3 research outputs found
Engineering the Aromaticity of Cationic Helical Polypeptides toward “Self-Activated” DNA/siRNA Delivery
The development of
potent yet nontoxic membrane-penetrating materials is in high demand
for effective intracellular gene delivery. We have recently developed
α-helical polypeptides which afford potent membrane activities
to facilitate intracellular DNA delivery via both endocytosis and
the nonendocytic “pore formation” mechanism. Endocytosis
will cause endosomal entrapment of the DNA cargo, while excessive
“pore formation” would cause appreciable cytotoxicity.
Additionally, helical polypeptides with stiff, rodlike structure suffer
from low siRNA binding affinity. To address such critical issues,
we herein incorporated various aromatic domains (benzyl, naphthyl,
biphenyl, anthryl, and pyrenyl) into the side-chain terminals of guanidine-rich,
helical polypeptides, wherein the flat-rigid shape, π-electronic
structures of aromatic motifs “self-activated” the membrane-penetrating
capabilities of polypeptides to promote intracellular gene delivery.
Benzyl (Bn)- and naphthyl (Naph)-modified polypeptides demonstrated
the highest DNA uptake level that outperformed the unmodified polypeptide,
P2, by ∼4 fold. More importantly, compared with P2, Bn- and
Naph-modified polypeptides allowed more DNA cargos to be internalized
via the nonendocytic pathway, which significantly bypassed the endosomal
entrapment and accordingly enhanced the transfection efficiency by
up to 42 fold, outperforming PEI 25k as the commercial reagent by
3–4 orders of magnitude. The aromatic modification also improved
the siRNA condensation capability of polypeptides, achieving notably
enhanced gene-silencing efficiency against tumor necrosis factor-α
to treat acute hepatic inflammation. Furthermore, we revealed that
aromaticity-augmented membrane activity was accompanied by comparable
or even significantly reduced “pore formation” capability,
thus leading to diminished cytotoxicity at high concentrations. This
study therefore provides a promising approach to manipulate the membrane
activities and penetration mechanisms of polycations, which overcomes
the multiple critical barriers preventing effective and safe gene
delivery
High Drug Loading and Sub-Quantitative Loading Efficiency of Polymeric Micelles Driven by Donor–Receptor Coordination Interactions
Polymeric micelles
are extensively used for the delivery of hydrophobic
drugs, which, however, suffer from unsatisfactory drug loading, colloidal
uniformity, formulation stability, and drug release. Herein, we demonstrate
a convenient strategy to prepare micelles with ultrahigh drug loading
via the incorporation of polymer–drug coordination interactions.
An amphiphilic copolymer containing pendant phenylboronic acid as
electron acceptor unit was synthesized, which afforded donor–acceptor
coordination with doxorubicin to obtain micelles with ultrahigh drug
loading (∼50%), nearly quantitative loading efficiency (>95%),
uniform size, and colloidal stability. Besides, the encapsulated drug
can be effectively and selectively released in response to the high
reactive oxygen species levels in cancer cells, which potentiated
the anticancer efficacy and reduced systemic toxicity. Apart from
doxorubicin, the current platform could be extended to other drugs
with electron-donating groups (e.g., epirubicin and irinotecan), rendering
a simple and robust strategy for enabling high drug loading in polymeric
micelles and cancer-specific drug release
Nanoscaled Poly(l‑glutamic acid)/Doxorubicin-Amphiphile Complex as pH-responsive Drug Delivery System for Effective Treatment of Nonsmall Cell Lung Cancer
Nonsmall cell lung cancer (NSCLC)
is the leading cause of cancer-related death worldwide. Herein, we
develop a polypeptide-based block ionomer complex formed by anionic
methoxy poly(ethylene glycol)-<i>b</i>-poly(l-glutamic
acid) (mPEG-<i>b</i>-PLG) and cationic anticancer drug doxorubicin
hydrochloride (DOX·HCl) for NSCLC treatment. This complex spontaneously
self-assembled into spherical nanoparticles (NPs) in aqueous solutions
via electrostatic interaction and hydrophobic stack, with a high loading
efficiency (almost 100%) and negative surface charge. DOX·HCl
release from the drug-loaded micellar nanoparticles (mPEG-<i>b</i>-PLG-DOX·HCl) was slow at physiological pH, but obviously
increased at the acidic pH mimicking the endosomal/lysosomal environment.
In vitro cytotoxicity and hemolysis assays demonstrated that the block
copolypeptide was cytocompatible and hemocompatible, and the presence
of copolypeptide carrier could reduce the hemolysis ratio of DOX·HCl
significantly. Cellular uptake and cytotoxicity studies suggested
that mPEG-<i>b</i>-PLG-DOX·HCl was taken up by A549
cells via endocytosis, with a slightly slower cellular internalization
and lower cytotoxicity compared with free DOX·HCl. The pharmacokinetics
study in rats showed that DOX·HCl-loaded micellar NPs significantly
prolonged the blood circulation time. Moreover, mPEG-<i>b</i>-PLG-DOX·HCl exhibited enhanced therapeutic efficacy, increased
apoptosis in tumor tissues, and reduced systemic toxicity in nude
mice bearing A549 lung cancer xenograft compared with free DOX·HCl,
which were further confirmed by histological and immunohistochemical
analyses. The results demonstrated that mPEG-<i>b</i>-PLG
was a promising vector to deliver DOX·HCl into tumors and achieve
improved pharmacokinetics, biodistribution and efficacy of DOX·HCl
with reduced toxicity. These features strongly supported the interest
of developing mPEG-<i>b</i>-PLG-DOX·HCl as a valid
therapeutic modality in the therapy of human NSCLC and other solid
tumors