Polysaccharides as stabilizing and coating agents of polymeric nanocarriers for chemotherapeutics delivery

Author(s)

Luana Corsi Antonio

• Document type: Master's Dissertation
• Press: São Carlos.
• Institution: Universidade de São Paulo (USP). Instituto de Física de São Carlos (IFSC/BT)
• Defense date: 2023-03-06

Examining board members

Valtencir Zucolotto; José Roberto de Souza de Almeida Leite; Renata Rank Miranda

• Advisor: Valtencir Zucolotto

Abstract

Polymeric nanocarriers (NCs) are efficient vehicles to delivery therapeutics to cancer, preventing drug unspecific biodistribution and increasing the drug amounts delivered to the tumor tissues. However, the NCs interaction with biological systems still lack a comprehensive assessment. In this dissertation we investigate how does polysaccharides affect the interactions between nanomaterials and cancer cells, as well as cancer-associated cells. In Chapter 1 we studied the interaction of poly (lactic acid-co-glycolic acid) (PLGA) NCs prepared using Dex as stabilizing and caping agents with myocardial cells (H9C2), breast adenocarcinoma cells (MCF-7) and macrophages (RAW 264.7). By emulsion diffusion method, doxorubicin-loaded NCs were prepared with no Dex (PLGA-DOX), 1 %(w/v) (Dex1/PLGA-DOX) and 5 %(w/v) (Dex5/PLGA-DOX) NCs. Our results highlight that control over the amount of Dex added to the formulation of PLGA NCs impacts their interaction with non-phagocytic cells due to the decrease of protein adsorption (protein corona formation) with the increase of dextran amount. For doxorubicin-loaded formulations, the highest amount of Dex (5 %(w/v)) led to oxidative membrane damage and increase of early apoptotic events, suggesting that it may contribute to the long-term adverse effects more substantially than formulations with lower Dex concentrations or without Dex. In Chapter 2 we explored the binding between hyaluronic acid (HA) and CD44, a receptor that mediates cell-cell and cell-matrix interactions, to transport a nanotherapeutic to the leukemic cells. To assess the macrophages ability to effectively deliver NCs via CD44-targeting to acute myeloid leukemia (AML) cells, we studied their interaction with the NCs in co-cultures of macrophages (RAW 264.7) and AML cells (C1498). Three configurations of PLGA-based NCs were evaluated, namely: i) NCs modified with polyethylene glycol (PEG), to evade the immune system; ii) NCs modified with HA, CD44-HA binding and iii) non-modified NCs (carboxyl moiety). Macrophages previously exposed to NCs were co-cultured with AML cells and the uptake and delivery of NCs to AML cells were analyzed by flow cytometry. As a consequence of CD44 increased intensity, (PLGA)-PEG-HA NCs adhered to the membrane of pro-leukemic macrophages. Also, (PLGA)-PEG-HA NCs were delivered to AML blasts by cell-to-cell interaction, accumulating into the leukemic cell and increasing cancer cells death. Overall, our results suggest that macrophage-based deliver of (PLGA)PEG-HA NCs loaded with ATO is a promising platform to treat AML as (PLGA)PEG-HA NCs can improve targetability by adhering to AML-related macrophages and reduce AML blasts viability in vitro. (AU)

• FAPESP's process: 20/02386-7 - Nanomedicine applied to acute promyelocytic leukemia treatment via CD44 receptors of macrophages
• Grantee: Luana Corsi Antonio
• Support Opportunities: Scholarships in Brazil - Master