatment aimed at the hypoxic tumor microenvironment.
Asunto(s)
Hipoxia de la Célula/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Nanopartículas/administración & dosificación , Neoplasias de la Próstata/genética , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/química , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Silenciador del Gen , Humanos , Masculino , Ratones , Ratones Desnudos , Micelas , Nanopartículas/química , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Tamaño de la Partícula , Polímeros/administración & dosificación , Polímeros/química , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Interferente Pequeño/química , Transfección/métodos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genéticaRESUMEN
Plasma membrane rupture is a promising strategy for drug-resistant cancer treatment, but its application is limited by the low tumour selectivity of membranolytic molecules. Here we report the design of 'proton transistor' nanodetergents that can convert the subtle pH perturbation signals of tumour tissues into sharp transition signals of membranolytic activity for selective cancer therapy. Our top-performing 'proton transistor' nanodetergent, P(C6-Bn20), can achieve a >32-fold change in cytotoxicity with a 0.1 pH input signal. At physiological pH, P(C6-Bn20) self-assembles into neutral nanoparticles with inactive membranolytic blocks shielded by poly(ethylene glycol) shells, exhibiting low toxicity. At tumour acidity, a sharp transition in its protonation state induces a morphological transformation and an activation of the membranolytic blocks, and the cation-π interaction facilitates the insertion of benzyl groups-containing hydrophobic domains into the cell membranes, resulting in potent membranolytic activity. P(C6-Bn20) is well tolerated in mice and shows high anti-tumour efficacy in various mouse tumour models.
Asunto(s)
Nanopartículas , Neoplasias , Animales , Concentración de Iones de Hidrógeno , Ratones , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Polietilenglicoles/química , ProtonesRESUMEN
Biomedical polymers have been extensively developed for promising applications in a lot of biomedical fields, such as therapeutic medicine delivery, disease detection and diagnosis, biosensing, regenerative medicine, and disease treatment. In this review, we summarize the most recent advances in the synthesis and application of biomedical polymers, and discuss the comprehensive understanding of their property-function relationship for corresponding biomedical applications. In particular, a few burgeoning bioactive polymers, such as peptide/biomembrane/microorganism/cell-based biomedical polymers, are also introduced and highlighted as the emerging biomaterials for cancer precision therapy. Furthermore, the foreseeable challenges and outlook of the development of more efficient, healthier and safer biomedical polymers are discussed. We wish this systemic and comprehensive review on highlighting frontier progress of biomedical polymers could inspire and promote new breakthrough in fundamental research and clinical translation.
RESUMEN
Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an 'adaptor' while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.
Asunto(s)
Anticuerpos Monoclonales/metabolismo , Inmunomodulación , Inmunoterapia , Nanopartículas/química , Neoplasias/inmunología , Neoplasias/terapia , Animales , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Citotoxicidad Inmunológica , Femenino , Proteínas Inmovilizadas/metabolismo , Inmunidad , Células Asesinas Naturales/inmunología , Masculino , Ratones Endogámicos C57BL , Nanopartículas/ultraestructura , Linfocitos T/inmunologíaRESUMEN
Reversibly cross-linked core-shell-corona micelles based on a triblock copolymer composed of poly(aliphatic ester), polyphosphoester, and poly(ethylene glycol) are reported. The triblock copolymer is synthesized through consecutive ring-opening polymerization of ε-caprolactone and 2,4-dinitrophenylthioethyl ethylene phosphate, followed by conjugation of poly(ethylene glycol). After deprotection under mild conditions, the amphiphilic polymer forms core-shell-corona micelles with free thiols in the shell. Cross-linking of the micelles within the shell reduces their critical micellization concentration and enhances their stability against severe conditions. The redox-sensitive cross-linkage allows the facilitated release of entrapped anticancer drugs in the cytoplasm in response to the intracellular reductive environment. With enhanced stability during circulation after administration, and accelerated intracellular drug release at the target site, the biocompatible and biodegradable shell-cross-linked polymeric micelle is promising as a drug vehicle for cancer chemotherapy.
RESUMEN
Since the development of bacterial resistance, the decreasing effectiveness of antibiotics is becoming one of the most critical problems worldwide. Novel antibacterial agents are urgently needed to prevent humanity from falling back into the "post-antibiotic era". As an important part of the innate immune system, antimicrobial peptides (AMPs) are one of the most promising antibacterial agents showing broad-spectrum activity against bacteria and low propensity for drug resistance. However, the shortcomings of AMPs, such as high toxicity and easy digestion by proteases, limit their clinical application. This review mainly focuses on the effect of the secondary structure on the antimicrobial activity and cytotoxicity of AMPs and the strategies of designing conformationally transitionable AMPs with improved selectivity towards bacteria.
Asunto(s)
Péptidos Catiónicos Antimicrobianos , Infecciones Bacterianas , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Bacterias , Humanos , Proteínas Citotóxicas Formadoras de PorosRESUMEN
Polymeric nanoparticles (NPs) are an important category of drug delivery systems, and their in vivo fate is closely associated with delivery efficacy. Analysis of the protein corona on the surface of NPs to understand the in vivo fate of different NPs has been shown to be reliable but complicated and time-consuming. In this work, we establish a simple approach for predicting the in vivo fate of polymeric NPs. We prepared a series of poly(ethylene glycol)-block-poly(d,l-lactide) (PEG-b-PLA) NPs with different protein binding behaviors by adjusting their PEG densities, which were determined by analyzing the serum protein adsorption. We further determined the protein binding affinity, denoted as the equilibrium association constant (KA), to correlate with in vivo fate of NPs. The in vivo fate, including blood clearance and Kupffer cell uptake, was studied, and the maximum concentration (Cmax), the area under the plasma concentration-time curve (AUC), and the mean residence time (MRT) were negatively linearly dependent, while Kupffer cell uptake was positively linearly dependent on KA. Subsequently, we verified the reliability of the approach for in vivo fate prediction using poly(methoxyethyl ethylene phosphate)-block-poly(d,l-lactide) (PEEP-b-PLA) and poly(vinylpyrrolidone)-block-poly(d,l-lactide) (PVP-b-PLA) NPs, and the linear relationship between the KA value and their PK parameters further suggests that the protein binding affinity of polymeric NPs can be a direct indicator of their pharmacokinetics.