A phase I study of doxorubicin-loaded anti-EGFR immunoliposomes in patients with advanced solid tumors.

Mamot, Christoph; Ritschard, Reto; Vogel, B.; Dieterle, Thomas; Bubendorf, Lukas; Hilker, C.; Deuster, Stefanie; Herrmann, R.; Rochlitz, Christoph

doi:10.1200/jco.2011.29.15_suppl.3029

Cited by 9 publications

(4 citation statements)

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“…Even for immunoconjugates <0.01% of the dose administered is actually delivered to the tumor tissue in the clinical setting . Although PEGylated liposomal-doxorubicin targeted using the Fab fragment of mAb C225 (cetuximab) or Herceptin (trastuzumab), folate receptor-targeted conjugates (e.g., EC0489 and EC0145) , and FCE28069 have shown some evidence of anticancer activity in early clinical trials, most anticancer nanomedicines in clinical development still rely on passive solid tumor targeting by the enhanced permeability and retention (EPR) effect or direct intratumoral administration (e.g., thermal ablation of glioblastoma using iron oxide (Fe 3 O 4 ) nanoparticles) for selectivity. Well-known challenges associated with receptor-mediated targeting include the limited number of specific antigens/receptors on the target cell, heterogeneity of their expression across the cell population, inefficient receptor internalization leading to suboptimal drug release rates intracellularly, and also clinically relevant factors such as receptor saturation at the clinical dose used and/or receptor downregulation on repeated dosing.…”

Section: Nanomedicines For Lysosomotropic Deliverymentioning

confidence: 99%

Endocytosis and Intracellular Trafficking as Gateways for Nanomedicine Delivery: Opportunities and Challenges

2012

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More than 40 nanomedicines are already in routine clinical use with a growing number following in preclinical and clinical development. The therapeutic objectives are often enhanced disease-specific targeting (with simultaneously reduced access to sites of toxicity) and, especially in the case of macromolecular biotech drugs, improving access to intracellular pharmacological target receptors. Successful navigation of the endocytic pathways is usually a prerequisite to achieve these goals. Thus a comprehensive understanding of endocytosis and intracellular trafficking pathways in both the target and bystander normal cell type(s) is essential to enable optimal nanomedicine design. It is becoming evident that endocytic pathways can become disregulated in disease and this, together with the potential changes induced during exposure to the nanocarrier itself, has the potential to significantly impact nanomedicine performance in terms of safety and efficacy. Here we overview the endomembrane trafficking pathways, discuss the methods used to determine and quantitate the intracellular fate of nanomedicines, and review the current status of lysosomotropic and endosomotropic delivery. Based on the lessons learned during more than 3 decades of clinical development, the need to use endocytosis-relevant clinical biomarkers to better select those patients most likely to benefit from nanomedicine therapy is also discussed.

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Section: Nanomedicines For Lysosomotropic Deliverymentioning

confidence: 99%

Endocytosis and Intracellular Trafficking as Gateways for Nanomedicine Delivery: Opportunities and Challenges

2012

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“…Several antibody-targeted forms of liposomal doxorubicin are in clinical trials [26,27] and at least one peptide-targeted form of liposomal doxorubicin is being manufactured using GMP to ease the transition to clinical trials [29]. These targeted forms of liposomal doxorubicin rely on both passive targeting from the EPR effect and on active targeting from the specificity of the targeting ligand for tumor or tumor vasculature cells.…”

Section: Discussionmentioning

confidence: 99%

“…Both antibody and peptide targeting ligands have been used to increase the efficacy and decrease the toxicity of liposomal doxorubicin by actively targeting tumor and tumor vasculature cells [8–25]. Of particular interest, anti-HER2 liposomal doxorubicin and anti-EGFR liposomal doxorubicin formulations are in Phase I clinical trials [26,27]. Additionally, liposomal doxorubicin conjugated to a peptide derivative of the tumor vasculature targeting NGR peptide [28] has been primed for potential future clinical trials by preparation using Good Manufacturing Practices (GMP) [29].…”

Section: Introductionmentioning

confidence: 99%

A Liposomal Drug Platform Overrides Peptide Ligand Targeting to a Cancer Biomarker, Irrespective of Ligand Affinity or Density

