Markedly Enhanced Permeability and Retention Effects Induced by Photo-immunotherapy of Tumors

A major barrier to cancer treatment is the inability to deliver sufficient concentrations of drug to the tumor without incurring systemic toxicities. Nanomaterials are appealing because they can carry a large drug payload; however, tumor delivery is limited by modest leakage and retention in most tumors. We observed that after photoimmunotherapy (PIT), which is a light-mediated treatment based on an antibody–photosensitizer conjugate, there was surprisingly high leakage of nanosized (10–200 nm) agents into the tumor bed. PIT rapidly induced death in perivascular cancer cells, leading to immediate and dramatic increases in vascular permeability, resulting in up to 24-fold greater accumulation of nanomaterials within the PIT-treated tumor compared with controls, an effect termed “super-enhanced permeability and retention”. In a treatment study, PIT followed by liposome-containing daunorubicin, DaunoXome (diameter 50 nm), resulted in greater survival in tumor-bearing mice than either PIT or DaunoXome alone. Thus, PIT greatly enhances delivery of nanosized reagents and thus holds promise to improve therapeutic responses

Markedly Enhanced Permeability and Retention Effects Induced by Photo-immunotherapy of Tumors

A major barrier to cancer treatment is the inability to deliver sufficient concentrations of drug to the tumor without incurring systemic toxicities. Nanomaterials are appealing because they can carry a large drug payload; however, tumor delivery is limited by modest leakage and retention in most tumors. We observed that after photoimmunotherapy (PIT), which is a light-mediated treatment based on an antibody–photosensitizer conjugate, there was surprisingly high leakage of nanosized (10–200 nm) agents into the tumor bed. PIT rapidly induced death in perivascular cancer cells, leading to immediate and dramatic increases in vascular permeability, resulting in up to 24-fold greater accumulation of nanomaterials within the PIT-treated tumor compared with controls, an effect termed “super-enhanced permeability and retention”. In a treatment study, PIT followed by liposome-containing daunorubicin, DaunoXome (diameter 50 nm), resulted in greater survival in tumor-bearing mice than either PIT or DaunoXome alone. Thus, PIT greatly enhances delivery of nanosized reagents and thus holds promise to improve therapeutic responses

Markedly Enhanced Permeability and Retention Effects Induced by Photo-immunotherapy of Tumors

A major barrier to cancer treatment is the inability to deliver sufficient concentrations of drug to the tumor without incurring systemic toxicities. Nanomaterials are appealing because they can carry a large drug payload; however, tumor delivery is limited by modest leakage and retention in most tumors. We observed that after photoimmunotherapy (PIT), which is a light-mediated treatment based on an antibody–photosensitizer conjugate, there was surprisingly high leakage of nanosized (10–200 nm) agents into the tumor bed. PIT rapidly induced death in perivascular cancer cells, leading to immediate and dramatic increases in vascular permeability, resulting in up to 24-fold greater accumulation of nanomaterials within the PIT-treated tumor compared with controls, an effect termed “super-enhanced permeability and retention”. In a treatment study, PIT followed by liposome-containing daunorubicin, DaunoXome (diameter 50 nm), resulted in greater survival in tumor-bearing mice than either PIT or DaunoXome alone. Thus, PIT greatly enhances delivery of nanosized reagents and thus holds promise to improve therapeutic responses

Markedly Enhanced Permeability and Retention Effects Induced by Photo-immunotherapy of Tumors

