Abstract:
:Infantile neural ceroid lipofuscinosis (INCL) is a lysosomal storage disorder characterized by mutations in the CLN1 gene that leads to lack of the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1), which causes the progressive death of cortical neurons. Enzyme replacement therapy (ERT) is one of the most promising treatments, but its translation toward a clinical use is hampered by the need to deliver the enzyme to the central nervous system and a more detailed understanding of its capability to restore physiologic conditions at the biochemical and protein level, beyond the simple regulation of enzymatic activity. Targeted nanoparticles can promote protein delivery to the central nervous system and affect biological pathways inside cells. Here, we describe an innovative peptide-based stealth nanoparticle that inhibits serum protein adsorption exploiting transferrin-driven internalization to convey the PPT1 enzyme to transferrin receptor-mediated pathways (endocytosis in this work, or transcytosis, in perspective, in vivo). These enzyme-loaded nanoparticles were able to restore stable levels of enzymatic activity in CLN1 patient's fibroblasts, comparable with the free enzyme, demonstrating that delivery after encapsulation in the nanocarrier does not alter uptake or intracellular trafficking. We also investigate, for the first time, dysregulated pathways of proteome and palmitoylome and their alteration upon enzyme delivery. Our nanoparticles were able of halving palmitoylated protein levels restoring conditions similar to the normal cells. From proteomic analysis, we also highlighted the reduction of the different groups of proteins after treatments with the free or encapsulated enzyme. In conclusion, our system is able to deliver the enzyme to a model of CLN1 disease restoring normal conditions in cells. Investigation of molecular details of pathologic state and enzyme-based correction reveals dysregulated pathways with unprecedented details for CLN1. Finally, we unveil for the first time the dysregulation landscape of palmitoylome and proteome in primary patient-derived fibroblasts and their modifications in response to enzyme administration. These findings will provide a guideline for the validation of future therapeutic strategies based on enzyme replacement therapy or acting at different metabolic levels.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Santi M,Finamore F,Cecchettini A,Santorelli FM,Doccini S,Rocchiccioli S,Signore Gdoi
10.1021/acs.molpharmaceut.0c00615subject
Has Abstractpub_date
2020-12-07 00:00:00pages
4510-4521issue
12eissn
1543-8384issn
1543-8392journal_volume
17pub_type
杂志文章abstract::Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To under...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00541
更新日期:2018-08-06 00:00:00
abstract::Heart transplantation (HT) is an effective treatment for end-stage heart disease. However, acute rejection (AR) is still the main cause of death within one year after HT. AR is an acute immune response mediated by T lymphocytes, mainly CD4+ T lymphocytes. This study innovatively develops a radiolabeled probe 99mTc-HYN...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c01155
更新日期:2021-01-28 00:00:00
abstract::A combination of microbubbles (MBs) and ultrasound (US) is an emerging method for noninvasive and targeted enhancement of anti-cancer drug uptake. This method showed an increase local drug extravasation in tumor tissue while reducing the systemic adverse effects in various tumor models. The present study aims to evalu...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00416
更新日期:2019-09-03 00:00:00
abstract::Metastatic breast cancer is incurable. The goal of this study was to develop a positron emission tomography (PET)/near-infrared fluorescent (NIRF) probe for imaging CD105 expression in breast cancer experimental lung metastasis. TRC105, a chimeric anti-CD105 antibody, was dual-labeled with a NIRF dye (IRDye 800CW) and...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300277f
更新日期:2012-08-06 00:00:00
abstract::The synthesis of a dendrimer based on melamine that displays multiple copies of four orthogonally reactive groups, three on the surface and one on the interior, is described. The three groups on the surface are nucleophilic and include four free hydroxyl groups, four hydroxyl groups masked as tert-butyldiphenylsilyl (...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp050030e
更新日期:2005-07-01 00:00:00
abstract::The controlled release of anticancer drugs at the tumor site is a central challenge in treating cancer. To achieve this goal, our strategy was based on tumor-specific targeting and ultrasound-triggered release of an anticancer agent from liposomal nanocarriers. To enhance the ultrasound-triggered drug release, we inco...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00194
更新日期:2019-07-01 00:00:00
