7 research outputs found
Enhancing Glioblastoma-Specific Penetration by Functionalization of Nanoparticles with an Iron-Mimic Peptide Targeting Transferrin/Transferrin Receptor Complex
Treatment
of glioblastoma (GBM) remains to be the most formidable challenge
because of the hindrance of the blood–brain barrier (BBB) along
with the poor drug penetration into the glioma parenchyma. Nanoparticulate
drug delivery systems (DDS) utilizing transferrin (Tf) as the targeting
ligand to target the glioma-associated transferrin receptor (TfR)
had met the problem of loss of specificity in biological environment
due to the high level of endogenous Tf. Here we conjugated CRT peptide,
an iron-mimicry moiety targeting the whole complex of Tf/TfR, to polyÂ(ethylene
glycol)-polyÂ(l-lactic-<i>co</i>-glycolic acid)
nanoparticles (CRT-NP), to open a new route to overcome such obstacle.
High cellular associations, advanced transport ability through the
BBB model, and penetration in 3-dimensional C6 glioma spheroids <i>in vitro</i> had preliminarily proved the advantages of CRT-NP
over Tf-nanoparticle conjugates (Tf-NP). Compared with Tf-NP, NP,
and Taxol, paclitaxel-loaded CRT-NP (CRT-NP-PTX) displayed a superior
antiproliferation effect on C6 glioma cells and stronger inhibitory
effect on glioma spheroids. Favored pharmacokinetics behavior and
enhanced accumulation in glioma foci was observed, together with a
much deeper distribution pattern in glioma parenchyma compared with
unmodified nanoparticles and Tf-NP. Eventually, mice treated with
CRT-NP-PTX showed a remarkably prolonged median survival compared
to those treated with Taxol, NP, or Tf-NP. In conclusion, the modification
of CRT to nanoparticles holds great promise for enhancement of antiglioma
therapy
GM1-Modified Lipoprotein-like Nanoparticle: Multifunctional Nanoplatform for the Combination Therapy of Alzheimer’s Disease
Alzheimer’s disease (AD) exerts a heavy health burden for modern society and has a complicated pathological background. The accumulation of extracellular β-amyloid (Aβ) is crucial in AD pathogenesis, and Aβ-initiated secondary pathological processes could independently lead to neuronal degeneration and pathogenesis in AD. Thus, the development of combination therapeutics that can not only accelerate Aβ clearance but also simultaneously protect neurons or inhibit other subsequent pathological cascade represents a promising strategy for AD intervention. Here, we designed a nanostructure, monosialotetrahexosylganglioside (GM1)-modified reconstituted high density lipoprotein (GM1-rHDL), that possesses antibody-like high binding affinity to Aβ, facilitates Aβ degradation by microglia, and Aβ efflux across the blood–brain barrier (BBB), displays high brain biodistribution efficiency following intranasal administration, and simultaneously allows the efficient loading of a neuroprotective peptide, NAP, as a nanoparticulate drug delivery system for the combination therapy of AD. The resulting multifunctional nanostructure, αNAP-GM1-rHDL, was found to be able to protect neurons from Aβ<sub>1–42</sub> oligomer/glutamic acid-induced cell toxicity better than GM1-rHDL <i>in vitro</i> and reduced Aβ deposition, ameliorated neurologic changes, and rescued memory loss more efficiently than both αNAP solution and GM1-rHDL in AD model mice following intranasal administration with no observable cytotoxicity noted. Taken together, this work presents direct experimental evidence of the rational design of a biomimetic nanostructure to serve as a safe and efficient multifunctional nanoplatform for the combination therapy of AD
Nanoparticles Coated with Neutrophil Membranes Can Effectively Treat Cancer Metastasis
The
dissemination, seeding, and colonization of circulating tumor
cells (CTCs) serve as the root of distant metastasis. As a key step
in the early stage of metastasis formation, colonization of CTCs in
the (pre-)Âmetastatic niche appears to be a valuable target. Evidence
showed that inflammatory neutrophils possess both a CTC- and niche-targeting
property by the intrinsic cell adhesion molecules on neutrophils.
