Nanotechnology: Regulatory Perspective for Drug Development in Cancer Therapeutics
Mansoor M. Amiji in Nanotechnology for Cancer Therapy, 2006
Another early nanomedicine, liposomal encapsulated doxorubicin (Doxil®), is regulated by the FDA and has been available in the clinic for treatment of various cancers since 1995. Drug incorporation inside the hydrophilic core or within the hydrophobic phospholipid bilayer coat of liposomes, has been shown to improve drug solubility, enhance drug transfer into cells and tissues, facilitate organ avoidance, and modify drug release profiles, minimizing toxicity.91 The liposomal formulation of the popular anthracyline, doxorubicin, which is commonly used to treat metastatic breast and ovarian cancer, is reported to have diminished cardiotoxicity and enhanced therapeutic efficacy compared to the free form of the drug.15–17 This increased efficacy is most likely due to the passive targeting of solid tumors through the enhanced permeability and retention effect inherent to tumor vasculature and aberrant tumor morphology.17 The approximate diameter of the doxorubicin–liposomal product is reported to be 100 nm, near the size limits described in the FDA definition of a nanomedicine.
Drug Delivery
David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack in Brain and Spinal Tumors of Childhood, 2020
For macromolecules and nanoparticles uptake into cells cannot occur by diffusion and it is usually affected by various endocytic mechanisms which may or may not be receptor-mediated. In some of the early literature on drug delivery to tumors the accumulation of macromolecules into tumors and particularly within the lysosomal compartment of cells was said to be enhanced compared to that in normal tissues and led to the promotion of the concept by De Duve et al. of lysosomotropic delivery to cells.8 This early theory was based on in vivo work, which was not repeatable in vitro.9 However, more recent work by one of us (M.G.) has shown that nanoparticles are endocytosed into tumor cells more effectively than normal brain cells when grown in three-dimensional tissue culture but not in two-dimensional (2D) tissue culture,10,11 thus giving us an in vitro model for these in vivo observations. This work is of significance not only because it suggests that it would further enhance the effectiveness of macromolecular and nanoparticulate delivery systems taking advantage of the enhanced permeability and retention effect, but may also enhance uptake of drugs specifically into tumor cells. This finding offers the prospect of delivery systems which show specificity between normal and tumor cells at the periphery of a tumor, without the disadvantages of the binding-site effect seen in the more complex targeted formulations.
Understanding the Interaction of Nanoparticles at the Cellular Interface
D. Sakthi Kumar, Aswathy Ravindran Girija in Bionanotechnology in Cancer, 2023
Cancer cell is quite different from normal cells in many ways; therefore, the interaction of NPs with cancer cells would encourage a new area of research. The selective accumulation of therapeutic nanomaterials of a particular size at a tumor site is based on the controversial enhanced permeability and retention effect (EPR). The leaky vasculature and tumor microenvironment, production of an abnormal amount of vascular growth factors, and vascular permeability enhancing elements (such as bradykinin, nitric oxide, and prostaglandins) are significant factors for controlling the EPR effect [74]. It has been found that less than a 2-fold increase of nanomedicine in tumor site compared to normal organ is sufficient to cure cancer completely [75]. There are numerous methods for increasing the concentration of NPs at a tumor site. Remote controlled and stimuli-responsive smart NPs are good candidates for therapeutic strategies.
Extended plasma half-life of albumin-binding domain fused human IgA upon pH-dependent albumin engagement of human FcRn in vitro and in vivo
Published in mAbs, 2021
Simone Mester, Mitchell Evers, Saskia Meyer, Jeannette Nilsen, Victor Greiff, Inger Sandlie, Jeanette Leusen, Jan Terje Andersen
Interestingly, it has been shown that tumors use albumin as a source of nutrition.86 As such, albumin-bound cancer drugs accumulate in solid tumors and show an enhanced anti-tumor effect.86–89 This is supported by studies demonstrating that albumin accumulation is caused by the so-called “enhanced permeability and retention effect” where higher permeability of blood capillaries increases accumulation in the tumor. Based on this, it may well be that ABD-fused IgA1 in complex with albumin could be taken up by tumors more efficiently that unfused IgA1. However, in light of data showing that both the molecular size and plasma half-life greatly affect anti-tumor efficacy,90 investigating how human IgA with and without albumin-binding properties behave in mouse tumor models will be valuable.
Investigation of dimyristoyl phosphatidyl glycerol and cholesterol based nanocochleates as a potential oral delivery carrier for methotrexate
Published in Journal of Liposome Research, 2022
Bothiraja Chellampillai, Sneha Kashid, Atmaram Pawar, Ashwin Mali
The MTX concentration was subsequently assayed in major organs such as liver, lungs, kidney, heart, spleen and brain at 8h after oral administration of a dose of 10mg/kg of free MTX, MTX-NLs and MTX-NCs. As shown in Figure 9, the MTX-NCs showed 3.2, 1.7, 1.8 and 3.1 fold lower distributions in heart, lung, spleen and brain with 2.1 fold higher distribution in the kidney as compared free MTX and a similar amount of free MTX and MTX-NCs in the liver due to endocytosis process which could be advantages to treat liver and kidney cancer. It can be noticed that the drug was distributed mainly in the liver where it was metabolised and in the kidneys, which were responsible for elimination. Cancer cells are rapidly dividing cells, where MTX can accumulate easily as a consequence of their requirement for high amounts of folates for replication. Further, NLs & NCs administration and extravasations of drug-loaded particles towards breast cancer and enhanced permeability and retention effect are probably favoured by leaky vascular architecture in neoplastic tissue.
New developments and clinical transition of hyaluronic acid-based nanotherapeutics for treatment of cancer: reversing multidrug resistance, tumour-specific targetability and improved anticancer efficacy
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Muhammad Hassan Safdar, Zahid Hussain, Mohammed A. S. Abourehab, Humna Hasan, Sajal Afzal, Hnin Ei Thu
Mechanistically, nanocarriers may be directed to the tumorigenic site by one of two processes: passive targeting or active targeting. In the former process, the enhanced permeability and retention effect aids nanomedicines to be passively extravagated through leaky vasculature, resulting in accumulation at the tumour site. However, this may lead to non-specific drug diffusion which may expose normal cells to cytotoxic effects of anticancer agents. Active targeting has thus been stepped up as a promising solution whereby the therapeutic efficacy of drugs is enhanced by the increased accumulation and cellular uptake through receptor-mediated endocytosis (RME). Nanocarriers may be synthesized to accommodate ligands, thus enhancing their ability to interact with endothelial cell surface receptors which are over-expressed on the surfaces of cancer cells. Hyaluronic acid (HA) cellular uptake receptors, CD44 and RHAMM, are such examples of over-expressed receptors on the surface of cancer cells, and thus have been exploited for the generation of target-specific drug delivery of these nanocarriers [4].