abstract::Diagnostic imaging of the liver by ultrasound, computed tomography (CT) and magnetic resonance tomography (MRT) is generally limited to the visualization of the morphology. In order to exploit the intriguing liver tropism of the human hepatitis B virus (HBV) for molecular imaging of the liver, peptidic tracers derived...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400038r
更新日期:2013-06-03 00:00:00
abstract::Improving the therapeutic index of anticancer agents is an enormous challenge. Targeting decreases the side effects of the therapeutic agents by delivering the drugs to the intended destination. Nanocarriers containing the nuclear localizing peptide sequences (NLS) translocate to the cell nuclei. However, the nuclear ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00014
更新日期:2017-06-05 00:00:00
abstract::Oleanolic acid (OA) is a well-known pentacyclic triterpenoid compound, which has been used as a dietary supplement and is supplied as an over-the-counter drug for the treatment of human liver diseases. These are reasons for the low bioavailability of OA which have restricted its wider application. In this study, two O...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00129
更新日期:2016-05-02 00:00:00
abstract::In humans, C-X-C chemokine receptor type 4 (CXCR4) is a protein that is encoded by the CXCR4 gene and binds the ligand CXCL12 (also known as SDF-1). The CXCR4-CXCL12 interaction in cancer elicits biological activities that result in tumor progression and has accordingly been the subject of significant investigation fo...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00069
更新日期:2019-05-06 00:00:00
abstract::The mechanism of cell death in A2780 human ovarian carcinoma cells induced by free doxorubicin (DOX) and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound DOX [P-(GFLG)-DOX] was investigated. In particular, the involvement of the Fas receptor system in drug-induced apoptosis was evaluated. P-(GFLG)-DOX was show...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp049967q
更新日期:2004-05-01 00:00:00
abstract::Within the immune system there is an exquisite ability to discriminate between "self" and "non-self" that is orchestrated by antigen-specific T lymphocytes. Genomic plasticity enables differentiation of naive CD4+ T lymphocytes into either regulatory cells (Treg) that express the transcription factor Foxp3 and activel...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp100203a
更新日期:2011-02-07 00:00:00
abstract::Barbital is a hypnotic agent that has been intensely studied for many decades. The aim of this work was to establish a clear and comprehensible picture of its polymorphic system. Four of the six known solid forms of barbital (denoted I(0), III, IV, and V) were characterized by various analytical techniques, and the th...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400515f
更新日期:2014-01-06 00:00:00
abstract::The adenosine triphosphate-binding cassette transporter P-glycoprotein (ABCB1/Abcb1a) restricts at the blood-brain barrier (BBB) brain distribution of many drugs. ABCB1 may be involved in drug-drug interactions (DDIs) at the BBB, which may lead to changes in brain distribution and central nervous system side effects o...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00168
更新日期:2015-09-08 00:00:00
abstract::HEPES has been widely employed as an organic buffer agent in cell culture medium as well as uptake and transport experiments in vitro. However, concentrations of HEPES used in such studies vary from one laboratory to another. In this study, we investigated the effect of HEPES on the uptake and bidirectional transport ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900193e
更新日期:2010-04-05 00:00:00
abstract::As a chronic inflammatory and angiogenic disease with increased morbidity and mortality, rheumatoid arthritis (RA) is characterized by the proliferation of synovial tissue and the accumulation of excessive mononuclear infiltration, which always results in the joint deformity, disability, and eventually the destruction...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00505
更新日期:2017-09-05 00:00:00
abstract::Here, we report the antiproliferative/cytotoxic properties of 8-hydroxyquinoline (8-HQ) derivatives on HeLa cells in the presence of transition metal ions (Cu(2+), Fe(3+), Co(2+), Ni(2+)). Two series of ligands were tested, the arylvinylquinolinic L1-L8 and the arylethylenequinolinic L9-L16, which can all interact wit...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400592n
更新日期:2014-04-07 00:00:00
abstract::Preferential interactions of formulation excipients govern their impact on the stability properties of proteins in solution. The ability to predict these interactions without the need to perform experiments would enable formulation design to begin early in the development of a new antibody therapeutic. With that in mi...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00629
更新日期:2020-09-08 00:00:00
