22 research outputs found
Mitochondria-Targeting Polyprodrugs to Overcome the Drug Resistance of Cancer Cells by Self-Amplified Oxidation-Triggered Drug Release
The
multi-drug resistance (MDR) of cancers is one of the main barriers
for the success of diverse chemotherapeutic methods and is responsible
for most cancer deaths. Developing efficient approaches to overcome
MDR is still highly desirable for efficient chemotherapy of cancers.
The delivery of targeted anticancer drugs that can interact with mitochondrial
DNA is recognized as an effective strategy to reverse the MDR of cancers
due to the relatively weak DNA-repairing capability in the mitochondria.
Herein, we report on a polyprodrug that can sequentially target cancer
cells and mitochondria using folic acid (FA) and tetraphenylphosphonium
(TPP) targeting moieties, respectively. They were conjugated to the
terminal groups of the amphiphilic block copolymer prodrugs composed
of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA)
and copolymerized monomers containing cinnamaldehyde (CNM) and doxorubicin
(DOX). After self-assembly into micelles with the suitable size (∼30
nm), which were termed as TF@CNM + DOX, and upon intravenous administration,
the micelles can accumulate in tumor tissues. After FA-mediated endocytosis,
the endosomal acidity (∼pH 5) can trigger the release of CNM
from TF@CNM + DOX micelles, followed by enhanced accumulation into
the mitochondria via the TPP target. This promotes the overproduction
of reactive oxygen species (ROS), which can subsequently enhance the
intracellular oxidative stress and trigger ROS-responsive release
of DOX into the mitochondria. TF@CNM + DOX shows great potential to
inhibit the growth of DOX-resistant MCF-7 ADR tumors without observable
side effects. Therefore, the tumor and mitochondria dual-targeting
polyprodrug design represents an ideal strategy to treat MDR tumors
through improvement of the intracellular oxidative level and ROS-responsive
drug release
Matrix Metalloproteinase-Responsive Multifunctional Peptide-Linked Amphiphilic Block Copolymers for Intelligent Systemic Anticancer Drug Delivery
The
amphiphilic block copolymer anticancer drug nanocarriers clinically
used or in the progress of clinical trials frequently suffer from
modest final therapeutic efficacy due to a lack of intelligent features.
For example, the biodegradable amphiphilic block copolymer, polyÂ(ethylene
glycol)-<i>b</i>-polyÂ(d,l-lactide) (PEG–PDLLA)
has been approved for clinical applications as a paclitaxel (PTX)
nanocarrier (Genexol–PM) due to the optimized pharmacokinetics
and biodistribution; however, a lack of intelligent features limits
the intracellular delivery in tumor tissue. To endow the mediocre
polymer with smart properties via a safe and facile method, we introduced
a matrix metalloproteinase (MMP)-responsive peptide GPLGVRGDG into
the block copolymer via efficient click chemistry and ring-opening
polymerization to prepare PEG–<i>GPLGVRGDG</i>–PDLLA
(<b>P1</b>). <b>P1</b> was further self-assembled into
micellar nanoparticles (NPs) to load PTX, which show MMP-2-triggered
dePEGylation due to cleavage of the peptide linkage. Moreover, the
residual VRGDG sequences are retained on the surface of the NPs after
dePEGylation, which can serve as ligands to facilitate the cellular
uptake. The cytotoxicity of PTX loaded in <b>P1</b> NPs against
4T1 cells is significantly enhanced as compared with free PTX or PTX-loaded
PEG–<i>GPLGVRG</i>–PDLLA (<b>P2</b>)
and PEG–PDLLA (<b>P3</b>) NPs. In vivo studies confirmed
that PTX-loaded <b>P1</b> NPs show prolonged blood circulation,
which are similar to <b>P2</b> and <b>P3</b> NPs but exhibit
more-efficient accumulation in the tumor site. Ultimately, PTX-loaded <b>P1</b> NPs display statistically significant improvement of antitumor
activity against tumor-bearing mice via systemic administration. Therefore,
the strategy by facile incorporation of a responsive peptide linkage
between PEG and PDLLA is a promising approach to improving the therapeutic
efficacy of anticancer-drug-loaded amphiphilic block copolymer micelles
Thiolactone Chemistry-Based Combinatorial Methodology to Construct Multifunctional Polymers for Efficacious Gene Delivery
Hydrophobic
segments and amino moieties in polymeric nonviral gene
vectors play important roles in overcoming a cascade of barriers for
efficient gene delivery. However, it remains a great challenge to
facilely construct well-defined multifunctional polymers through optimization
of the amino and hydrophobic groups. Herein, we choose thiolactone
chemistry to perform the ring opening reaction of varying hydrophobic
groups-modified thiolactones by various amines to generate mercapto
groups for further Michael addition reaction with polyÂ[2-(acryloyloxy)Âethyl
methacrylate] (PAOEMA). Based on the combinatorial methodology, a
series of multifunctional polymers were prepared and screened. The
polymer (P3D) from tetraethylenepentamine and heptafluorobutyric acid-functionalized
thiolactone is the most efficacious one with significantly higher
gene transfection efficiency and lower cytotoxicity compared with
polyethylenimine (PEI) (branched average <i>M</i><sub>w</sub> ∼ 25 000 Da) and Lipofectamine 2000. Cellular uptake
and intracellular distribution studies indicate that P3D complexes
show high-efficiency endocytosis and excellent endosomal escape. Accordingly,
thiolactone chemistry-based combinatorial methodology allows for facile
integration of multifunctional groups to prepare simultaneous efficacious
and low-cytotoxic gene delivery vectors
Precise Ratiometric Control of Dual Drugs through a Single Macromolecule for Combination Therapy
A major challenge of combinatorial
therapy is the unification of
the pharmacokinetics and cellular uptake of various drug molecules
with precise control of the dosage thereby maximizing the combined
effects. To realize ratiometric delivery and synchronized release
of different drugs from a single carrier, a novel approach was designed
in this study to load dual drugs onto the macromolecular carrier with
different molar ratio by covalently preconjugating dual drugs through
peptide linkers to form drug conjugates. In contrast to loading individual
types of drugs separately, these drug conjugates enable the loading
of dual drugs onto the same carrier in a precisely controllable manner
to reverse multidrug resistance (MDR) of human hepatoma (HepG2) cells.
As a proof of concept, the synthesis and characterization of xyloglucan–mitomycin
C/doxorubicin (XG–MMC/DOX) conjugates were demonstrated. This
approach enabled MMC and DOX to be conjugated to the same polymeric
carrier with precise control of drug dosage. The cytotoxicity and
combinatorial effects were significantly improved compared to the
cocktail mixtures of XG–MMC and XG–DOX as well as the
individual conjugate of the mixture. Moreover, the results also showed
that there was an optimum ratio of dual drugs showing the best cytotoxicity
effect and greatest synergy among other tested polymeric conjugate
formulations