Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection

Varghese, Jomy J.; Schmale, Isaac L.; Mickelsen, Deanne; Hansen, Mollie Eva; Newlands, Shawn D.; Benoit, Danielle S. W.; Korshunov, Vyacheslav A.; Ovitt, Catherine E.

doi:10.1177/0022034518767408

Cited by 41 publications

(39 citation statements)

References 39 publications

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“…In contrast to duct ligation, irradiation of the salivary glands causes permanent loss of acinar cells (Konings et al, 2005). Although histological analysis and immunohistochemistry show that Mist1-positive acinar cells are still present at 30 days after irradiation (Figure 4D2) (Varghese et al, 2018), few remain at 90 days (Figure 4E2). However, large acinar cell-like clusters were observed in irradiated SMG in all three genetic models analyzed (Figures 4B, J and S3Q).…”

Section: Discussionmentioning

confidence: 99%

Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

et al. 2018

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In the adult salivary glands, the origin of replacement and regenerated acinar cells remains unclear. Although many reports describe the identification of stem cells in adult salivary glands, we have shown that differentiated acinar cells can be maintained and regenerated through self-duplication. Here, we have used genetic mouse models to further investigate acinar cell replacement and regeneration during homeostasis and after injury. Under normal conditions or after duct ligation, replacement of duct and acinar cells occurs through lineage-restricted progenitors. In contrast, after irradiation, in vivo lineage tracing shows that acinar, as well as duct, cells contribute to acinar cell regeneration, revealing that cellular plasticity is involved in salivary gland repair. Our results also indicate that even after radiation damage, several cell populations have regenerative potential for restoring salivary gland function.

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Section: Discussionmentioning

confidence: 99%

Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

et al. 2018

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“…ROS/RNS scavengers aim to reduce the effective radiation dose to the tissue, thereby potentially sparing normal tissue cells but not the tumor. One such scavenger is amifostine, which in rat salivary glands shows amelioration of function loss depending on the irradiated region in rat salivary glands [42] and improved protection when it is injected in a retrograde manner in the secretory ducts [43], where SSPCs seem to be located [32]. However, amifostine clinical trials have been inconclusive, owing to limited statistical power or a lack of proper control arms [41].…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Prevention and treatment of radiotherapy‐induced side effects

2020

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Radiotherapy remains a mainstay of cancer treatment, being used in roughly 50% of patients. The precision with which the radiation dose can be delivered is rapidly improving. This precision allows the more accurate targeting of radiation dose to the tumor and reduces the amount of surrounding normal tissue exposed. Although this often reduces the unwanted side effects of radiotherapy, we still need to further improve patients' quality of life and to escalate radiation doses to tumors when necessary. Highprecision radiotherapy forces one to choose which organ or functional organ substructures should be spared. To be able to make such choices, we urgently need to better understand the molecular and physiological mechanisms of normal tissue responses to radiotherapy. Currently, oversimplified approaches using constraints on mean doses, and irradiated volumes of normal tissues are used to plan treatments with minimized risk of radiation side effects. In this review, we discuss the responses of three different normal tissues to radiotherapy: the salivary glands, cardiopulmonary system, and brain. We show that although they may share very similar local cellular processes, they respond very differently through organ-specific, nonlocal mechanisms. We also discuss how a better knowledge of these mechanisms can be used to treat or to prevent the effects of radiotherapy on normal tissue and to optimize radiotherapy delivery.

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“…The long-term effects of these pilocarpine mats are to be explored in different in vivo SG hypofunction models using a clinically relevant radiotherapy fractionated dose regimen. Despite this, acute single-dose radiotherapy SG models, like the one used herein, can better induce epithelial damage promptly within 48 h [32], and are pertinent to study localized short-term effects for our proposed once daily pilocarpine intradermal mat administration. Pre-clinical trials determining the pilocarpine release pharmacokinetics are the next step if intradermal applications are to be tested.…”

Section: Discussionmentioning

confidence: 99%

Localized Delivery of Pilocarpine to Hypofunctional Salivary Glands through Electrospun Nanofiber Mats: An Ex Vivo and In Vivo Study

Muthumariappan

Adine

et al. 2019

IJMS

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Dry mouth or xerostomia is a frequent medical condition among the polymedicated elderly population. Systemic pilocarpine is included in the first line of pharmacological therapies for xerostomia. However, the efficacy of existing pilocarpine formulations is limited due to its adverse side effects and multiple daily dosages. To overcome these drawbacks, a localized formulation of pilocarpine targeting the salivary glands (SG) was developed in the current study. The proposed formulation consisted of pilocarpine-loaded Poly(lactic-co-glycolic acid) (PLGA)/poly(ethylene glycol) (PEG) nanofiber mats via an electrospinning technique. The nanofiber mats were fully characterized for their size, mesh porosity, drug encapsulation efficiency, and in vitro drug release. Mat biocompatibility and efficacy was evaluated in the SG organ ex vivo, and the expression of proliferation and pro-apoptotic markers at the cellular level was determined. In vivo short-term studies were performed to evaluate the saliva secretion after acute SG treatment with pilocarpine-loaded nanofiber mats, and after systemic pilocarpine for comparison purposes. The outcomes demonstrated that the pilocarpine-loaded mats were uniformly distributed (diameter: 384 ± 124 nm) in a highly porous mesh, and possessed a high encapsulation efficiency (~81%). Drug release studies showed an initial pilocarpine release of 26% (4.5 h), followed by a gradual increase (~46%) over 15 d. Pilocarpine-loaded nanofiber mats supported SG growth with negligible cytotoxicity and normal cellular proliferation and homeostasis. Salivary secretion was significantly increased 4.5 h after intradermal SG treatment with drug-loaded nanofibers in vivo. Overall, this study highlights the strengths of PLGA/PEG nanofiber mats for the localized daily delivery of pilocarpine and reveals its potential for future clinical translation in patients with xerostomia.

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Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection

Cited by 41 publications

References 39 publications

Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

Prevention and treatment of radiotherapy‐induced side effects

Localized Delivery of Pilocarpine to Hypofunctional Salivary Glands through Electrospun Nanofiber Mats: An Ex Vivo and In Vivo Study

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