A major barrier to cancer treatment is the inability to deliver sufficient concentrations of drug to the tumor without incurring systemic toxicities. Nanomaterials are appealing because they can carry a large drug payload; however, tumor delivery is limited by modest leakage and retention in most tumors. We observed that after photoimmunotherapy (PIT), which is a light-mediated treatment based on an antibody–photosensitizer conjugate, there was surprisingly high leakage of nanosized (10–200 nm) agents into the tumor bed. PIT rapidly induced death in perivascular cancer cells, leading to immediate and dramatic increases in vascular permeability, resulting in up to 24-fold greater accumulation of nanomaterials within the PIT-treated tumor compared with controls, an effect termed “super-enhanced permeability and retention”. In a treatment study, PIT followed by liposome-containing daunorubicin, DaunoXome (diameter 50 nm), resulted in greater survival in tumor-bearing mice than either PIT or DaunoXome alone. Thus, PIT greatly enhances delivery of nanosized reagents and thus holds promise to improve therapeutic responses

Markedly Enhanced Permeability and Retention Effects Induced by Photo-immunotherapy of Tumors

A major barrier to cancer treatment is the inability to deliver sufficient concentrations of drug to the tumor without incurring systemic toxicities. Nanomaterials are appealing because they can carry a large drug payload; however, tumor delivery is limited by modest leakage and retention in most tumors. We observed that after photoimmunotherapy (PIT), which is a light-mediated treatment based on an antibody–photosensitizer conjugate, there was surprisingly high leakage of nanosized (10–200 nm) agents into the tumor bed. PIT rapidly induced death in perivascular cancer cells, leading to immediate and dramatic increases in vascular permeability, resulting in up to 24-fold greater accumulation of nanomaterials within the PIT-treated tumor compared with controls, an effect termed “super-enhanced permeability and retention”. In a treatment study, PIT followed by liposome-containing daunorubicin, DaunoXome (diameter 50 nm), resulted in greater survival in tumor-bearing mice than either PIT or DaunoXome alone. Thus, PIT greatly enhances delivery of nanosized reagents and thus holds promise to improve therapeutic responses

Short PEG-Linkers Improve the Performance of Targeted, Activatable Monoclonal Antibody-Indocyanine Green Optical Imaging Probes

The ability to switch optical imaging probes from the quenched (off) to the active state (on) has greatly improved target to background ratios. The optimal activation efficiency of an optical probe depends on complete quenching before activation and complete dequenching after activation. For instance, monoclonal antibody-indocyanine green (mAb-ICG) conjugates, which are promising agents for clinical translation, are normally quenched, but can be activated when bound to a cell surface receptor and internalized. However, the small fraction of commonly used ICG derivative (ICG-Sulfo-OSu) can bind noncovalently to its mAb and is, thus, gradually released from the mAb leading to relatively high background signal especially in the liver and the abdomen. In this study, we re-engineered a mAb-ICG conjugate, (Panitumumab-ICG) using bifunctional ICG derivatives (ICG-PEG4-Sulfo-OSu and ICG-PEG8-Sulfo-OSu) with short polyethylene glycol (PEG) linkers. Higher covalent binding (70–86%) was observed using the bifunctional ICG with short PEG linkers resulting in less <i>in vivo</i> noncovalent dissociation. Panitumumab-ICG conjugates with short PEG linkers were able to detect human epidermal growth factor receptor 1 (EGFR)-positive tumors with high tumor-to-background ratios (15.8 and 6.9 for EGFR positive tumor-to-negative tumor and tumor-to-liver ratios, respectively, at 3 d postinjection)

Construction of nanostructured DNA harbouring phosphorodiamidate morpholino oligonucleotide for controlled tissue distribution in mice