2013

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One method for improving cancer treatment is the use of nanoparticle drugs functionalized with targeting ligands that recognize receptors expressed selectively by tumor cells. In theory such targeting ligands should specifically deliver the nanoparticle drug to the tumor, increasing drug concentration in the tumor and delivering the drug to its site of action within the tumor tissue. However, the leaky vasculature of tumors combined with a poor lymphatic system allows the passive accumulation, and subsequent retention, of nanosized materials in tumors. Furthermore, a large nanoparticle size may impede tumor penetration. As such, the role of active targeting in nanoparticle delivery is controversial, and it is difficult to predict how a targeted nanoparticle drug will behave in vivo. Here we report in vivo studies for αvβ6-specific H2009.1 peptide targeted liposomal doxorubicin, which increased liposomal delivery and toxicity to lung cancer cells in vitro. We systematically varied ligand affinity, ligand density, ligand stability, liposome dosage, and tumor models to assess the role of active targeting of liposomes to αvβ6. In direct contrast to the in vitro results, we demonstrate no difference in in vivo targeting or efficacy for H2009.1 tetrameric peptide liposomal doxorubicin, compared to control peptide and no peptide liposomes. Examining liposome accumulation and distribution within the tumor demonstrates that the liposome, and not the H2009.1 peptide, drives tumor accumulation, and that both targeted H2009.1 and untargeted liposomes remain in perivascular regions, with little tumor penetration. Thus H2009.1 targeted liposomes fail to improve drug efficacy because the liposome drug platform prevents the H2009.1 peptide from both actively targeting the tumor and binding to tumor cells throughout the tumor tissue. Therefore, using a high affinity and high specificity ligand targeting an over-expressed tumor biomarker does not guarantee enhanced efficacy of a liposomal drug. These results highlight the complexity of in vivo targeting.

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“…siRNA, plasmid DNA, miRNA) using targeting ligands such as RGD peptide, PTD (HIV) peptide, folic acid and transferrin, have been broadly used in the treatment of cancers, infectious diseases and neurodegenerative diseases [151]. Notably, some ligand-targeted liposomal systems, such as SGC-53 [152], anti-EGFR ILs-DOX [153], Lipovaxin-MM [154], MM-302 [155] and SGT-94 [156], have already completed clinical phase I/II trials in cancer patients. Most recently, the US FDA has approved Vyxeos, which is a liposomal system loaded with cytarabine and daunorubicin, for the treatment of acute myeloid leukemia.…”

Section: Liposomementioning

confidence: 99%

Nanocarriers for effective delivery: modulation of innate immunity for the management of infections and the associated complications

Zang

Zhou

et al. 2022

J Nanobiotechnol

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Innate immunity is the first line of defense against invading pathogens. Innate immune cells can recognize invading pathogens through recognizing pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs). The recognition of PAMPs by PRRs triggers immune defense mechanisms and the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. However, sustained and overwhelming activation of immune system may disrupt immune homeostasis and contribute to inflammatory disorders. Immunomodulators targeting PRRs may be beneficial to treat infectious diseases and their associated complications. However, therapeutic performances of immunomodulators can be negatively affected by (1) high immune-mediated toxicity, (2) poor solubility and (3) bioactivity loss after long circulation. Recently, nanocarriers have emerged as a very promising tool to overcome these obstacles owning to their unique properties such as sustained circulation, desired bio-distribution, and preferred pharmacokinetic and pharmacodynamic profiles. In this review, we aim to provide an up-to-date overview on the strategies and applications of nanocarrier-assisted innate immune modulation for the management of infections and their associated complications. We first summarize examples of important innate immune modulators. The types of nanomaterials available for drug delivery, as well as their applications for the delivery of immunomodulatory drugs and vaccine adjuvants are also discussed.

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A phase I study of doxorubicin-loaded anti-EGFR immunoliposomes in patients with advanced solid tumors.

Cited by 9 publications

References 0 publications

Endocytosis and Intracellular Trafficking as Gateways for Nanomedicine Delivery: Opportunities and Challenges

Endocytosis and Intracellular Trafficking as Gateways for Nanomedicine Delivery: Opportunities and Challenges

A Liposomal Drug Platform Overrides Peptide Ligand Targeting to a Cancer Biomarker, Irrespective of Ligand Affinity or Density

Nanocarriers for effective delivery: modulation of innate immunity for the management of infections and the associated complications

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