A quantitative MRI-based approach to estimate the permeation and retention of nanomedicines in tumors.

Despite the potential of the enhanced permeability and retention (EPR) effect in tumor passive targeting, many nanotherapeutics have failed to produce meaningful clinical outcomes due to the variable and challenging nature of the tumor microenvironment (TME) and EPR effect. This EPR variability across tumors and inconsistent translation of nanomedicines from preclinical to clinical settings necessitates a reliable method to assess its presence in individual tumors. This study aimed to develop a reliable and non-invasive approach to estimate the EPR effect in tumors using a clinically compatible quantitative magnetic resonance imaging (qMRI) technique combined with a nano-sized MRI contrast agent. A quantitative MR imaging was developed using a dynamic contrast-enhanced (DCE) MRI protocol. Then, the permeability and retention of the nano-sized MRI contrast agent were evaluated in three different ovarian xenograft tumor models. Results showed significant differences in EPR effects among the tumor models, with tumor growth influencing the calculated parameters of permeability (Ktrans) and retention (Ve) based on Tofts pharmacokinetic (PK) modeling. Our data indicate that the developed quantitative DCE-MRI method, combined with the Tofts PK modeling, provides a robust and non-invasive approach to screen tumors for their responsiveness to nanotherapeutics. These results imply that the developed qMRI method can be beneficial for personalized cancer treatments by ensuring that nanotherapeutics are administered only to patients with tumors showing sufficient EPR levels.

Ultrasound-responsive microbubbles and nanodroplets: A pathway to targeted drug delivery.

Ultrasound-responsive agents have shown great potential as targeted drug delivery agents, effectively augmenting cell permeability and facilitating drug absorption. This review focuses on two specific agents, microbubbles and nanodroplets, and provides a sequential overview of their drug delivery process. Particular emphasis is given to the mechanical response of the agents under ultrasound, and the subsequent physical and biological effects on the cells. Finally, the state-of-the-art in their pre-clinical and clinical implementation are discussed. Throughout the review, major challenges that need to be overcome in order to accelerate their clinical translation are highlighted.

Synthesis of Multi-Functional Nano-Vectors for Target-Specific Drug Delivery.

Magnetic nanoparticles have gained attention in cancer therapy due to their non-toxic properties and high bio-compatibility. In this report, we synthesize a dual-responsive magnetic nanoparticle (MNP) that is sensitive to subtle pH and temperature change as in the tumor microenvironment. Thus, the functional doxorubicin (DOX)-loaded MNP (DOX-PNIPAM-PMAA@Fe3O4) can perform specific DOX releases in the cancer cell. The particle was characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), zeta-potential, Fourier-transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). The microscopy data revealed the particle as having a spherical shape. The zeta-potential and size distribution analysis data demonstrated the difference for the stepwise modified MNPs. The FTIR spectrum showed characteristic absorption bands of NH2-SiO2@Fe3O4, CPDB@Fe3O4, PMAA@Fe3O4, and PNIPAM-PMAA@Fe3O4. Drug-loading capacity and releasing efficiency were evaluated under different conditions. Through an in vitro analysis, we confirmed that PNIPAM-PMAA@Fe3O4 has enhanced drug releasing efficiency under acidic and warmer conditions. Finally, cellular uptake and cell viability were estimated via different treatments in an MDA-MB-231 cell line. Through the above analysis, we concluded that the DOX-loaded particles can be internalized by cancer cells, and such a result is positive and prospective.

Improving nanotherapy delivery and action through image-guided systems pharmacology.

Despite recent advances in the translation of therapeutic nanoparticles (TNPs) into the clinic, the field continues to face challenges in predictably and selectively delivering nanomaterials for the treatment of solid cancers. The concept of enhanced permeability and retention (EPR) has been coined as a convenient but simplistic descriptor of high TNP accumulation in some tumors. However, in practice EPR represents a number of physiological variables rather than a single one (including dysfunctional vasculature, compromised lymphatics and recruited host cells, among other aspects of the tumor microenvironment) - each of which can be highly heterogenous within a given tumor, patient and across patients. Therefore, a clear need exists to dissect the specific biophysical factors underlying the EPR effect, to formulate better TNP designs, and to identify patients with high-EPR tumors who are likely to respond to TNP. The overall pharmacology of TNP is governed by an interconnected set of spatially defined and dynamic processes that benefit from a systems-level quantitative approach, and insights into the physiology have profited from the marriage between in vivo imaging and quantitative systems pharmacology (QSP) methodologies. In this article, we review recent developments pertinent to image-guided systems pharmacology of nanomedicines in oncology. We first discuss recent developments of quantitative imaging technologies that enable analysis of nanomaterial pharmacology at multiple spatiotemporal scales, and then examine reports that have adopted these imaging technologies to guide QSP approaches. In particular, we focus on studies that have integrated multi-scale imaging with computational modeling to derive insights about the EPR effect, as well as studies that have used modeling to guide the manipulation of the EPR effect and other aspects of the tumor microenvironment for improving TNP action. We anticipate that the synergistic combination of imaging with systems-level computational methods for effective clinical translation of TNPs will only grow in relevance as technologies increase in resolution, multiplexing capability, and in the ability to examine heterogeneous behaviors at the single-cell level.