Inspired by this mechanism, we developed a nanosize neutrophil-mimicking
drug delivery system (NM-NP) by coating neutrophils membranes on the
surface of polyÂ(latic-<i>co</i>-glycolic acid) nanoparticles
(NPs). The membrane-associated protein cocktails on neutrophils membrane
were mostly translocated to the surface of NM-NP <i>via</i> a nondisruptive approach, and the biobinding activity of neutrophils
was highly preserved. Compared with uncoated NP, NM-NP exhibited enhanced
cellular association in 4T1 cell models under shear flow <i>in
vitro</i>, much higher CTC-capture efficiency <i>in vivo</i>, and improved homing to the premetastatic niche. Following loading
with carfilzomib, a second generation of proteasome inhibitor, the
NM-NP-based nanoformulation (NM-NP-CFZ) selectively depleted CTCs
in the blood, prevented early metastasis and potentially inhibited
the progress of already-formed metastasis. Our NP design can neutralize
CTCs in the circulation and inhibit the formation of a metastatic
niche
Tumor-Homing and Penetrating Peptide-Functionalized Photosensitizer-Conjugated PEG-PLA Nanoparticles for Chemo-Photodynamic Combination Therapy of Drug-Resistant Cancer
The
combination of photodynamic therapy (PDT) and chemotherapy
holds great potential in combating drug-resistant cancers. However,
the major challenge that lies ahead is how to achieve high coloading
capacity for both photosensitizer and chemo-drugs and how to gain
efficient delivery of drugs to the drug-resistant tumors. In this
study, we prepared a nanovehicle for codelivery of photosensitizer
(pyropheophorbide-a, PPa) and chemo-drugs (paclitaxel, PTX) based
on the synthesis of PPa-conjugated amphiphilic copolymer PPa-PLA-PEG-PLA-PPa.
The obtained nanoparticles (PP NP) exhibited a satisfactory high drug-loading
capacity for both drugs. To achieve effective tumor-targeting therapy,
the surface of PP NP was decorated with a tumor-homing and penetrating
peptide F3. <i>In vitro</i> cellular experiments showed
that F3-functionalized PP NP (F3-PP NP) exhibited higher cellular
association than PP NP and resulted in the strongest antiproliferation
effect. In addition, compared with the unmodified nanoparticles, F3-PP
NP exhibited a more preferential enrichment at the tumor site. Pharmacodynamics
evaluation <i>in vivo</i> demonstrated that a longer survival
time was achieved by the tumor-bearing mice treated with PP NP (+laser)
than those treated with chemotherapy only or PDT only. Such antitumor
efficacy of combination therapy was further improved following the
F3 peptide functionalization. Collectively, these results suggested
that targeted combination therapy may pave a promising way for the
therapy of drug-resistant tumor
Lipoprotein-Based Nanoparticles Rescue the Memory Loss of Mice with Alzheimer’s Disease by Accelerating the Clearance of Amyloid-Beta
Amyloid-beta (Aβ) accumulation in the brain is believed to play a central role in Alzheimer’s disease (AD) pathogenesis, and the common late-onset form of AD is characterized by an overall impairment in Aβ clearance. Therefore, development of nanomedicine that can facilitate Aβ clearance represents a promising strategy for AD intervention. However, previous work of this kind was concentrated at the molecular level, and the disease-modifying effectiveness of such nanomedicine has not been investigated in clinically relevant biological systems. Here, we hypothesized that a biologically inspired nanostructure, apolipoprotein E3–reconstituted high density lipoprotein (ApoE3–rHDL), which presents high binding affinity to Aβ, might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance. Surface plasmon resonance, transmission electron microscopy, and co-immunoprecipitation analysis showed that ApoE3–rHDL demonstrated high binding affinity to both Aβ monomer and oligomer. It also accelerated the microglial, astroglial, and liver cell degradation of Aβ by facilitating the lysosomal transport. One hour after intravenous administration, about 0.4% ID/g of ApoE3–rHDL gained access to the brain. Four-week daily treatment with ApoE3–rHDL decreased Aβ deposition, attenuated microgliosis, ameliorated neurologic changes, and rescued memory deficits in an AD animal model. The findings here provided the direct evidence of a biomimetic nanostructure crossing the blood–brain barrier, capturing Aβ and facilitating its degradation by glial cells, indicating that ApoE3–rHDL might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance, which also justified the concept that nanostructures with Aβ-binding affinity might provide a novel nanoplatform for AD therapy
Tailored Apoptotic Vesicle Delivery Platform for Inflammatory Regulation and Tissue Repair to Ameliorate Ischemic Stroke
Apoptotic
vesicles (ApoVs) hold great promise for inflammatory
regulation and tissue repair. However, little effort has been dedicated
to developing ApoV-based drug delivery platforms, while the insufficient
targeting capability of ApoVs also limits their clinical applications.
