Doxorubicin

Summary

Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used together with other chemotherapy agents. Doxorubicin is given by injection into a vein. Common side effects include hair loss, bone marrow suppression, vomiting, rash, and inflammation of the mouth. Other serious side effects may include allergic reactions such as anaphylaxis, heart damage, tissue damage at the site of injection, radiation recall, and treatment-related leukemia. People often experience red discoloration of the urine for a few days. Doxorubicin is in the anthracycline and antitumor antibiotic family of medications. It works in part by interfering with the function of DNA. Dox

Official source

https://en.wikipedia.org/wiki/Doxorubicin

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Controlling and Monitoring Intracellular Drug Delivery Using PHPMA-Based Polymer Nanomedicines

Claudia Battistella

Polymer nanomedicine is an attractive approach for the delivery of anticancer drugs. Firstly designed to increase drug bioavailability, polymer conjugates and polymer nanoparticles have rapidly emerged in the field of cancer therapy after the discovery of the enhanced permeation and retention (EPR) effect. The leaky and disordered tumor neovascularization provides opportunities to guide the accumulation of polymer nanomedicines to the tumor tissue therefore enhancing therapy selectivity and reducing off-target-associated side effects. However, since many chemotherapeutics act on targets that are located in well-defined subcellular compartments, controlling the intracellular fate of polymer nanomedicines and/or their payload is another important factor that contributes to therapy efficiency. Polymer conjugates and polymer nanoparticles generally access the cell interior via endocytosis. The physiochemical and biochemical parameters that distinguish the endolysosomal compartments from the extracellular environment have been widely exploited to trigger intracellular drug release from the polymer carriers. Amongst a range of other polymers and polymer nanoparticles that have been investigated over the past 30 years, poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA)-based conjugates have been extensively explored for the endolysosomal release of anticancer drugs. While the modern polymer chemistry toolbox provides many opportunities to tailor the molecular weight and functionality of PHPMA and to introduce features that allow the polymer to respond to the different endolysosomal environments, the development of tools and methods to monitor these processes is also crucial for the future development of advanced delivery systems. The aim of this Thesis is to design dual-functional PHPMA polymers that offer the possibility to control the endolysosomal release of anticancer drug combinations as well as to monitor the PHPMA endolysosomal trafficking. Chapter 1 of this Thesis provides an overview of the different approaches that have been described in literature to control and monitor the intracellular delivery of polymer nanomedicines. Chapter 2 describes a synthetic approach to prepare alpha- and alpha,omega-fluorine labeled pentafluorophenyl methacrylate (PPFMA) polymers via reversible addition fragmentation chain transfer (RAFT) polymerization. In Chapter 3 post-polymerization modification of the alpha-fluorine labeled PPFMA precursor will be used to prepare a series of PHPMA conjugates carrying either the anticancer drug doxorubicin (Dox) or the P-glycoprotein inhibitor zosuquidar (Zos) or both drugs at the polymer side chains. The ability of the conjugates to overcome doxorubicin efflux and therefore reverse P-gp-mediated multidrug resistance in resistant ovarian carcinoma cells will be assessed. Finally, Chapter 4 will study the cellular internalization and endolysosomal trafficking of PHPMA. The synthesis of a dual-labeled PHPMA polymer containing both a fluorescent as well as a fluorinated label will be used for flow cytometry and confocal fluorescence microscopy studies and to demonstrate the potential of nanoscale secondary ion mass spectrometry (NanoSIMS) to map and localize fluorine-containing polymers in cells.

EPFL2017

Angiostatic treatment prior to chemo- or photodynamic therapy improves anti-tumor efficacy

Débora Bonvin, Paul Joseph Dyson, Patrycja Nowak-Sliwinska, Edoardo Scherrer

Tumor vasculature is known to be poorly organized leading to increased leakage of molecules to the extravascular space. This process can potentially increase interstitial fluid pressure impairing intra-tumoral blood flow and oxygen supply, and can affect drug uptake. Anti-angiogenic therapies are believed to reduce vascular permeability, potentially reducing interstitial fluid pressure and improving the extravasation of small molecule-based chemotherapeutics. Here we show that pretreatment of human ovarian carcinoma tumors with sub-optimal doses of the VEGFR targeting tyrosine kinase inhibitor axitinib, but not the EGFR targeting kinase inhibitor erlotinib, induces a transient period of increased tumor oxygenation. Doxorubicin administered within this window was found to enter the extravascular tumor space more rapidly compared to doxorubicin when applied alone or outside this time window. Treatment with the chemotherapeutics, doxorubicin and RAPTA-C, as well as applying photodynamic therapy during this period of elevated oxygenation led to enhanced tumor growth inhibition. Improvement of therapy was not observed when applied outside the window of increased oxygenation. Taken together, these findings further confirm the hypothesis of angiostasis-induced vascular normalization and also help to understand the interactions between anti-angiogenesis and other anti-cancer strategies.

2015

Inhibition of P-glycoprotein (P-gp) transporter is an attractive approach for the reversion of cancer-associated multidrug resistance (MDR). Poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA)-based carriers that are able to release the anticancer drug doxorubicin in the lysosomes have shown promise to reduce P-gp mediated resistance. This is attributed to the release of the drug in close proximity to the nucleus and distant from the P-gp transporter. This work presents a strategy to maximize P-gp inhibition and enhance doxorubicin cytotoxicity in cancer cell by using a dual functional PHPMA conjugate carrying both the anticancer drug doxorubicin and the P-glycoprotein inhibitor zosuquidar (Zos). While doxorubicin was connected to the polymer backbone via a lysosomally cleavable spacer, the P-gp inhibitor Zos was attached by a hydrazone linker in order to promote release in the early stage of the endocytic process and maximize its,cytosolic, concentration in proximity of P-gp transporter. Following Zos modification and determination of its ability to inhibit P-gp, conjugation to the PHPMA polymer backbone resulted in enhanced doxorubicin cytotoxicity in resistant A2780ADR ovarian carcinoma cells. Finally, the incorporation of both Dox and Zos in a single polymer carrier enhanced P-gp inhibition as compared to a control PHPMA conjugate containing only Dox.

2017

Controlling and Monitoring Intracellular Drug Delivery Using PHPMA-Based Polymer Nanomedicines

Claudia Battistella

EPFL2017