Cancer is a leading cause of disease worldwide and breast cancer, which exists in four major molecular subtypes, is the second most common cause of cancer mortality. Although there are many therapeutic options, chemotherapy is still subject to failures, due to (1) the low selectivity of drugs, which requires high doses with side effects and the risk of recurrence and (2) the development of resistance by different mechanisms that cells put in place to defend themselves from the action of drugs. In my PhD project I exploited the unique features of a nanoparticle based on recombinant heavy-chain ferritin cages (HFn) for the targeted delivery of various active molecules to improve the treatment efficacy in breast cancer. My work is divided into three main subprojects, all sharing the use of HFn. Initially, I exploited HFn nanocages for the encapsulation of a chemotherapeutic drug, doxorubicin (DOX). HFn-DOX acts as a “Trojan Horse”: nanoparticles are internalized in cancer cells faster and more efficiently compared to free DOX, then promptly translocated into the nucleus with a self-triggered mechanism, thus promoting a fast and massive delivery of the drug inside the nuclear compartment, strongly affecting viability and circumventing MDR mechanisms. Then, I tested HFn-DOX on an aggressive breast cancer model, in vitro and in vivo, under a Low Dose Nanometronomic regimen (LDNM). Metronomic HFn-DOX strongly improved the antitumor potential of DOX chemotherapy arresting the tumor progression. Such effect is attributable to multiple nanodrug actions, including inhibition of tumor angiogenesis and avoidance of chemoresistance. Moreover, metronomic HFn-DOX drastically reduced cardiotoxicity. In the second project, curcumin was encapsulated in HFn (CFn) and used to treat triple negative breast cancer (TNBC) cell lines. Curcumin is a natural anti tumor compound, but is rapidly degraded and scantily bioavailable. CFn had instead good stability and solubility and was able to enhance the sensitization of TNBC cells to DOX treatment. Finally, HFn was used as a vehicle to transport anti-microRNAs, since miR21 plays a role in the development of resistance against Trastuzumab (TZ), the treatment of choice for HER2 positive breast cancer. The major limiting factor in gene therapy is the ability to specifically deliver nucleotide sequences: however, anti-miR21 cross-linked to HFn, was released into the cytoplasm. Based on our results, ferritin is an effective system for the delivery of anti-tumor molecules, promoting their chemotherapic action and/or overcoming the problem of resistance that limits the effectiveness of many therapies.

Cancer is a leading cause of disease worldwide and breast cancer, which exists in four major molecular subtypes, is the second most common cause of cancer mortality. Although there are many therapeutic options, chemotherapy is still subject to failures, due to (1) the low selectivity of drugs, which requires high doses with side effects and the risk of recurrence and (2) the development of resistance by different mechanisms that cells put in place to defend themselves from the action of drugs. In my PhD project I exploited the unique features of a nanoparticle based on recombinant heavy-chain ferritin cages (HFn) for the targeted delivery of various active molecules to improve the treatment efficacy in breast cancer. My work is divided into three main subprojects, all sharing the use of HFn. Initially, I exploited HFn nanocages for the encapsulation of a chemotherapeutic drug, doxorubicin (DOX). HFn-DOX acts as a “Trojan Horse”: nanoparticles are internalized in cancer cells faster and more efficiently compared to free DOX, then promptly translocated into the nucleus with a self-triggered mechanism, thus promoting a fast and massive delivery of the drug inside the nuclear compartment, strongly affecting viability and circumventing MDR mechanisms. Then, I tested HFn-DOX on an aggressive breast cancer model, in vitro and in vivo, under a Low Dose Nanometronomic regimen (LDNM). Metronomic HFn-DOX strongly improved the antitumor potential of DOX chemotherapy arresting the tumor progression. Such effect is attributable to multiple nanodrug actions, including inhibition of tumor angiogenesis and avoidance of chemoresistance. Moreover, metronomic HFn-DOX drastically reduced cardiotoxicity. In the second project, curcumin was encapsulated in HFn (CFn) and used to treat triple negative breast cancer (TNBC) cell lines. Curcumin is a natural anti tumor compound, but is rapidly degraded and scantily bioavailable. CFn had instead good stability and solubility and was able to enhance the sensitization of TNBC cells to DOX treatment. Finally, HFn was used as a vehicle to transport anti-microRNAs, since miR21 plays a role in the development of resistance against Trastuzumab (TZ), the treatment of choice for HER2 positive breast cancer. The major limiting factor in gene therapy is the ability to specifically deliver nucleotide sequences: however, anti-miR21 cross-linked to HFn, was released into the cytoplasm. Based on our results, ferritin is an effective system for the delivery of anti-tumor molecules, promoting their chemotherapic action and/or overcoming the problem of resistance that limits the effectiveness of many therapies.