abstract::Despite advances in cancer therapies, glioblastoma multiforme treatment remains inefficient due to the brain-blood barrier (BBB) inhibitory activity and to the low temozolomide (TMZ) chemotherapeutic selectivity. To improve therapeutic outcomes, in this work we propose two strategies, (i) photodynamic therapy (PDT) as...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b01001
更新日期:2019-03-04 00:00:00
abstract::The antiviral drug tenofovir (TFV) is orally administered as the fumarate salt of its disoproxil prodrug (TFV disoproxil fumarate (TDF)). TFV is a dianion at physiological pH and, as a result, has poor lipid membrane permeability. Administration of the lipophilic and cell-permeable prodrug, TFV disoproxil, enhances th...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900036s
更新日期:2009-07-01 00:00:00
abstract::There are an increasing number of studies showing the order of drug presentation plays a critical role in achieving optimal combination therapy. Here, a nanoparticle design is presented using ion pairing and drug-polymer conjugate for the sequential delivery of gefitinib (Gi) and doxorubicin (Dox) targeting epidermal ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00669
更新日期:2017-12-04 00:00:00
abstract::In the postprandial stomach, processes such as secretion, digestion, and gastric emptying all occur simultaneously. Therefore, the system is highly heterogeneous and dynamically changing, for instance, in terms of various physicochemical parameters such as pH value or viscosity. Thus, the administration of a drug toge...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00799
更新日期:2019-11-04 00:00:00
abstract::Nonviral gene delivery has seen limited clinical application due in part to the inefficiency with which most nonviral vehicles navigate the intracellular gene delivery pathway. One key problem is the inability of most DNA-packaging materials to release DNA and enable its efficient transcription. Thus, our aim was to d...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200373p
更新日期:2012-05-07 00:00:00
abstract::Ritonavir is a protease inhibitor utilized primarily as a pharmaco-enhancer with concomitantly administered antiviral drugs including other protease inhibitors. However, poor tolerance, serious side effects, and toxicities associated with drug-drug interactions are common during exposure to ritonavir. The aim of this ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00204
更新日期:2015-10-05 00:00:00
abstract::Similar to glycolysis, glutaminolysis acts as a vital energy source in tumor cells, providing building blocks for the metabolic needs of tumor cells. To capture glutaminolysis in tumors, 18F-(2S,4R)4-fluoroglutamine ([18F]FGln) and 18F-fluoroboronoglutamine ([18F]FBQ) have been successfully developed for positron emis...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00891
更新日期:2019-12-02 00:00:00
abstract::Novel multivalent copper(II)-conjugated phosphorus dendrimers and their corresponding mononuclear copper(II) complexes were synthesized, characterized, and screened for antiproliferative activity against human cancer cell lines. Selected copper ligands were grafted on the surface of phosphorus dendrimers of generation...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp4000184
更新日期:2013-04-01 00:00:00
abstract::Reversible aqueous lipidization (REAL) at the interdisulfide bond has been shown to improve the deliverability of some peptide drugs. Recently, we developed a nonreversible aqueous lipidization method targeted at the interdisulfide bond of salmon calcitonin (sCT). The resultant derivative had comparable hypocalcemic a...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp8000167
更新日期:2008-07-01 00:00:00
abstract::The small molecule fluorescein is commonly used to guide the repair of cerebral spinal fluid leaks (CSFLs) in the clinic. We modified fluorescein so that it is also visible by positron emission tomography (PET). This probe was used to quantitatively track the fast distribution of small molecules in the CSF of rats. We...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00485
更新日期:2019-08-05 00:00:00
abstract::Polysorbate 20 (PS20) is a commonly used surfactant in biopharmaceutical formulations. It is a heterogeneous surfactant containing a distribution of fatty acid esters, which are subject to hydrolytic degradation, generating free fatty acids (FFAs). The FFAs can form visible or subvisible particles in drug product on s...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00794
更新日期:2020-11-02 00:00:00
abstract::Deacetylated gellan gum and two sodium alginate polymer types were used each at three concentrations in the suitable range for their sol-gel transition. The prepared nine droppable gels were evaluated in vitro, ex vivo through sheep nasal mucosa, as well as in vivo in comparison to drug solution given intravenously an...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500825n
更新日期:2015-06-01 00:00:00