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Targeted Nanoscale Drug and Nucleic Acid Delivery for Pancreatic Cancer Treatment /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Targeted Nanoscale Drug and Nucleic Acid Delivery for Pancreatic Cancer Treatment // Brianna M White.
作者:	White, Brianna M.,
面頁冊數:	1 electronic resource (177 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
標題:	Chemical engineering. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31940667
ISBN:	9798286431298

Targeted Nanoscale Drug and Nucleic Acid Delivery for Pancreatic Cancer Treatment /
White, Brianna M.,

Targeted Nanoscale Drug and Nucleic Acid Delivery for Pancreatic Cancer Treatment /Brianna M White. - 1 electronic resource (177 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Pancreatic cancer (PC) is an aggressive and deadly type of cancer. Despite a multitude of advancements in cancer treatments in the last three decades, the 5-year survival rate for PC patients remains stagnant at 13%. These poor outcomes are due to a lack of early detection and ineffective treatments. The efficacy of current PC treatments is limited by off-target toxicity and the hostile tumor microenvironment (TME), which promotes drug resistance, invasion, and metastasis. Targeted and stimuli-sensitive nanocarriers are a prominently researched form of drug delivery to overcome the challenges associated with the TME and increase the accumulation of the drug in the tumor. In addition to tumor-targeted delivery, novel combinations of therapeutics will likely be necessary to overcome drug resistance in PC. Two options for developing new combination treatments are to utilize therapeutic miRNA, such as miR-345, and to repurpose drugs that are approved to treat other diseases, such as niclosamide. Given their different characteristics, miR-345 and niclosamide require tailored delivery vehicles for effective administration. Two polymer nanoparticle platforms were designed to enable tumor-specific delivery of the novel combinations of gemcitabine with miR-345 or niclosamide.The first polymer nanoparticle platform was used for the targeted dual delivery of miR-345 and gemcitabine. It was based on a pentablock copolymer (PB) with cationic poly(diethylamino ethylmethacrylate) end groups and Pluronic F17 middle blocks. The PB was functionalized with the tumor-penetrating peptide iRGD and then complexed with miR-345 and gemcitabine-loaded micelles. This dual delivery system was stable against RNase A and serum for at least 24 hours and demonstrated a sustained release of both miR-345 and gemcitabine over one week and two days, respectively. The iRGD functionalized delivery system showed targeted accumulation in subcutaneous PC tumors in mice compared to nontargeted treatment groups. Metastasis and tumor burden were also significantly decreased in orthotopically implanted PC tumor-bearing mice when treated with the dual delivery system. The second polymer nanoparticle platform utilizes polyanhydrides, which are biodegradable with tailorable erosion rates, to encapsulate hydrophobic drugs. Niclosamide, a hydrophobic antiparasitic, was loaded in 1,6-bis(p-carboxyphenoxy)hexane-co-sebacic acid (CPH:SA) nanoparticles (NicNp). Orthotopically implanted PC tumor-bearing mice were treated with NicNp and showed increased accumulation of Nic in the tumor compared to free Nic. NicNp acted synergistically with gemcitabine to reduce PC cell survival in cell viability assays and significantly improved survival and reduced tumor burden in orthotopically implanted PC tumor-bearing mice. To incorporate tumor-specific release of niclosamide, a reduction-sensitive monomer, 3,3'-dithiodipropionic acid (DTDP), was added to the CPH:SA polymer to target the hypoxic TME. An initial test of 10:75:10 CPH:SA:DTDP NicNps showed a reduction-mediated release of niclosamide in hypoxic TME simulated conditions. To optimize the redox sensitivity of CPH:SA:DTDP, a library of ten copolymers with varying ratios of monomers was synthesized and characterized. This novel library of copolymers establishes the basis for continued research on their potential for redox-sensitive drug delivery for hypoxic tumor targeting in vitro as well as in vivo. In summary, this work demonstrated the successful design and use of targeted and stimulus-sensitive polymer nanoparticles for drug and miRNA delivery to PC. While further in vivo studies and scale-up are required before the potential clinical use of these delivery systems, it is evident that innovative therapeutic combinations with tumor-specific delivery will be necessary to improve outcomes for PC patients.