<p>Phosphorodiamidate morpholino oligonucleotides (PMOs) are a class of antisense oligonucleotides used in the treatment of neuromuscular diseases. Their major drawbacks are high blood clearance and poor cellular delivery. Previously, we demonstrated that tripod-like nanostructured DNA, or tripodna, was efficiently taken up by macrophages and dendritic cells. In this study, we used iodine-125(¹²⁵I)-labelled PMOs, designed a tripodna harbouring an ¹²⁵I-PMO (¹²⁵I-PMO/tripodna), and evaluated whether this tripodna could control the pharmacokinetic properties of PMO. Gel electrophoresis showed that ¹²⁵I-PMO was almost completely incorporated into the tripodna. Compared to ¹²⁵I-PMO, ¹²⁵I-PMO/tripodna was more efficiently taken up by macrophage-like RAW264.7 cells. Moreover, after intravenous injection into mice, the area under the plasma concentration–time curve of ¹²⁵I-PMO/tripodna was significantly larger than that of ¹²⁵I-PMO. The distribution of ¹²⁵I-PMO/tripodna in the liver and spleen at 24 h was 32- and 51-fold higher than that of ¹²⁵I-PMO, respectively. The fractionation of liver cells revealed that non-parenchymal cells were the major cells contributing to the hepatic uptake of ¹²⁵I-PMO/tripodna. These results indicate that tripodna has the potential to deliver PMO, particularly to the liver and spleen.</p

Galactosyl Human Serum Albumin-NMP1 Conjugate: A Near Infrared (NIR)-Activatable Fluorescence Imaging Agent to Detect Peritoneal Ovarian Cancer Metastases

Patient survival depends on the completeness of resection of peritoneal ovarian cancer metastases (POCM), and therefore, it is important to develop methods to enhance detection. Previous probe designs based on activatable galactosyl human serum albumin (hGSA)–fluorophore pairs, which target lectin receptors expressed on POCM, have used only visible range dyes conjugated to hGSA. However, imaging probes emitting fluorescence in the NIR range are advantageous because NIR photons have deeper <i>in vivo</i> tissue penetration and result in lower background autofluorescence than those emitting in the visible range. A NIR-activatable hGSA fluorophore was synthesized using a bacteriochlorin-based dye, NMP1. NMP1 has two unique absorption peaks, one in the green range and the other in the NIR range, but emits at a NIR peak of 780 nm. NMP1, thus, has two different Stokes shifts that have the potential to allow imaging of POCM both at the peritoneal surface and just below it. hGSA was conjugated with 2 NMP1 molecules to create a self-quenching complex (hGSA-NMP1). The activation ratio of hGSA-NMP1 was measured by the fluorescence intensity before and after exposure to 10% SDS. The activation ratio of hGSA-NMP1 was ∼100-fold <i>in vitro</i>. Flow cytometry, fluorescence microscopy, and <i>in vivo</i> spectral fluorescence imaging were carried out to compare hGSA-NMP1 with hGSA-IR800 and hGSA-ICG (two always-on control agents with similar emission to NMP1) in terms of comparative fluorescence signal and the ability to detect POCM in mice models. The sensitivity and specificity of hGSA-NMP1 for POCM implant detection were determined by colocalizing NMP1 emission spectra with red fluorescent protein (RFP) expressed constitutively in SHIN3 tumor implants at different depths below the peritoneal surface. In vitro, SHIN3 cells were easily detectable after 3 h of incubation with hGSA-NMP1. <i>In vivo</i> submillimeter POCM foci were clearly detectable with spectral fluorescence imaging using hGSA-NMP1. Among 555 peritoneal lesions, hGSA-NMP, using NIR and green excitation light, respectively, detect 75% of all lesions and 91% of lesions ∼0.8 mm or greater in diameter. Few false positives were encountered. Nodules located at a depth below the small bowel surface were only depicted with hGSA-NMP1. We conclude that hGSA-NMP1 is useful in imaging peritoneal ovarian cancer metastases, located both superficially and deep in the abdominal cavity

Radioactivity biodistribution after intravenous administration of MDAP_CV in tumor bearing mice.

<p>Data are presented as % injected dose per gram. Each value represents the mean ± s.d. for 3 animals at each interval. T/B means tumor to blood ratio.</p>a<p>Presented as % injected dose per organ.</p

Concept of a novel drug design strategy for a MMP-2 activity-dependent anchoring probe (MDAP).

<p>Concept of a novel drug design strategy for a MMP-2 activity-dependent anchoring probe (MDAP).</p