Contact-mediated intracellular delivery of hydrophobic drugs from polymeric nanoparticles.

Sofie Snipstad,Andreas Ko Åslund,Catharina De Lange Davies,Mercy Afadzi,Sara Westrøm,Yrr Mørch

doi:10.1186/s12645-014-0008-4

Abstract

Encapsulation of drugs in nanoparticles can enhance the accumulation of drugs in tumours, reduce toxicity toward healthy tissue, and improve pharmacokinetics compared to administration of free drug. To achieve efficient delivery and release of drugs at the target site, mechanisms of interaction between the nanoparticles and cells and the mechanism of delivery of the encapsulated drug are crucial to understand. Our aim was to determine the mechanisms for cellular uptake of a fluorescent hydrophobic model drug from poly(butylcyanoacrylate) nanoparticles. Prostate adenocarcinoma cells were incubated with Nile Red-loaded nanoparticles or free Nile Red. Uptake and intracellular distribution were evaluated by flow cytometry and confocal laser scanning microscopy. The nanoparticles mediated a higher intracellular level and more rapid uptake of encapsulated Nile Red compared to model drug administered alone. The main mechanism for delivery was not by endocytosis of nanoparticles but by nanoparticle-cell contact-mediated transfer directly to the cytosol and, to a smaller extent, release of payload from nanoparticles into the medium followed by diffusion into cells. The payload thus avoids entering the endocytic pathway, evading lysosomal degradation and instead gains direct access to intracellular targets. The nanoparticles are promising tools for efficient intracellular delivery of hydrophobic anticancer drugs; therefore, they are clinically relevant for improved cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12645-014-0008-4) contains supplementary material, which is available to authorized users.

Highlights

Cancer treatment based on systemic chemotherapy is not cancer-specific, and toxic effects toward normal healthy tissue are challenging [1]
We have developed a novel, multimodal, multifunctional drug delivery system consisting of microbubbles stabilised by polymeric PACA nanoparticles [14]
The aim of the present work was to study the mechanisms of cellular uptake of the hydrophobic model drug Nile Red from poly(butylcyanoacrylate) (PBCA) nanoparticles in vitro and to determine whether the uptake was based on endocytosis of nanoparticles, extracellular release of Nile Red followed by diffusion into cells, or a contact-based transfer from nanoparticles to cells [30]

Summary

Introduction

Cancer treatment based on systemic chemotherapy is not cancer-specific, and toxic effects toward normal healthy tissue are challenging [1]. To increase the fraction of nanoparticles reaching the tumour, a common strategy is to extend their time in systemic circulation [3]. This can be achieved by coating the nanoparticle surface with polyethylene glycol (PEG) [4,5] thereby preventing adsorption of opsonins via steric hindrance [6,7] and avoiding elimination through the mononuclear phagocyte system (MPS) [8,9]. Various possibilities for delivering substances directly into cytosol have been discussed [22,23,25] Such directed cytoplasmic delivery into a target cell could provide an avenue for delivering greater amounts of agent with more efficient and immediate access to intracellular targets [27]. An example is delivery of load from nanoparticles to cells by collisional interactions [28,29]

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