3 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
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
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