English

ISBN: 9798286431298Subjects--Topical Terms:

560457
Chemical engineering.
Subjects--Index Terms:

Drug delivery

Targeted Nanoscale Drug and Nucleic Acid Delivery for Pancreatic Cancer Treatment /
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500 $a Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
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520 $a Pancreatic cancer (PC) is an aggressive and deadly type of cancer. Despite a multitude of advancements in cancer treatments in the last three decades, the 5-year survival rate for PC patients remains stagnant at 13%. These poor outcomes are due to a lack of early detection and ineffective treatments. The efficacy of current PC treatments is limited by off-target toxicity and the hostile tumor microenvironment (TME), which promotes drug resistance, invasion, and metastasis. Targeted and stimuli-sensitive nanocarriers are a prominently researched form of drug delivery to overcome the challenges associated with the TME and increase the accumulation of the drug in the tumor. In addition to tumor-targeted delivery, novel combinations of therapeutics will likely be necessary to overcome drug resistance in PC. Two options for developing new combination treatments are to utilize therapeutic miRNA, such as miR-345, and to repurpose drugs that are approved to treat other diseases, such as niclosamide. Given their different characteristics, miR-345 and niclosamide require tailored delivery vehicles for effective administration. Two polymer nanoparticle platforms were designed to enable tumor-specific delivery of the novel combinations of gemcitabine with miR-345 or niclosamide.The first polymer nanoparticle platform was used for the targeted dual delivery of miR-345 and gemcitabine. It was based on a pentablock copolymer (PB) with cationic poly(diethylamino ethylmethacrylate) end groups and Pluronic F17 middle blocks. The PB was functionalized with the tumor-penetrating peptide iRGD and then complexed with miR-345 and gemcitabine-loaded micelles. This dual delivery system was stable against RNase A and serum for at least 24 hours and demonstrated a sustained release of both miR-345 and gemcitabine over one week and two days, respectively. The iRGD functionalized delivery system showed targeted accumulation in subcutaneous PC tumors in mice compared to nontargeted treatment groups. Metastasis and tumor burden were also significantly decreased in orthotopically implanted PC tumor-bearing mice when treated with the dual delivery system. The second polymer nanoparticle platform utilizes polyanhydrides, which are biodegradable with tailorable erosion rates, to encapsulate hydrophobic drugs. Niclosamide, a hydrophobic antiparasitic, was loaded in 1,6-bis(p-carboxyphenoxy)hexane-co-sebacic acid (CPH:SA) nanoparticles (NicNp). Orthotopically implanted PC tumor-bearing mice were treated with NicNp and showed increased accumulation of Nic in the tumor compared to free Nic. NicNp acted synergistically with gemcitabine to reduce PC cell survival in cell viability assays and significantly improved survival and reduced tumor burden in orthotopically implanted PC tumor-bearing mice. To incorporate tumor-specific release of niclosamide, a reduction-sensitive monomer, 3,3'-dithiodipropionic acid (DTDP), was added to the CPH:SA polymer to target the hypoxic TME. An initial test of 10:75:10 CPH:SA:DTDP NicNps showed a reduction-mediated release of niclosamide in hypoxic TME simulated conditions. To optimize the redox sensitivity of CPH:SA:DTDP, a library of ten copolymers with varying ratios of monomers was synthesized and characterized. This novel library of copolymers establishes the basis for continued research on their potential for redox-sensitive drug delivery for hypoxic tumor targeting in vitro as well as in vivo. In summary, this work demonstrated the successful design and use of targeted and stimulus-sensitive polymer nanoparticles for drug and miRNA delivery to PC. While further in vivo studies and scale-up are required before the potential clinical use of these delivery systems, it is evident that innovative therapeutic combinations with tumor-specific delivery will be necessary to improve outcomes for PC patients.
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590 $a School code: 0097
650 4 $a Chemical engineering. $3 560457
650 4 $a Oncology. $3 751006
650 4 $a Biochemistry. $3 518028
650 4 $a Pharmacology. $3 634543
650 4 $a Polymer chemistry. $3 3173488
653 $a Drug delivery
653 $a Nanoparticles
653 $a Pancreatic cancer
653 $a Polymers
653 $a Tumor microenvironment
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690 $a 0992
690 $a 0487
690 $a 0419
690 $a 0495
710 2 $a Iowa State University. $b Chemical and Biological Engineering. $e degree granting institution. $3 3827304
720 1 $a Mallapragada, Surya $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 86-12B.
790 $a 0097
791 $a Ph.D.
792 $a 2025
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