Protein corona presents a major obstacle to bench-to-bedside translation of targeted drug delivery systems, severely affecting targeting yields and directing unfavorable biodistribution. ...Corona-mediated targeting provides a new impetus for specific drug delivery by precisely manipulating interaction modes of functional plasma proteins on nano-surface. Here bio-inspired liposomes (SP-sLip) were developed by modifying liposomal surface with a short nontoxic peptide derived from Aβ
that specifically interacts with the lipid-binding domain of exchangeable apolipoproteins. SP-sLip absorb plasma apolipoproteins A1, E and J, consequently exposing receptor-binding domain of apolipoproteins to achieve brain-targeted delivery. Doxorubicin loaded SP-sLip (SP-sLip/DOX) show significant enhancement of brain distribution and anti-brain cancer effect in comparison to doxorubicin loaded plain liposomes. SP-sLip preserve functions of the absorbed human plasma ApoE, and the corona-mediated targeting strategy works in SP modified PLGA nanoparticles. The present study may pave a new avenue to facilitate clinical translation of targeted drug delivery systems.
Treatment of malignant gliomas remains a challenge irrespective of the recent improvements. Chemotherapeutic agents for malignant gliomas have been particularly inefficient for the existence of ...blood-tumor barrier (BTB), which hampers the accumulation and uptake in tumor. Moreover, even though blood-brain barrier (BBB) is compromised to some extent under the situation of malignant gliomas, it remains to be the obstacle influencing the therapeutic efficacies via systemic administration. Fortunately, there are many receptors over-expressed on the BTB (glioma cells and/or tumor microvessels) that can mediate ligand modified drug delivery systems targeting to gliomas and enhance tumor uptake. On the other hand, numerous routes have also been explored to circumvent the BBB. In this manuscript, we elucidate the BBB/BTB status under the situation of malignant gliomas and review the receptors over-expressed on BTB and the malignant gliomas targeted drug delivery strategies. We also discuss the perspective of malignant gliomas targeted drug delivery systems with new concepts.
Targeting ligands are anticipated to facilitate the precise delivery of therapeutic agents to diseased tissues; however, they may also severely affect the interaction of nanocarriers with plasma ...proteins. Here, we study the immunocompatibility of brain-targeted liposomes, which inversely correlates with absorbed natural IgM. Modification of long, stable positively charged peptide ligands on liposomes is inclined to absorb natural IgM, leading to rapid clearance and enhanced immunogenicity. Small peptidomimetic D8 developed by computer-aided peptide design exhibits improved immunocompatibility by attenuating natural IgM absorption. The present study highlights the effects of peptide ligands on the formed protein corona and in vivo fate of liposomes. Stable positively charged peptide ligands play double-edged roles in targeted delivery, preserving in vivo bioactivities for binding receptors and long-term unfavorable interactions with the innate immune system. The development of D8 provides insights into how to rationally design immunocompatible drug delivery systems by modulating the protein corona composition.
The use of glioblastoma-targeted drug delivery system facilitates efficient delivery of chemotherapeutic agents to malignant gliomas in the central nervous system while minimizing high systemic doses ...associated with debilitating toxicities. To employ the high binding affinity of a cyclic RGD peptide (c(RGDyK), cyclic Arginine–Glycine–Aspartic acid-
d-Tyrosine-Lysine) with integrin α
vβ
3 over-expressed on tumor neovasculature and U87MG glioblastoma cells, we prepared paclitaxel-loaded c(RGDyK)-Poly(ethylene glycol)-
block-poly(lactic acid) micelle (c(RGDyK)-PEG-PLA-PTX).
In vitro physicochemical characterization of these novel micelles showed satisfactory encapsulated efficiency, loading capacity and size distribution.
In vitro cytotoxicity studies proved that the presence of c(RGDyK) enhanced the anti-glioblastoma cell cytotoxic efficacy by 2.5 folds. The binding affinity of c(RGDyK)-PEG-PLA micelle with U87MG cells was also investigated. The competitive binding IC
50 value of c(RGDyK)-PEG-PLA micelle was 26.30
nM, even lower than that of c(RGDyK) (56.23
nM). In U87MG glioblastoma-bearing nude mice model, biodistribution of
125I-radiolabeled c(RGDyK)-PEG-PLA or DiR encapsulated micelles and anti-glioblastoma pharmacological effect was investigated after intravenous administration. c(RGDyK)-PEG-PLA micelle accumulated in the subcutaneous and intracranial tumor tissue, and when loaded with PTX (c(RGDyK)-PEG-PLA-PTX), exhibited the strongest tumor growth inhibition among the studied paclitaxel formulations. The anti-glioblastoma effect of c(RGDyK)-PEG-PLA-PTX micelle was also reflected in the median survival time of mice bearing intracranial U87MG tumor xenografts where the median survival time of c(RGDyK)-PEG-PLA-PTX micelle-treated mice (48
days) was significantly longer than that of mice treated with PEG-PLA-PTX micelle (41.5
days), Taxol® (38.5
days) or saline (34
days). Therefore, our results suggested that c(RGDyK)-PEG-PLA micelle may be a potential drug delivery system in the treatment of integrin α
vβ
3 over-expressed glioblastoma.
Paclitaxel-loaded c(RGDyK)-PEG-PLA micelle was developed. It was much effective to the subcutaneous and intracranial glioblastoma models.