(2017). Development of apoferritin nanoparticles for chemotherapeutic delivery and drug resistance overcoming in breast cancer models. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2017).

Development of apoferritin nanoparticles for chemotherapeutic delivery and drug resistance overcoming in breast cancer models

BELLINI, MICHELA
2017

Abstract

Cancer is a leading cause of disease worldwide and breast cancer, which exists in four major molecular subtypes, is the second most common cause of cancer mortality. Although there are many therapeutic options, chemotherapy is still subject to failures, due to (1) the low selectivity of drugs, which requires high doses with side effects and the risk of recurrence and (2) the development of resistance by different mechanisms that cells put in place to defend themselves from the action of drugs. In my PhD project I exploited the unique features of a nanoparticle based on recombinant heavy-chain ferritin cages (HFn) for the targeted delivery of various active molecules to improve the treatment efficacy in breast cancer. My work is divided into three main subprojects, all sharing the use of HFn. Initially, I exploited HFn nanocages for the encapsulation of a chemotherapeutic drug, doxorubicin (DOX). HFn-DOX acts as a “Trojan Horse”: nanoparticles are internalized in cancer cells faster and more efficiently compared to free DOX, then promptly translocated into the nucleus with a self-triggered mechanism, thus promoting a fast and massive delivery of the drug inside the nuclear compartment, strongly affecting viability and circumventing MDR mechanisms. Then, I tested HFn-DOX on an aggressive breast cancer model, in vitro and in vivo, under a Low Dose Nanometronomic regimen (LDNM). Metronomic HFn-DOX strongly improved the antitumor potential of DOX chemotherapy arresting the tumor progression. Such effect is attributable to multiple nanodrug actions, including inhibition of tumor angiogenesis and avoidance of chemoresistance. Moreover, metronomic HFn-DOX drastically reduced cardiotoxicity. In the second project, curcumin was encapsulated in HFn (CFn) and used to treat triple negative breast cancer (TNBC) cell lines. Curcumin is a natural anti tumor compound, but is rapidly degraded and scantily bioavailable. CFn had instead good stability and solubility and was able to enhance the sensitization of TNBC cells to DOX treatment. Finally, HFn was used as a vehicle to transport anti-microRNAs, since miR21 plays a role in the development of resistance against Trastuzumab (TZ), the treatment of choice for HER2 positive breast cancer. The major limiting factor in gene therapy is the ability to specifically deliver nucleotide sequences: however, anti-miR21 cross-linked to HFn, was released into the cytoplasm. Based on our results, ferritin is an effective system for the delivery of anti-tumor molecules, promoting their chemotherapic action and/or overcoming the problem of resistance that limits the effectiveness of many therapies.
TORTORA, PAOLO
apoferritin,; nanoparticles,; cancer,; targeting,; resistance
apoferritin,; nanoparticles,; cancer,; targeting,; resistance
BIO/10 - BIOCHIMICA
English
27-apr-2017
SCIENZE DELLA VITA - 81R
29
2015/2016
open
(2017). Development of apoferritin nanoparticles for chemotherapeutic delivery and drug resistance overcoming in breast cancer models. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2017).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/158296
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