46 research outputs found
Ultrasound Triggered Tumor Oxygenation with Oxygen-Shuttle Nanoperfluorocarbon to Overcome Hypoxia-Associated Resistance in Cancer Therapies
Tumor hypoxia is known to be one
of critical reasons that limit the efficacy of cancer therapies, particularly
photodynamic therapy (PDT) and radiotherapy (RT) in which oxygen is
needed in the process of cancer cell destruction. Herein, taking advantages
of the great biocompatibility and high oxygen dissolving ability of
perfluorocarbon (PFC), we develop an innovative strategy to modulate
the tumor hypoxic microenvironment using nano-PFC as an oxygen shuttle
for ultrasound triggered tumor-specific delivery of oxygen. In our
experiment, nanodroplets of PFC stabilized by albumin are intravenously
injected into tumor-bearing mice under hyperoxic breathing. With a
low-power clinically adapted ultrasound transducer applied on their
tumor, PFC nanodroplets that adsorb oxygen in the lung would rapidly
release oxygen in the tumor under ultrasound stimulation, and then
circulate back into the lung for reoxygenation. Such repeated cycles
would result in dramatically enhanced tumor oxygenation and thus remarkably
improved therapeutic outcomes in both PDT and RT treatment of tumors.
Importantly, our strategy may be applied for different types of tumor
models. Hence, this work presents a simple strategy to promote tumor
oxygenation with great efficiency using agents and instruments readily
available in the clinic, so as to overcome the hypoxia-associated
resistance in cancer treatment
Drug-Induced Self-Assembly of Modified Albumins as Nano-theranostics for Tumor-Targeted Combination Therapy
Paclitaxel (PTX) can bind to human serum albumin (HSA) <i>via</i> hydrophobic interaction, forming Abraxane, which is a U.S. Food and Drug Administration (FDA) approved effective antitumor nanomedicine drug. Herein, the effective antitumor drug PTX is used to induce the self-assembly of HSA modified with either a photosensitizer chlorin e6 (Ce6), which at the same time serves as a chelating agent for Mn<sup>2+</sup> to enable magnetic resonance imaging, or acyclic Arg-Gly-Asp (cRGDyK) peptide that targets Ī±vĪ²3-integrin overexpressed on tumor angiogenic endothelium. Two types of tumor-targeting theranostic nanoparticles are constructed, either by coassembly of both HSA-Ce6 and HSA-RGD simultaneously or by forming an HSA-Ce6@HSA-RGD coreāshell structure, with the assistance of PTX-induced albumin aggregation. Such albumin-based nanoparticles on one hand could targetĪ±vĪ²3-integrin, as evidenced by both <i>in vitro</i> and <i>in vivo</i> experiments, and on the other hand enable combined photodynamic/chemotherapy, which offers remarkably improved therapeutic efficacy to kill cancer in comparison to the respective monotherapies. Our work presents a new type of tumor-targeted multifunctional albumin-based nanoparticles by drug-induced self-assembly, which is a rather simple method without any sophisticated chemistry or materials engineering and is promising for multimodel imaging-guided combination therapy of cancer
Patterned Substrates of Nano-Graphene Oxide Mediating Highly Localized and Efficient Gene Delivery
A facile
approach was developed to fabricate patterned substrates
of nano-graphene oxide, demonstrating highly localized and efficient
gene delivery to multiple cell lines in a substrate-mediated manner.