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Lysosomes of brain capillary endothelial cells are implicated in nicotine acetylcholine receptor (nAChR)‐mediated transcytosis and act as an enzymatic barrier for the transport of peptide ligands to ...the brain. A D‐peptide ligand of nAChRs (termed DCDX), which binds to nAChRs with an IC50 value of 84.5 nM, was developed by retro–inverso isomerization. DCDX displayed exceptional stability in lysosomal homogenate and serum, and demonstrated significantly higher transcytosis efficiency in an in vitro blood–brain barrier monolayer compared with the parent L‐peptide. When modified on liposomal surface, DCDX facilitated significant brain‐targeted delivery of liposomes. As a result, brain‐targeted delivery of DCDX modified liposomes enhanced therapeutic efficiency of encapsulated doxorubicin for glioblastoma. This study illustrates the importance of ligand stability in nAChRs‐mediated transcytosis, and paves the way for developing stable brain‐targeted entities.
A D‐peptide ligand of nicotine acetylcholine receptors (nAChRs), termed DCDX, was developed. The function of DCDX as a D‐peptide antagonist of nAChRs was experimentally and computationally validated. DCDX exhibits exceptional stability during nAChRs‐mediated transcytosis and in blood circulation, offering potential for brain‐targeted drug delivery in the treatment of central nervous system diseases.
A large proportion of the payload delivered by nanoparticulate therapies is deposited not in the desired target destination but in off-target locations such as the liver and spleen. Here, we ...demonstrate that phototargeting can improve the specific targeting of nanoparticles to tumors. The combination of efficient triplet–triplet annihilation upconversion (TTA-UC) and Förster resonance energy transfer (FRET) processes allowed in vivo phototargeting at a safe irradiance (200 mW/cm2) over a short period (5 min) using green light.
The blood–brain barrier (BBB) prevents most drugs from reaching the site of central nervous system (CNS) diseases, intensively confining the therapeutic efficiency. Angiopep-2 (here termed ...LAngiopep), which is a 19-mer peptide derived from human Kunitz domain, can trigger transcytosis and traverse the BBB by recognizing low density lipoprotein-related protein 1 (LRP-1) expressed on the brain capillary endothelial cells. Various enzymes in the blood and the BBB, however, present multiple metabolic barriers to peptide-inspired brain-targeted drug delivery. Here we designed a retro-inverso isomer of LAngiopep, termed DAngiopep, to inspire brain-targeted drug delivery. Both DAngiopep and LAngiopep displayed high uptake capacity in LRP-1 overexpressed cells, including bEnd.3 and U87 cells. DAngiopep demonstrated lower uptake efficiency in both cell lines than did LAngiopep, suggestive of lower binding affinity to LRP-1 of the d-peptide. DAngiopep was resistant to proteolysis in fresh rat blood serum, while more than 85% of LAngiopep disappeared within 2 h. Endocytosed DAngiopep and LAngiopep were found to be colocalized with lysosomal compartments of bEnd.3 cells, indicating that susceptibility to proteolysis of LAngiopep in the BBB may further attenuate its transcytosis efficiency. In vivo, DAngiopep modified PEG-DSPE micelles displayed high distribution in normal brain and intracranial glioblastoma. Due to the expression of LRP-1 on the BBB and glioblastoma cells, proteolytically stable DAngiopep holds much potential for designing two-order brain tumor targeted delivery systems.
Abstract Intrahepatic accumulation dominates organ distribution for most nanomedicines. However, obscure intrahepatic fate largely hampers regulation on their in vivo performance. Herein, PEGylated ...liposomal doxorubicin is exploited to clarify the intrahepatic fate of both liposomes and the payload in male mice. Kupffer cells initiate and dominate intrahepatic capture of liposomal doxorubicin, following to deliver released doxorubicin to hepatocytes with zonated distribution along the lobule porto-central axis. Increasing Kupffer cells capture promotes doxorubicin accumulation in hepatocytes, revealing the Kupffer cells capture-payload release-hepatocytes accumulation scheme. In contrast, free doxorubicin is overlooked by Kupffer cells, instead quickly distributing into hepatocytes by directly crossing fenestrated liver sinusoid endothelium. Compared to free doxorubicin, liposomal doxorubicin exhibits sustained metabolism/excretion due to the extra capture-release process. This work unveils the pivotal role of Kupffer cells in intrahepatic traffic of PEGylated liposomal therapeutics, and quantitively describes the intrahepatic transport/distribution/elimination process, providing crucial information for guiding further development of nanomedicines.
Pain management would be greatly enhanced by a formulation that would provide local anesthesia at the time desired by patients and with the desired intensity and duration. To this end, we have ...developed near-infrared (NIR) light-triggered liposomes to provide on-demand adjustable local anesthesia. The liposomes contained tetrodotoxin (TTX), which has ultrapotent local anesthetic properties. They were made photo-labile by encapsulation of a NIR-triggerable photosensitizer; irradiation at 730 nm led to peroxidation of liposomal lipids, allowing drug release. In vitro, 5.6% of TTX was released upon NIR irradiation, which could be repeated a second time. The formulations were not cytotoxic in cell culture. In vivo, injection of liposomes containing TTX and the photosensitizer caused an initial nerve block lasting 13.5 ± 3.1 h. Additional periods of nerve block could be induced by irradiation at 730 nm. The timing, intensity, and duration of nerve blockade could be controlled by adjusting the timing, irradiance, and duration of irradiation. Tissue reaction to this formulation and the associated irradiation was benign.
Candid candoxin: A 16‐residue peptide (CDX) that is derived from candoxin binds with a high affinity to nicotinic acetylcholine receptors (see picture), which are highly expressed on the blood–brain ...barrier. In vivo biodistribution and the anti‐glioblastoma effect indicate the potential of CDX as a ligand to enable brain‐targeted drug delivery.
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