Insight into nanoparticle cellular uptake and intracellular targeting

Yulin Li,*,†,‡ Dina Maciel,† Joaõ Rodrigues,*,† Xiangyang Shi,*,†,§ and Helena Tomaś*,† †CQM-Centro de Química da Madeira, MMRG, Universidade da Madeira, Campus da Penteada 9000-390, Funchal, Portugal ‡The State Key Laboratory of Bioreactor Engineering, Key Laboratory for Ultrafine Materials of Ministry of Education, Engineering Research Centre for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, People’s Republic of China College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People’s Republic of China

Biodegradable Polymer Nanogels for Drug/Nucleic Acid Delivery.

Every year, cancer is responsible for millions of deaths worldwide and, even though much progress has been achieved in medicine, there are still many issues that must be addressed in order to improve cancer therapy. For this reason, oncological research is putting a lot of effort towards finding new and efficient therapies which can alleviate critical side effects caused by conventional treatments. Different technologies are currently under evaluation in clinical trials or have been already introduced into clinical practice. While nanomedicine is contributing to the development of biocompatible materials both for diagnostic and therapeutic purposes, bioengineering of extracellular vesicles and cells derived from patients has allowed designing ad hoc systems and univocal targeting strategies. In this review, we will provide an in-depth analysis of the most innovative advances in basic and applied cancer research.

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Innovative approaches for cancer treatment: current perspectives and new challenges.

PICALM is a highly validated genetic risk factor for Alzheimer's disease (AD). We found that reduced expression of PICALM in AD and murine brain endothelium correlated with amyloid-β (Aβ) pathology and cognitive impairment. Moreover, Picalm deficiency diminished Aβ clearance across the murine blood-brain barrier (BBB) and accelerated Aβ pathology in a manner that was reversible by endothelial PICALM re-expression. Using human brain endothelial monolayers, we found that PICALM regulated PICALM/clathrin-dependent internalization of Aβ bound to the low density lipoprotein receptor related protein-1, a key Aβ clearance receptor, and guided Aβ trafficking to Rab5 and Rab11, leading to Aβ endothelial transcytosis and clearance. PICALM levels and Aβ clearance were reduced in AD-derived endothelial monolayers, which was reversible by adenoviral-mediated PICALM transfer. Inducible pluripotent stem cell-derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced Aβ clearance. Thus, PICALM regulates Aβ BBB transcytosis and clearance, which has implications for Aβ brain homeostasis and clearance therapy.

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Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance

Controlled Drug Release from Pharmaceutical Nanocarriers.

Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances.

Purpose
This review discusses the molecular mechanism involved in the targeting and delivery of antibody-drug conjugates (ADCs), the new class of biopharmaceuticals mainly designed for targeted cancer therapy.

Internalization, Trafficking, Intracellular Processing and Actions of Antibody-Drug Conjugates.

Despite observations that the lacrimal gland has been identified as the principal source of dimeric immunoglobulin A (dIgA) in tears, the mechanism used by lacrimal gland acinar cells (LGACs) to transcytose dIgA produced by interstitial plasma cells is not well-characterized. This study identifies a transcytotic pathway in LGACs regulated by Rab11a for polymeric immunoglobulin receptor (pIgR) and dIgA. EGFP-tagged Rab11a expressed in primary LGACs labeled a unique membrane compartment of comparable localization to endogenous Rab11a beneath the apical plasma membrane. This compartment was enriched in pIgR and clearly distinct from the regulated secretory pathway. Comparison of dIgA uptake in LGACs expressing wild type and dominant negative EGFP-Rab11a showed that the rapid exocytosis of dIgA was inhibited in acini expressing the dominant-negative protein, which additionally redistributed subapical pIgR. The trafficking of EGFP-Rab11a-enriched vesicles was regulated by microtubule-based and myosin Vb motors at distinct steps. Our data suggest that Rab11a is a crucial regulator of dIgA trafficking in primary acinar secretory epithelial cells and further support a role for microtubules, cytoplasmic dynein, actin filaments and myosin Vb in the maintenance of the Rab11a compartment in this primary secretory epithelial cell.

A Rab11a-enriched subapical membrane compartment regulates a cytoskeleton-dependent transcytotic pathway in secretory epithelial cells of the lacrimal gland

The polymeric immunoglobulin receptor (pIgR) mediates transcytosis of dimeric immunoglobulin A (dIgA) and its release into mucosal secretions. The present study reveals the complexity of the trafficking of pIgR to the apical plasma membrane in epithelial cells with exocrine secretory functions; in rabbit lacrimal gland acinar cells (LGACs), trafficking of pIgR involves both the transcytotic pathway and one arm of the regulated secretory pathway. By specifically tracking pIgR endocytosed from the basolateral membrane, we show here that the Rab11a-regulated transcytotic pathway mediates the basal-to-apical transport of pIgR, and that pIgR sorted into the transcytotic pathway does not access the regulated secretory pathway. However, previous work in LGACs expanded in the present study has shown that some pIgR is localized to Rab3D-enriched mature secretory vesicles (SVs). Myosin Vb and myosin Vc motors modulate release of proteins from the Rab11a-regulated transcytotic pathway and the Rab3D-enriched secretory pathway in LGACs, respectively. Confocal fluorescence microscopy and biochemical assays showed that inhibition of myosin Vb and myosin Vc activity by overexpression of their dominant-negative mutants each significantly but differentially impaired aspects of apically targeted pIgR trafficking and secretory component release, suggesting that these motors function to regulate pIgR trafficking in both the transcytotic and exocytotic pathways. Intriguingly, a second mature SV population enriched in Rab27b was devoid of pIgR cargo, suggesting the specialization of Rab3D-enriched mature SVs to carry a particular subset of cargo proteins from the trans-Golgi network to the apical plasma membrane.

Shi Xu

Papers

Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances.

Internalization, Trafficking, Intracellular Processing and Actions of Antibody-Drug Conjugates.

A Rab11a-enriched subapical membrane compartment regulates a cytoskeleton-dependent transcytotic pathway in secretory epithelial cells of the lacrimal gland

Polymeric immunoglobulin receptor traffics through two distinct apically targeted pathways in primary lacrimal gland acinar cells.

Tear-mediated delivery of nanoparticles through transcytosis of the lacrimal gland.