The GO substrates served as a valid platform to preconcentrate PEI/pDNA
complexes and maintain their gradual releasing for a relatively long
period of time. Our approach allowed successful gene delivery in selected
groups of cells on the stripe-patterned GO substrates, without transfecting
their neighbor cells directly cultured on glass. These GO substrates
exhibited excellent biocompatibility and enabled effective gene transfection
for various cell lines including stem cells, thus promising important
applications in stem cell research and tissue engineering
Formulation and Evaluation of a Drug-in-Adhesive Patch for Transdermal Delivery of Colchicine
Gout is one of the most prevalent rheumatic diseases, globally. Colchicine (COL) is the first-line drug used for the treatment of acute gout. However, the oral administration of COL is restricted, owing to serious adverse reactions. Therefore, this study aimed to develop a drug-in-adhesive (DIA) patch to achieve transdermal delivery of COL. We investigated the solubility of COL in different pressure-sensitive adhesives (PSAs) using slide crystallization studies. The COL-DIA patches were optimized based on in vitro skin penetration studies and evaluated by in vivo pharmacokinetics and pharmacodynamics. The results showed that the optimized COL-DIA patch contained 10% COL, Duro-Tak 87-2516 as PSA, 5% oleic acid (OA) and 5% propylene glycol (PG) as permeation enhancer, exhibiting the highest in vitro cumulative penetration amount of COL (235.14 ± 14.47 μg∙cm−2 over 48 h). Pharmacokinetic studies demonstrated that the maximum plasma drug concentration (Cmax) was 2.65 ± 0.26 ng/L and the mean retention time (MRT) was 37.47 ± 7.64 h of the COL-DIA patch, effectively reducing the drug side effects and prolonging drug activity. In addition, pharmacodynamic studies showed the patch significantly decreased the expression levels of inflammatory factors of gouty rats and reduced pathological damage in the ankle joint of rats, making it an attractive alternative to the administration of COL for the treatment of gout
Functionalization of Graphene Oxide Generates a Unique Interface for Selective Serum Protein Interactions
Potential toxicity and risk of inducing allergy and inflammation
have always been a great concern of using nanomaterials in biomedicine.
In this work, we investigate the serum behaviors of graphene oxide
(GO) and how such behaviors are affected by its surface modification
such as PEGylation. The results show that, when incubated with human
sera, unfunctionalized GO adsorbs a significant amount of serum proteins
and strongly induces complement C3 cleavage (part of the complement
activation cascade), generating C3a/C3aĀ(des-Arg), an anaphylatoxin
involved in local inflammatory responses, whereas PEGylated nano-GO
(nGO-PEG) exhibits dramatic reductions in both protein binding in
general and complement C3 activation. Moreover, we uncover that PEGylation
on GO nanosheets apparently generates an interesting nanointerface,
evidenced by the acquired certain selectivity and increased binding
capacities of nGO-PEG toward a few serum proteins. Further mass spectrometry
analysis identifies six nGO-PEG binding proteins, four of which are
immune-related factors, including C3a/C3aĀ(des-Arg). A series of Western
blot analysis demonstrate that nGO-PEG binds up to 2-fold amount of
C3a/C3aĀ(des-Arg) than unfunctionalized GO, and can efficiently decrease
the level of C3a/C3aĀ(des-Arg) in treated sera, preventing the normal
interaction of C3a with its receptor. In a proof-of-concept experiment,
we demonstrate that nGO-PEG may serve to help eliminate the C3a/C3aĀ(des-Arg)
induced by other nanomaterials such as as-made GO, indicating a new
strategy to modulate the immune responses evoked by one nanomaterial
through the addition of another type of nanomaterial. Our results
highlight the great importance of nanobio interface in regulating
the biological effects of nanomaterials
Photosensitizer Decorated Red Blood Cells as an Ultrasensitive Light-Responsive Drug Delivery System
Red blood cells (RBCs) have been
widely explored as a natural drug delivery system (DDS) owing to their
inherent biocompatibility and large internal cavities to load various
types of functional molecules. Herein, we uncover that a photosensitizer,
chlorin e6 (Ce6), could be decorated into the membrane of RBCs upon
simple mixing, without affecting the membrane integrity and stability
in dark. Upon light irradiation with a rather low power density, the
