6 research outputs found
Enhanced Cancer Immunotherapy by Microneedle Patch-Assisted Delivery of Anti-PD1 Antibody
Despite recent advances in melanoma
treatment through the use of
anti-PD-1 (aPD1) immunotherapy, the efficacy of this method remains
to be improved. Here we report an innovative self-degradable microneedle
(MN) patch for the sustained delivery of aPD1 in a physiologically
controllable manner. The microneedle is composed of biocompatible
hyaluronic acid integrated with pH-sensitive dextran nanoparticles
(NPs) that encapsulate aPD1 and glucose oxidase (GOx), which converts
blood glucose to gluconic acid. The generation of acidic environment
promotes the self-dissociation of NPs and subsequently results in
the substantial release of aPD1. We find that a single administration
of the MN patch induces robust immune responses in a B16F10 mouse
melanoma model compared to MN without degradation trigger or intratumoral
injection of free aPD1 with the same dose. Moreover, this administration
strategy can integrate with other immunomodulators (such as anti-CTLA-4)
to achieve combination therapy for enhancing antitumor efficacy
Synergistic Transcutaneous Immunotherapy Enhances Antitumor Immune Responses through Delivery of Checkpoint Inhibitors
Despite
the promising efficacy of immunoregulation in cancer therapy,
the clinical benefit has been restricted by inefficient infiltration
of lymphocytes in the evolution of immune evasion. Also, immune-related
adverse events have often occurred due to the off-target binding of
therapeutics to normal tissues after systematic treatment. In light
of this, we have developed a synergistic immunotherapy strategy that
locally targets the immunoinhibitory receptor programmed cell death
protein 1 (PD1) and immunosuppressive enzyme indoleamine 2,3-dioxygenase
(IDO) for the treatment of melanoma through a microneedle-based transcutaneous
delivery approach. The embedded immunotherapeutic nanocapsule loaded
with anti-PD1 antibody (aPD1) is assembled from hyaluronic acid modified
with 1-methyl-dl-tryptophan (1-MT), an inhibitor of IDO.
This formulation method based on the combination strategy of “drug
A in carriers formed by incorporation of drug B” facilitates
the loading capacity of therapeutics. Moreover, the resulting delivery
device elicits the sustained release and enhances retention of checkpoint
inhibitors in the tumor microenvironment. Using a B16F10 mouse melanoma
model, we demonstrate that this synergistic treatment has achieved
potent antitumor efficacy, which is accompanied by enhanced effective
T cell immunity as well as reduced immunosuppression in the local
site
Stretch-Triggered Drug Delivery from Wearable Elastomer Films Containing Therapeutic Depots
Mechanical force-based stimulus provides a simple and easily accessible manner for spatiotemporally controlled drug delivery. Here we describe a wearable, tensile strain-triggered drug delivery device consisting of a stretchable elastomer and microgel depots containing drug loaded nanoparticles. By applying a tensile strain to the elastomer film, the release of drug from the microdepot is promoted due to the enlarged surface area for diffusion and Poisson’s ratio-induced compression on the microdepot. Correspondingly, both sustained drug release by daily body motions and pulsatile release by intentional administration can be conveniently achieved. Our work demonstrated that the tensile strain, applied to the stretchable device, facilitated release of therapeutics from microdepots for anticancer and antibacterial treatments. Moreover, polymeric microneedles were further integrated with the stretch-responsive device for transcutaneous delivery of insulin and regulation of blood glucose levels of chemically induced type 1 diabetic mice
Tumor Microenvironment-Mediated Construction and Deconstruction of Extracellular Drug-Delivery Depots
Protein therapy has been considered
the most direct and safe approach to treat cancer. Targeting delivery
of extracellularly active protein without internalization barriers,
such as membrane permeation and endosome escape, is efficient and
holds vast promise for anticancer treatment. Herein, we describe a
“transformable” core–shell based nanocarrier
(designated CS-NG), which can enzymatically assemble into microsized
extracellular depots at the tumor site with assistance of hyaluronidase
(HAase), an overexpressed enzyme at the tumor microenvironment. Equipped
with an acid-degradable modality, the resulting CS-NG can substantially
release combinational anticancer drugsî—¸tumor necrosis factor
(TNF)-related apoptosis inducing ligand (TRAIL) and antiangiogenic
cilengitide toward the membrane of cancer cells and endothelial cells
at the acidic tumor microenvironment, respectively. Enhanced cytotoxicity
on MDA-MB-231 cells and improved antitumor efficacy were observed
using CS-NG, which was attributed to the inhibition of cellular internalization
and prolonged retention time in vivo
Photo-Cross-Linked Scaffold with Kartogenin-Encapsulated Nanoparticles for Cartilage Regeneration
The regeneration of cartilage, an
aneural and avascular tissue,
is often compromised by its lack of innate abilities to mount a sufficient
healing response. Kartogenin (KGN), a small molecular compound, can
induce bone marrow-derived mesenchymal stem cells (BMSCs) into chondrocytes.
The previous <i>in vitro</i> study showed that kartogenin
also had a chondrogenesis effect on synovium derived mesenchymal stem
cells (SMSCs). Herein, we present the effect of an ultraviolet-reactive,
rapidly cross-linkable scaffold integrated with kartogenin-loaded
nanoparticles using an innovational one-step technology. <i>In
vivo</i> studies showed its potential role for cell homing, especially
for recruiting the host’s endogenous cells, including BMSCs
and SMSCs, without cell transplantation. Of note, the regenerated
tissues were close to the natural hyaline cartilage based on the histological
tests, specific markers analysis, and biomechanical tests. This innovative
KGN release system makes the chondrogenesis efficient and persistent
Core–Shell Microneedle Gel for Self-Regulated Insulin Delivery
A bioinspired glucose-responsive
insulin delivery system for self-regulation
of blood glucose levels is desirable for improving health and quality
of life outcomes for patients with type 1 and advanced type 2 diabetes.
Here we describe a painless core–shell microneedle array patch
consisting of degradable cross-linked gel for smart insulin delivery
with rapid responsiveness and excellent biocompatibility. This gel-based
device can partially dissociate and subsequently release insulin when
triggered by hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) generated
during the oxidation of glucose by a glucose-specific enzyme covalently
attached inside the gel. Importantly, the H<sub>2</sub>O<sub>2</sub>-responsive microneedles are coated with a thin-layer embedding H<sub>2</sub>O<sub>2</sub>-scavenging enzyme, thus mimicking the complementary
function of enzymes in peroxisomes to protect normal tissues from
injury caused by oxidative stress. Utilizing a chemically induced
type 1 diabetic mouse model, we demonstrated that this smart insulin
patch with a bioresponsive core and protective shell could effectively
regulate the blood glucose levels within a normal range with improved
biocompatibility