This work presents a platform architecture that integrates apoptosis
induction, drug loading, and functionalized proteome regulation, followed
by targeting modification, enabling the creation of an apoptotic vesicle
delivery system to treat ischemic stroke. Briefly, α-mangostin
(α-M) was utilized to induce mesenchymal stem cell (MSC) apoptosis
while being loaded onto MSC-derived ApoVs as an anti-oxidant and anti-inflammatory
agent for cerebral ischemia/​reperfusion injury. Matrix metalloproteinase
activatable cell-penetrating peptide (MAP), a microenvironment-responsive
targeting peptide, was modified on the surface of ApoVs to obtain
the MAP-functionalized α-M-loaded ApoVs. Such engineered ApoVs
targeted the injured ischemic brain after systemic injection and achieved
an enhanced neuroprotective activity due to the synergistic effect
of ApoVs and α-M. The internal protein payloads of ApoVs, upon
α-M activation, were found engaged in regulating immunological
response, angiogenesis, and cell proliferation, all of which contributed
to the therapeutic effects of ApoVs. The findings provide a universal
framework for creating ApoV-based therapeutic drug delivery systems
for the amelioration of inflammatory diseases and demonstrate the
potential of MSC-derived ApoVs to treat neural injury
Tailored Apoptotic Vesicle Delivery Platform for Inflammatory Regulation and Tissue Repair to Ameliorate Ischemic Stroke
Apoptotic
vesicles (ApoVs) hold great promise for inflammatory
regulation and tissue repair. However, little effort has been dedicated
to developing ApoV-based drug delivery platforms, while the insufficient
targeting capability of ApoVs also limits their clinical applications.
This work presents a platform architecture that integrates apoptosis
induction, drug loading, and functionalized proteome regulation, followed
by targeting modification, enabling the creation of an apoptotic vesicle
delivery system to treat ischemic stroke. Briefly, α-mangostin
(α-M) was utilized to induce mesenchymal stem cell (MSC) apoptosis
while being loaded onto MSC-derived ApoVs as an anti-oxidant and anti-inflammatory
agent for cerebral ischemia/​reperfusion injury. Matrix metalloproteinase
activatable cell-penetrating peptide (MAP), a microenvironment-responsive
targeting peptide, was modified on the surface of ApoVs to obtain
the MAP-functionalized α-M-loaded ApoVs. Such engineered ApoVs
targeted the injured ischemic brain after systemic injection and achieved
an enhanced neuroprotective activity due to the synergistic effect
of ApoVs and α-M. The internal protein payloads of ApoVs, upon
α-M activation, were found engaged in regulating immunological
response, angiogenesis, and cell proliferation, all of which contributed
to the therapeutic effects of ApoVs. The findings provide a universal
framework for creating ApoV-based therapeutic drug delivery systems
for the amelioration of inflammatory diseases and demonstrate the
potential of MSC-derived ApoVs to treat neural injury