4 research outputs found
Specific Cancer Cytosolic Drug Delivery Triggered by Reactive Oxygen Species-Responsive Micelles
Cytosolic
drug delivery, a major route in cancer therapy, is limited
by the lack of efficient and safe endosomal escape techniques. Herein,
we demonstrate a reactive oxygen species (ROS)-responsive micelle
composed of methoxy polyethylene glycol-<i>b</i>-polyÂ(diethyl
sulfide) (mPEG–PS) copolymers which can induce specific endosome
escape in cancer cells by changes in the hydrophobicity of copolymers.
Owing to the more ROS levels in cancer cells than normal cells, the
copolymers can be converted into more hydrophilic and insert into
and destabilize the cancer intracellular endosome membrane after cellular
uptake. More importantly, we show that acid-intolerant drugs successfully
maintain their bioactivity and cause selective cytotoxicity for cancer
cells over normal cells. Our results suggest that the endosomal escape
induced by hydrophobic–hydrophilic exchange of copolymers has
great potential to locally and efficiently deliver biological agents
(e.g., proteins and genes) in the cancer cell cytosol
Sterically Polymer-Based Liposomal Complexes with Dual-Shell Structure for Enhancing the siRNA Delivery
The sterically polymer-based liposomal complexes (SPLexes)
were
formed by cationic polymeric liposomes and pH-sensitive diblock copolymer
were studied for their capabilities in improving the stability with
high efficiency of siRNA delivery. The SPLexes were formed a dual-shelled
structure and uniform size distribution. The PEGylated outer shell
could mitigate the phagocytosis and reduce the cytotoxicity. Moreover,
the folated SPLexes improved 42.9Ă— accumulation in vitro and
1.7Ă— tumor uptake in vivo in contrast with nonfolated SPLexes.
The protonated copolymer at low pH would improve the siRNA released
into cytoplasm following SPLexes fusion with the endo/lysosome membrane
and inhibited the protein expression to 75.6 ± 4.5% efficiently.
Results of this study significantly contribute to efforts to develop
lipoplexes based siRNA delivery systems
Radiotherapy-Controllable Chemotherapy from Reactive Oxygen Species-Responsive Polymeric Nanoparticles for Effective Local Dual Modality Treatment of Malignant Tumors
Radiotherapy
is one of the general approaches to deal with malignant
solid tumors in clinical treatment. To improve therapeutic efficacy,
chemotherapy is frequently adopted as the adjuvant treatment in combination
with radiotherapy. In this work, a reactive oxygen species (ROS)-responsive
nanoparticle (NP) drug delivery system was developed to synergistically
enhance the antitumor efficacy of radiotherapy by local ROS-activated
chemotherapy, taking advantages of the enhanced concentration of reactive
oxygen species (ROS) in tumor during X-ray irradiation and/or reoxygenation
after X-ray irradiation. The ROS-responsive polymers, polyÂ(thiodiethylene
adipate) (PSDEA) and PEG–PSDEA–PEG, were synthesized
and employed as the major components assembling in aqueous phase into
polymer NPs in which an anticancer camptothecin analogue, SN38, was
encapsulated. The drug-loaded NPs underwent structural change including
swelling and partial dissociation in response to the ROS activation
by virtue of the oxidation of the nonpolar sulfide residues in NPs
into the polar sulfoxide units, thus leading to significant drug unloading.
The in vitro performance of the chemotherapy from the X-ray irradiation
preactivated NPs against BNL 1MEA.7R.1 murine carcinoma cells showed
comparable cytotoxicity to free drug and appreciably enhanced effect
on killing cancer cells while the X-ray irradiation being incorporated
into the treatment. The in vivo tumor growth was fully inhibited with
the mice receiving the local dual modality treatment of X-ray irradiation
together with SN38-loaded NPs administered by intratumoral injection.
The comparable efficacy of the local combinational treatment of X-ray
irradiation with SN38-loaded NPs to free SN38/irradiation dual treatment
corroborated the effectiveness of ROS-mediated drug release from the
irradiated NPs at tumor site. The IHC examination of tumor tissues
confirmed the significant reduction of VEGFA and CD31 expression with
the tumor receiving the local dual treatment developed in this work,
thus accounting for the absence of tumor regrowth compared to other
single modality treatment
Tumor Microenvironment-Responsive Nanoparticle Delivery of Chemotherapy for Enhanced Selective Cellular Uptake and Transportation within Tumor
A novel drug delivery
strategy featured with enhanced uptake of
nanoparticles (NPs) by targeted tumor cells and subsequent intratumoral
cellular hitchhiking of chemotherapy to deep tumor regions was described.
The NP delivery system was obtained from assembly of polyÂ(lactic acid-<i>co</i>-glycolic acid)-grafted hyaluronic acid (HA-<i>g</i>-PLGA) together with an anticancer drug, SN38, in aqueous phase,
followed by implementing the NP surface with a layer of methoxypolyÂ(ethylene
glycol)-<i>b</i>-polyÂ(histamine methacrylamide) (mPEG-<i>b</i>-PHMA) via hydrophobic association to improve the colloidal
stability both in vitro and in vivo. Upon arrival of these PEGylated
NPs at the acidic tumor site through the EPR effect, mPEG-<i>b</i>-PHMA became detached from the NP surface by the charge
transition of the PHMA blocks from neutral (hydrophobic) to positively
charged (hydrophilic) state via acid-induced protonation of their
imidazole groups in tumor microenvironment. The exposure of HA shell
on the naked NP thus resulted in enhanced uptake of NPs by CD44-expressed
tumor cells, including cancer cells and tumor-associated macrophages
(TAMs). Along with the TAMs being further chemotactically recruited
by hypoxia cells, the engulfed nanotherapeutics was thus transported
into the avascular area in which the anticancer action of chemotherapy
occurred by virtue of the drug release alongside PLGA degradation,
similar to those arising in other tumor nonhypoxia regions