PMID- 33112630
OWN - NLM
STAT- MEDLINE
DCOM- 20210917
LR  - 20210917
IS  - 1543-8392 (Electronic)
IS  - 1543-8384 (Linking)
VI  - 17
IP  - 12
DP  - 2020 Dec 7
TI  - Protein Delivery by Peptide-Based Stealth Liposomes: A Biomolecular Insight into 
      Enzyme Replacement Therapy.
PG  - 4510-4521
LID - 10.1021/acs.molpharmaceut.0c00615 [doi]
AB  - 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.
FAU - Santi, Melissa
AU  - Santi M
AUID- ORCID: 0000-0002-9374-883X
AD  - Center for Nanotechnology Innovation@NEST, Istituto Italiano di Tecnologia, Pisa 
      56127, Italy.
AD  - NEST, Scuola Normale Superiore and Istituto Nanoscienze-CNR, Pisa 56127, Italy.
FAU - Finamore, Francesco
AU  - Finamore F
AD  - Institute of Clinical Physiology-CNR, Pisa 56127, Italy.
FAU - Cecchettini, Antonella
AU  - Cecchettini A
AD  - University of Pisa, Dept. of Clinical and Experimental Medicine, Pisa 56126, 
      Italy.
FAU - Santorelli, Filippo Maria
AU  - Santorelli FM
AD  - Molecular Medicine, IRCCS Stella Maris, Pisa 56128, Italy.
FAU - Doccini, Stefano
AU  - Doccini S
AD  - Molecular Medicine, IRCCS Stella Maris, Pisa 56128, Italy.
FAU - Rocchiccioli, Silvia
AU  - Rocchiccioli S
AD  - Institute of Clinical Physiology-CNR, Pisa 56127, Italy.
FAU - Signore, Giovanni
AU  - Signore G
AD  - NEST, Scuola Normale Superiore and Istituto Nanoscienze-CNR, Pisa 56127, Italy.
AD  - Fondazione Pisana per la Scienza, Pisa 56017, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201028
PL  - United States
TA  - Mol Pharm
JT  - Molecular pharmaceutics
JID - 101197791
RN  - 0 (Liposomes)
RN  - 0 (Membrane Proteins)
RN  - 0 (Peptides)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (PPT1 protein, human)
SB  - IM
MH  - Cells, Cultured
MH  - Drug Compounding/methods
MH  - Drug Liberation
MH  - Enzyme Assays
MH  - Enzyme Replacement Therapy/*methods
MH  - Fibroblasts
MH  - Humans
MH  - Liposomes
MH  - Membrane Proteins/*administration & dosage/genetics/pharmacokinetics
MH  - Nanoparticles/*chemistry
MH  - Neuronal Ceroid-Lipofuscinoses/*drug therapy/genetics
MH  - Peptides/*chemistry
MH  - Primary Cell Culture
MH  - Thiolester Hydrolases/*administration & dosage/genetics/pharmacokinetics
OTO - NOTNLM
OT  - blood brain barrier (BBB)
OT  - enzyme replacement therapy (ERT)
OT  - liposomes
OT  - lysosomal storage disorders (LSDs)
OT  - peptide aptamers
EDAT- 2020/10/29 06:00
MHDA- 2021/09/18 06:00
CRDT- 2020/10/28 17:14
PHST- 2020/10/29 06:00 [pubmed]
PHST- 2021/09/18 06:00 [medline]
PHST- 2020/10/28 17:14 [entrez]
AID - 10.1021/acs.molpharmaceut.0c00615 [doi]
PST - ppublish
SO  - Mol Pharm. 2020 Dec 7;17(12):4510-4521. doi: 10.1021/acs.molpharmaceut.0c00615. 
      Epub 2020 Oct 28.