Doxorubicin (DOX) is a chemotherapeutic agent broadly used in the treatment of a range of solid tumors. In spite of its high potency,

 

Abstract

Doxorubicin (DOX) is a chemotherapeutic agent broadly used in the treatment of a range of solid tumors. In spite of its high potency, as is the case for many other chemotherapeutic drugs, there are many challenges associated with the use of DOX in clinical oncology. This is particularly true for DOX in the treatment of lung cancer where in vitro potency is shown to be very high, but low lung distribution and off-target toxicity (particularly cardiotoxicity) restricts its use. Nanocarrier-based drug delivery systems (nanoDDS) have been shown to help alter biodistribution and alleviate off-target toxicity associated with DOX. While significant understanding exists regarding the design parameters to achieve those clinical benefits, much less is known regarding the design of nanoDDS capable of enhancing tumor penetration of DOX (and other drugs), which is another major factor leading to DOX's reduced efficacy. The purpose of this study was to design a dendrimer-based nanoDDS capable of enhancing the penetration of DOX as measured in an in vitro 3D lung tumor model and to correlate those results with its efficacy. Spheroids formed with A549 human lung adenocarcinoma cells/murine fibroblasts cell line (NIH/3T3 cell line) are shown to produce the essential components of the extracellular matrix (ECM), which is known as a physical barrier that hinder the transport of DOX. DOX was conjugated to generation 4, succinamic acid-terminated poly (amido-amine) (PAMAM) dendrimers (G4SA) through an enzyme-liable tetrapeptide (G4SA-GFLG-DOX) resulting in a nanoDDS with ~5.5 DOX, -17 mV surface (zeta) potential, and 10 nm in hydrodynamic diameter (HD). Penetration of DOX to the core of the spheroid in term of DOX fluorescence's was determined to be 3.1-fold greater compared to free DOX, which positively correlated with enhanced efficacy as measured by Caspase 3/7 assay. This improved penetration happens as the interactions between the G4SA-GFLG-DOX and the highly negatively charged ECM are minimized by shielding the protonatable amine of DOX upon conjugation, and the HD of the conjugate is kept smaller than the estimated mesh size of the ECM. Interestingly, the conjugate provide has more specificity for DOX to tumor cells compared to fibroblasts, while free DOX is equally distributed in both tumor and fibroblasts as assessed in the co-culture spheroids. Growth inhibition studies show that the released DOX maintains its activity, and leads to tumor reduction to the same extent as free DOX. The results obtained here are of relevance for the design of dendrimer-based nanoDDS for the treatment of solid tumors as they provide critical information regarding desirable surface characteristics and sizes for efficient tumor penetration.

PMID: 32227969 [PubMed - as supplied by publisher]

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Cancer & Heart (Cardio-Oncology, Cardiotoxicity, TEV)

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