Drug delivery to solid tumors is hindered by hydrostatic and physical barriers that limit the penetration of nanocarriers into tumor tissue. When exploiting the enhanced permeability and retention (EPR) effect for passive targeting of nanocarriers, the increased interstitial fluid pressure and dense extracellular matrix in tumors limits the distribution of the nanocarriers to perivascular regions. Previous strategies have shown that magnetophoresis enhances accumulation and penetration of nanoparticles into solid tumors. However, because magnetic fields fall off rapidly with distance from the magnet, these methods have been limited to use in superficial tumors. To overcome this problem, we have developed a system comprising two oppositely-polarized magnets that enables the penetration of magnetic nanocarriers into more deeply-seeded tumors. Using this method, we demonstrate a 5-fold increase in the penetration and a 3-fold increase in the accumulation of magnetic nanoparticles within solid tumors compared to EPR.
pH‐responsive liposomes are prepared by conjugating glycol chitosan (GC) to the outer lipid membrane. This functionalization allows the liposomes to transition from a negative charge at physiologic pH to a positive charge in the acidic extracellular tumor microenvironment. Upon obtaining a positive charge, the GC‐liposomes loaded with doxorubicin exhibited enhanced cellular uptake and improved anticancer efficacy.
The ability to produce nanotherapeutics at large-scale with high drug loading efficiency, high drug loading capacity, high stability, and high potency is critical for clinical translation. However, many nanoparticle-based therapeutics under investigation suffer from complicated synthesis, poor reproducibility, low stability, and high cost. In this work, a simple method for preparing multifunctional nanoparticles is utilized that act as both a contrast agent for magnetic resonance imaging and a photosensitizer for photodynamic therapy for the treatment of cancer. In particular, the photosensitizer protoporphyrin IX (PpIX) is used to solubilize small nanoclusters of superparamagnetic iron oxide nanoparticles (SPIONs) without the use of any additional carrier materials. These nanoclusters are characterized with a high PpIX loading efficiency; a high loading capacity, stable behavior; high potency; and a synthetic approach that is amenable to large-scale production. In vivo studies of photodynamic therapy (PDT) efficacy show that the PpIX-coated SPION nanoclusters lead to a significant reduction in the growth rate of tumors in a syngeneic murine tumor model compared to both free PpIX and PpIX-loaded poly(ethylene glycol)-polycaprolactone micelles, even when injected at 1/8th the dose. These results suggest that the nanoclusters developed in this work can be a promising nanotherapeutic for clinical translation.
A common cause of local tumor recurrence in brain tumor surgery results from incomplete surgical resection. Adjunctive technologies meant to facilitate gross total resection have had limited efficacy to date. Contrast agents used to delineate tumors pre-operatively cannot be easily or accurately used in the real-time operative setting. Although multimodal imaging contrast agents have been developed to help the surgeon discern tumor from normal tissue in the operating room, these contrast agents are not readily translatable. We have developed a novel contrast agent comprised solely of two FDA-approved components, indocyanine green (ICG) and superparamagnetic iron oxide (SPIO) nanoparticles - with no additional amphiphiles or carrier-materials, to enable pre-operative detection by MRI and intraoperative photoacoustic (PA) imaging. The encapsulation efficiency of both ICG and SPIO within the formulated clusters is ~100% and the total ICG payload is 20–30% of the total weight (ICG + SPIO). The ICG-SPIO clusters are stable in physiologic conditions, can be taken up within tumors by enhanced permeability and retention, and are detectable by MRI. In a pre-clinical surgical resection model in mice following injection of ICG-SPIO clusters, animals undergoing PA-guided surgery demonstrated increased progression-free survival compared to animals undergoing microscopic surgery.
Photodynamic therapy (PDT) is an approved modality for the treatment of various types of maligancies and diseased states. However, most of the available photosensitizers (PS) are highly hydrophobic, which limits their solubility and dispersion in biological fluids and can lead to self-quenching and sub-optimal therapeutic efficacy. In this study, chlorin e6 (Ce6)-coated superparamagnetic iron oxide nanoparticle (SPION) nanoclusters (Ce6-SCs) were prepared via an oil-in-water emulsion. The physical-chemical properties of the Ce6-SCs were systematically evaluated. Dual-mode imaging and PDT was subsequently performed in tumor-bearing mice. Chlorin e6 is capable of solubilizing hydrophobic SPION into stable, water-soluble nanoclusters without the use of any additional amphiphiles or carriers. The method is reproducible and the Ce6-SCs are highly stable under physiological conditions. The Ce6-SCs have an average diameter of 92 nm and low polydispersity (average PDI < 0.2). Encapsulation efficiency of both Ce6 and SPION is ≈100%, and the total Ce6 payload can be as high as 56% of the total weight (Ce6 + Fe). The Ce6-SCs localize within tumors via enhanced permeability and retention and are detectable by magnetic resonance (MR) and optical imaging. With PDT, Ce6-SCs demonstrate high singlet oxygen generation and produce a significant delay in tumor growth in mice.
Overproduction
of reactive oxygen species (ROS) is often related to inflammation
or cancer and can cause tissue damage. Probes that have been previously
reported to image ROS typically rely on imaging techniques that have
low depth penetration in tissue, thus limiting their use to superficial
disease sites. We report herein a novel formulation of hybrid nanogels
loaded with gold nanoparticles (AuNP) to produce contrast for computed
tomography (CT) and photoacoustics (PA), both being deep-tissue imaging
techniques. The polyphosphazene polymer has been designed to selectively
degrade upon ROS exposure, which triggers a switch-off of the PA signal
by AuNP disassembly. This ROS-triggered degradation of the nanoprobes
leads to a significant decrease in the PA contrast, thus allowing
ratiometric ROS imaging by comparing the PA to CT signal. Furthermore,
ROS imaging using these nanoprobes was applied to an in vitro model
of inflammation, that is, LPS-stimulated macrophages, where ROS-triggered
disassembly of the nanoprobe was confirmed via reduction of the PA
signal. In summary, these hybrid nanoprobes are a novel responsive
imaging agent that have the potential to image ROS overproduction
by comparing PA to CT contrast.
Gold is a highly useful nanomaterial
for many clinical applications,
but its poor biodegradability can impair long-term physiological clearance.
Large gold nanoparticles (∼10–200 nm), such as those
required for long blood circulation times and appreciable tumor localization,
often exhibit little to no dissolution and excretion. This can be
improved by incorporating small gold particles within a larger entity,
but elimination may still be protracted due to incomplete dispersion
of gold. The present study describes a novel gold nanoparticle formulation
capable of environmentally triggered decomposition. Ultrasmall gold
nanoparticles are coated with thiolated dextran, and hydrophobic acetal
groups are installed through direct covalent modification of the dextran.
This hydrophobic exterior allows gold to be densely packed within
∼150 nm polymeric micelles. Upon exposure to an acidic environment,
the acetal groups are cleaved and the gold nanoparticles become highly
water-soluble, leading to destabilization of the micelle. Within 24
h, the ultrasmall water-soluble gold particles are released from the
micelle and readily dispersed. Micelle degradation and gold nanoparticle
dispersion was imaged in cultured macrophages, and micelle-treated
mice displayed progressive physiological clearance of gold, with >85%
elimination from the liver over three months. These particles present
a novel nanomaterial formulation and address a critical unresolved
barrier for clinical translation of gold nanoparticles.
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