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Noninvasive Characterization and Development of in Situ Forming Implants For Use as a Local Pancreatic Cancer Therapy.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Noninvasive Characterization and Development of in Situ Forming Implants For Use as a Local Pancreatic Cancer Therapy./
Author:	Hopkins, Kelsey Ann.
Description:	1 online resource (212 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-01, Section: B.
Contained By:	Dissertations Abstracts International85-01B.
Subject:	Biomarkers. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30505980click for full text (PQDT)
ISBN:	9798379840068

Noninvasive Characterization and Development of in Situ Forming Implants For Use as a Local Pancreatic Cancer Therapy.
Hopkins, Kelsey Ann.

Noninvasive Characterization and Development of in Situ Forming Implants For Use as a Local Pancreatic Cancer Therapy. - 1 online resource (212 pages)

Source: Dissertations Abstracts International, Volume: 85-01, Section: B.

Thesis (Ph.D.)--Purdue University, 2022.

Includes bibliographical references

Pancreatic ductal adenocarcinoma is an especially deadly disease having the lowest 5-year survival rate of any major cancer at just 11%. As in many cancers, systemically-delivered chemotherapy forms the backbone of clinical treatment. However, limitations of systemic delivery exacerbated by the unique desmoplastic and avascular microenvironment surrounding the pancreatic tumor cells result in the failed efficacy of current treatments. The high stromal content in the microenvironment, which is especially overabundant in hyaluronic acid, is thought to physically impede drug perfusion into the tissue. Thus, there is clearly a critical need to develop novel treatments for pancreatic ductal adenocarcinoma that can overcome these drug delivery barriers. Long-acting injectable implants offer an attractive drug delivery method that can provide sustained drug release directly at the local targeted site, rather than transient, systemic release. Here we use in situ forming implants (ISFIs), which are a low-viscosity solution outside of the body but transition into a solid drug-eluting depot after injection into an aqueous environment. Our objective is to develop and characterize an ISFI that can provide sustained release of bioactive hyaluronidase for use as an intratumoral injection to degrade hyaluronic acid in pancreatic tumors. This work was accomplished in four aims. First, a method was developed using diffusion-weighted MRI for noninvasive characterization of the implants. Second, because hyaluronidase is a protein drug, we studied factors affecting protein release from ISFIs, focusing on external factors of the injection site. Third, we showed that basic salt additives can be used to neutralize the acidic environment created by the implants which may improve protein stability. Finally, we formulated an implant to provide sustained release of hyaluronidase and demonstrated retention of its bioactivity both in vitro and ex vivo.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798379840068Subjects--Topical Terms:

2205735
Biomarkers.
Index Terms--Genre/Form:

542853
Electronic books.

Noninvasive Characterization and Development of in Situ Forming Implants For Use as a Local Pancreatic Cancer Therapy.
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520 $a Pancreatic ductal adenocarcinoma is an especially deadly disease having the lowest 5-year survival rate of any major cancer at just 11%. As in many cancers, systemically-delivered chemotherapy forms the backbone of clinical treatment. However, limitations of systemic delivery exacerbated by the unique desmoplastic and avascular microenvironment surrounding the pancreatic tumor cells result in the failed efficacy of current treatments. The high stromal content in the microenvironment, which is especially overabundant in hyaluronic acid, is thought to physically impede drug perfusion into the tissue. Thus, there is clearly a critical need to develop novel treatments for pancreatic ductal adenocarcinoma that can overcome these drug delivery barriers. Long-acting injectable implants offer an attractive drug delivery method that can provide sustained drug release directly at the local targeted site, rather than transient, systemic release. Here we use in situ forming implants (ISFIs), which are a low-viscosity solution outside of the body but transition into a solid drug-eluting depot after injection into an aqueous environment. Our objective is to develop and characterize an ISFI that can provide sustained release of bioactive hyaluronidase for use as an intratumoral injection to degrade hyaluronic acid in pancreatic tumors. This work was accomplished in four aims. First, a method was developed using diffusion-weighted MRI for noninvasive characterization of the implants. Second, because hyaluronidase is a protein drug, we studied factors affecting protein release from ISFIs, focusing on external factors of the injection site. Third, we showed that basic salt additives can be used to neutralize the acidic environment created by the implants which may improve protein stability. Finally, we formulated an implant to provide sustained release of hyaluronidase and demonstrated retention of its bioactivity both in vitro and ex vivo.
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