Nanomedicine-mediated alteration of the pharmacokinetic profile of small molecule cancer immunotherapeutics

Herck, Simon Van; Geest, Bruno G. De

doi:10.1038/s41401-020-0425-3

Cited by 26 publications

(17 citation statements)

References 167 publications

(197 reference statements)

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“…Effector molecules such as siRNA cannot target and have very low uptake. Coupling them with antibodies shows enhanced tumor uptake and reduced side effects [59]. An example is CXC chemokine receptor siRNA delivered by coupling with anti-HER2 peptide fusion protein e23sFv-9R is used to target breast cancer cells, having an excess of HER-2 receptors, which promotes apoptosis.…”

Section: Targeted Drug Deliverymentioning

confidence: 99%

Targeted Cancer Therapy Using Nanoparticles and Antibody Fragments

Bhattacharya¹,

Gore²

2021

Advances in Precision Medicine Oncology

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Cancer is caused by an uncontrolled cell division, forming a tumor capable of metastasis. Cancer is the second leading cause of death worldwide. Conventional treatments kill healthy cells, causing side effects. Recently, nanomaterials are explored due to properties such as as- nano-size, high loading, and ligands’ attachment for a selective delivery. Apart from normal body cells, cancer cells express many receptors in excess, which serve as ‘targets’ for attacking the cells. Various ligands like proteins, peptides, polysaccharides can be attached to nanoparticles to allow proper and specific reach to the tumor. Such nanoparticles go to their desired site and stick onto the receptors, taken inside the cells by various methods. Antibodies are natural proteins that bind to foreign substances and remove them. IgG being the most explored antibody, suffers from many disadvantages such as non-specificity for required antigen, limited binding sites, low tumor penetration. Hence many researchers experimented by removing and adjusting the binding sites, using only the binding sites, enhancing the valency of naturally available IgG. It gave many benefits such as enhanced penetration, reduced immunogenicity, better delivery of drugs with fewer side effects. Continuing advancements in the field of protein engineering will help scientists to come up with better solutions. The properties allow easy surface interaction and entry, achieve better biodistribution, and reduce the amount of drug required. Targeting is based on Paul Ehrlich’s ‘magic bullet, ‘where the therapeutic moiety has two parts-one to identify the target and the second to eliminate it. This concept is revised to incorporate a third component, a carrier. Many nanocarriers can be used to target cancer cells containing ligands to identify malignant cells. Approaches to targeting are passive, active and physical targeting. Many such nanoparticles are in clinical trials and can be a better solution to cancer therapy.

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Section: Targeted Drug Deliverymentioning

confidence: 99%

Targeted Cancer Therapy Using Nanoparticles and Antibody Fragments

Bhattacharya¹,

Gore²

2021

Advances in Precision Medicine Oncology

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“…[10,11] Imidazoquinoilines (IMDQ) are potent small molecule agonists of TLR7/8 and induces activation of the MyD88dependent classical TLR signaling pathway to trigger an immune reaction. [12] Systemic administration of TLR7/8 agonists has been shown in pre-clinical models of breast cancer, colon cancer, and metastatic melanoma. However, due to an unfavorable pharmacokinetic profile of this class of drugs, clinical translation remains hampered.…”

Section: Introductionmentioning

confidence: 99%

In Situ Tumor Vaccination with Calcium‐Linked Degradable Coacervate Nanocomplex Co‐Delivering Photosensitizer and TLR7/8 Agonist to Trigger Effective Anti‐Tumor Immune Responses

Liu

Zhao

et al. 2022

Adv Healthcare Materials

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In situ anti-tumor vaccination is an attractive type of cancer immunotherapy which relies on the effectiveness of dendritic cells (DCs) to engulf tumor antigens, become activated, and present antigens to T cells in lymphoid tissue. Here, a multifunctional nanocomplex based on calcium crosslinked polyaspartic acid conjugated to either a toll-like receptor (TLR)7/8 agonist or a photosensitizer is reported. Intratumoral administration of the nanocomplex followed by laser irradiation induces cell killing and hence generation of a pool of tumor-associated antigens, with concomitant promotion of DCs maturation and expansion of T cells in tumor-draining lymph nodes. Suppression of tumor growth is observed both at the primary site and at the distal site, thereby hinting at successful induction of an adaptive anti-tumor response. This strategy holds promise for therapeutic application in a pre-operative and post-operative setting to leverage to mutanome of the patient's own tumor to mount immunological memory to clear residual tumor cells and metastasis.

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“…Although TLR agonists can activate immune cells via recognition by TLR, some small molecules often fail to demonstrate satisfactory in vivo immune response. For example, unavailable pharmacokinetic profiles of some TLR agonists in the dynamic body environment [ 25 ], or easy dissipation and low accumulation in a lymph node due to the small size of TLR agonists, might reduce the chance of contact with immune cells, cause insufficient threshold for immune cell activation, and thereby hinder the effectiveness of the downstream signal transduction of TLR–TLR agonist recognition [ 26 ]. Rapid diffusion and dissipation from a localized site can also lead to the low therapeutic dose level of TLR agonists, with unwanted cytokine surges, and severe adverse immune-toxicity effects occurring by the agonist [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Engineering Therapeutic Strategies in Cancer Immunotherapy via Exogenous Delivery of Toll-like Receptor Agonists

2021

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As a currently spotlighted method for cancer treatment, cancer immunotherapy has made a lot of progress in recent years. Among tremendous cancer immunotherapy boosters available nowadays, Toll-like receptor (TLR) agonists were specifically selected, because of their effective activation of innate and adaptive immune cells, such as dendritic cells (DCs), T cells, and macrophages. TLR agonists can activate signaling pathways of DCs to express CD80 and CD86 molecules, and secrete various cytokines and chemokines. The maturation of DCs stimulates naïve T cells to differentiate into functional cells, and induces B cell activation. Although TLR agonists have anti-tumor ability by activating the immune system of the host, their drawbacks, which include poor efficiency and remarkably short retention time in the body, must be overcome. In this review, we classify and summarize the recently reported delivery strategies using (1) exogenous TLR agonists to maintain the biological and physiological signaling activities of cargo agonists, (2) usage of multiple TLR agonists for synergistic immune responses, and (3) co-delivery using the combination with other immunomodulators or stimulants. In contrast to naked TLR agonists, these exogenous TLR delivery strategies successfully facilitated immune responses and subsequently mediated anti-tumor efficacy.

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Nanomedicine-mediated alteration of the pharmacokinetic profile of small molecule cancer immunotherapeutics

Cited by 26 publications

References 167 publications

Targeted Cancer Therapy Using Nanoparticles and Antibody Fragments

Targeted Cancer Therapy Using Nanoparticles and Antibody Fragments

In Situ Tumor Vaccination with Calcium‐Linked Degradable Coacervate Nanocomplex Co‐Delivering Photosensitizer and TLR7/8 Agonist to Trigger Effective Anti‐Tumor Immune Responses

Engineering Therapeutic Strategies in Cancer Immunotherapy via Exogenous Delivery of Toll-like Receptor Agonists

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