singlet oxygen generated by Ce6 would lead to rather efficient disruption
of RBC membrane. With doxorubicin (DOX), a typical chemotherapy drug,
as the model, we engineer a unique type of light-responsive RBC-based
DDS by decorating Ce6 on the cell membrane and loading DOX inside
cells. The light triggered cell membrane breakdown would thus trigger
instant release of DOX, enabling light-controlled chemotherapy with
great specificity. Beyond that our RBC system could also be utilized
for loading of larger biomolecules such as enzymes, whose release
as well as catalytic function is also controlled by light. Our work
thus presents a unique type of biocompatible cell-based DDS that can
be precisely controlled by mild external stimuli, promising not only
for cancer therapy but also for other potential applications in biotechnologies
Re-assessing the enhanced permeability and retention effect in peripheral arterial disease using radiolabeled long circulating nanoparticles
As peripheral arterial disease (PAD) results in muscle ischemia and neovascularization, it has been claimed that nanoparticles can passively accumulate in ischemic tissues through the enhanced permeability and retention (EPR) effect. At this time, a quantitative evaluation of the passive targeting capabilities of nanoparticles has not been reported in PAD. Using a murine model of hindlimb ischemia, we quantitatively assessed the passive targeting capabilities of Cu-64-labeled PEGylated reduced graphene oxide iron oxide nanoparticles (Cu-64-RGO-IONP-PEG) through the EPR effect using positron emission tomography (PET) imaging. Serial laser Doppler imaging was performed to monitor changes in blood perfusion upon surgical induction of ischemia. Nanoparticle accumulation was assessed at 3, 10, and 17 days post-surgery and found to be highest at 3 days post-surgery, with the ischemic hindlimb displaying an accumulation of 14.7 +/- 0.5% injected dose per gram (%ID/g). Accumulation of Cu-64-RGO-IONP-PEG was lowest at 17 days post-surgery, with the ischemic hindlimb displaying only 5.1 +/- 0.5%ID/g. Furthermore, nanoparticle accumulation was confirmed by photoacoustic imaging (PA). The combination of PET and serial Doppler imaging showed that nanoparticle accumulation in the ischemic hindlimb negatively correlated with blood perfusion. Thus, we quantitatively confirmed that Cu-64-RGO-IONP-PEG passively accumulated in ischemic tissue via the EPR effect, which is reduced as the perfusion normalizes. As Cu-64-RGO-IONP-PEG displayed substantial accumulation in the ischemic tissue, this nanoparticle platform may function as a future theranostic agent, providing both imaging and therapeutic applications. (C) 2016 Elsevier Ltd. All rights reserved.OAIID:RECH_ACHV_DSTSH_NO:T201701509RECH_ACHV_FG:RR00200001ADJUST_YN:EMP_ID:A080459CITE_RATE:8.387DEPT_NM:ģµķ©ź³¼ķė¶EMAIL:[email protected]_YN:YCONFIRM:
Theranostic Liposomes with Hypoxia-Activated Prodrug to Effectively Destruct Hypoxic Tumors Post-Photodynamic Therapy
A hypoxia-responsive albumin-based nanosystem for deep tumor penetration and excellent therapeutic efficacy
Uncontrolled cancer cell proliferation, insufficient blood flow, and inadequate endogenous oxygen lead to hypoxia in tumor tissues. Herein, a unique type of hypoxia-responsive human serum albumin (HSA)-based nanosystem (HCHOA) is reported, prepared by cross-linking the hypoxia-sensitive azobenzene group between photosensitizer chlorin e6 (Ce6)-conjugated HSA (HC) and oxaliplatin prodrug-conjugated HSA (HO). The HCHOA nanosystem is stable under normal oxygen partial pressure with a size of 100ā150 nm. When exposed to the hypoxic tumor microenvironment, the nanosystem can quickly dissociate into ultrasmall HC and HO therapeutic nanoparticles with a diameter smaller than 10 nm, significantly enabling their enhanced intratumoral penetration. After the dissociation, the quenched fluorescence of Ce6 in the produced HC nanoparticles can be recovered for bioimaging. At the same time, the production of singlet oxygen is increased because of the enhancement in the photoactivity of the photosensitizer. On account of these improvements, combined photodynamic therapy and chemotherapy is realized to display superior antitumor efficacy in vivo. Based on this simple strategy, it is possible to achieve the dissociation of hypoxic-responsive nanosystem to enhance the tumor penetration and therapeutic effect.NRF (Natl Research Foundation, Sāpore)ASTAR (Agency for Sci., Tech. and Research, Sāpore)Accepted versio