CT and CEST MRI bimodal imaging of the intratumoral distribution of iodinated liposomes.

BACKGROUND: To develop liposomes loaded with iodinated agents as nanosized CT/MRI bimodal contrast agents for monitoring liposome-mediated drug delivery. METHODS: Rhodamine-labeled iodixanol (VisipaqueTM)-loaded liposomes (IX-lipo) were prepared and tested for their properties as a diamagnetic CEST contrast agent in vitro. Mice bearing subcutaneous CT26 colon tumors were injected i.v. with 1 g/kg (535 mg iodine/kg) IX-lipo, and in vivo CT and CEST MR images were acquired on day 3. CT and CEST MR images were also acquired for tumor-bearing mice co-injected with IX-lipo and tumor necrosis factor (TNF-α). RESULTS: In addition to CT contrast, IX-lipo exhibited a strong CEST contrast similar to its non-liposomal form, with a detectability of ~2 nM per liposome. Both CT imaging and CEST MRI showed that i.v. injection of IX-lipo resulted in a rim enhancement of CT26 tumors with a heterogeneous central distribution. In contrast, co-injection of TNF-α caused a significantly augmented CT/MRI contrast in the tumor center. The intratumoral biodistribution of IX-lipo correlated well to the rhodamine patterns observed with fluorescence microscopy. CONCLUSIONS: We have developed a CT/MRI bimodal imaging approach for monitoring the delivery and biodistribution of liposomes by loading them with the clinically approved X-ray/CT contrast agent iodixanol. Our approach may be easily adapted for other-FDA approved iodinated agents and thus has great translational potential.

Styrene maleic acid encapsulated raloxifene micelles for management of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) comprises a group of disorders that manifest through chronic inflammation of the colon and small intestine. Although the exact cause of IBD is still unclear, dysfunctional immunoregulation involving overproduction of inflammatory cytokines such as TNF-α, and IL-6 have been implicated in pathogenesis. Current therapy relies on immunosuppression, cytotoxic drugs, and monoclonal antibodies against TNF-α. These classes of drugs have severe side-effects, especially when used for long duration. Our previous work with raloxifene, a selective estrogen receptor modulator, has shown that the drug, and to a greater extent its micellar formulation, has a significant suppressive effect on NF-κB, an essential immune-regulator. This finding directed the current work towards testing the anti-inflammatory and immunomodulatory effects of raloxifene using cell lines, as well as testing the potential use of the styrene maleic acid (SMA) micelles loaded with raloxifene (SMA-Ral) against dextran sulfate sodium (DSS) induced colitis in an in vivo model of IBD. RESULTS: Treatment of MCF-7 cells with TNF-α was shown to protect the cells from the cytotoxic effect of raloxifene (42 vs. 10% cell death, with TNF-α. Treating CaCo-2 cells with both free and SMA-Ral improved cell survival after exposure to 2% DDS with significantly higher protection with SMA-Ral. Treatment of U-937 with SMA-Ral and free-Ral resulted in down-regulation of TNF-α, IL-1ß, IL-6, and MIP1α, with greater inhibition of the SMA-Ral, compared to free Ral. Balb/c mice treated with raloxifene and SMA-Ral showed weight gain at 14 days, compared to the control group (122, and 115% respectively). Treatment with raloxifene prevented DSS-induced diarrhea in 6/6 of free raloxifene treated mice and in 5/6 mice treated with SMA-Ral. Control group of DSS-treated mice showed average colon length of 7.4 cm compared to 13 cm in the control group. The average colon length was 12.3 and 11.5 cm for raloxifene and SMA-Ral treated groups, respectively. Furthermore, inflammatory cytokines such as IL-6 and TNF-α were reduced in serum of animals treated with free-Ral and SMA-Ral. CONCLUSIONS: Raloxifene and its micellar formulation warrants further studies to understand their effect on the treatment of colitis. Graphical abstract SMA-Raloxifene preparation and its in vivo and in vitro effect on colitis.

Applications of indocyanine green based near-infrared fluorescence imaging in thoracic surgery.

Near-infrared (NIR) fluorescence guided surgery is an emerging technique. This technique uses the combination of dyes and NIR imaging devices to expand the visible spectrum. Thus it can provide more anatomic and functional information, and may facilitate a more complete resection of cancer, or better protection of important normal structures. Recently, significant progress has been made in the field of NIR fluorescence guided thoracic surgery. This may lead to better prognosis and health-economic outcomes. In this article, the current studies of indocyanine green (ICG) based NIR fluorescence guided thoracic surgeries are reviewed. The applications are classified into four categories, which are applications based on blood supply, lymphatic drainage, the enhanced permeability and retention (EPR) effect, and the other mechanisms.