ReviewInsight into nanoparticle cellular uptake and intracellular targeting☆
Graphical abstract
Introduction
Multidisciplinary and integrative research efforts in the field of nanomedicine have led to the development of a variety of nanoparticle-based carrier systems suitable for site-specific delivery of diagnostic and therapeutic agents [1]. The original foundation for the recent dramatic progress in the use of nanomaterials for biomedical applications is considered to be the famous 1960 lecture of R. Feyman, “There is plenty of room at the bottom” [2]. However, the work of Paul Ehrlich, who coined the visionary term “magic bullets” to describe cell-specific diagnostics and cell-targeted therapies, is also of seminal importance [3], [4]. The field of nanomedicine has established its capability to overcome the low solubility, non-specific cytotoxicity, poor bioavailability, and suboptimal pharmacokinetics and pharmacodynamics associated with the cytotoxic agents employed in cancer chemotherapy. With some nanomedicines already making their way into the clinic, liposomes, polymeric nanoparticles, dendrimers, and gold nanoparticles have demonstrated remarkable potential as carrier systems [5], [6], [7], [8]. On one hand, the entire field of nanomedicines has been greatly expanded by the development of a wide range of nanomaterials with a high degree of control over their physical (e.g., size, surface charge, shape, mechanical strength) and chemical attributes. At the same time, a better understanding of the physiopathological nature of different diseases and insight into the interaction of nanomaterials with biological systems at various levels (i.e., systemic, organ, tissue, and cell) are of paramount importance for further progress towards bench-to-bedside translation. The recent strides forward in nanomedicines stem from some key multidisciplinary efforts. The non-fouling nature of hydrophilic materials such as polyethylene glycol (PEG) and polycarboxybetaine (PCB) [9], [10] against biological materials, and recognition of the enhanced permeability and retention (EPR) effect are two such examples [11]. The development of hydrophilic polymer functionalization at the surface of nanoparticles imparts a stealth character against the immune system and enhances their systemic circulation [12]. The groundbreaking discovery of the EPR effect [13], [14], which stems from the abnormal and leaky microvasculature common to tumors, has laid the foundation for the first generation of passively targeted nanomedicines that preferentially accumulate in tumor tissue [15], [16]. While the EPR effect has also been observed during inflammation caused by other diseases, in that context this review is mainly focusing on the EPR effect in tumor tissues. The combination of long systemic circulation made possible by hydrophilic polymers and the EPR effect results in the accumulation of nanoparticle-based carrier systems in the tumor tissue followed by the release of therapeutic agent, either in proximity to diseased tissue or inside the cells after internalization. The EPR effect results from many complex biological processes including differences in cancer genetics as reviewed in ref. [11], consequently the therapeutic outcomes based on exploiting the EPR effect can be inconsistent due in part to the heterogeneity of tumor tissue. Recently, exploitation of the specific affinity of receptors to certain ligand molecules has led to the second generation of nanomedicines, which are preferentially targeted to particular organs, tissues, or cells. The ligands, with specific affinity towards a particular receptor or molecule differentially expressed at the target site, are displayed on the surface of nanocarriers, resulting in the preferential accumulation and uptake at the site of action [1], [17]. Although some concerns have been raised about poor systemic circulation, enhanced clearance by the mononuclear phagocyte system, and limited tissue penetration, the new paradigm of ligand-conjugated actively targeted nanocarriers has been shown to improve the cellular uptake and efficacy of their payload when compared to their passively targeted counterparts [18], [19]. The enhanced cellular uptake of nanoparticles at the disease site is of paramount importance, because targets for many theranostic agents against several disorders (including cancer) are localized in the subcellular compartments [20]. This fact not only highlights the importance of a better understanding of cellular uptake mechanisms but has also fueled recent research into the development of nanocarriers capable of subcellular- and organelle-level targeting, referred to as the third generation of nanomedicines [21]. After giving an account of the endocytic pathways relevant to non-targeted and ligand-conjugated targeted nanoparticles, we provide a comprehensive review of recent developments and outline future strategies in designing nanomedicines capable of efficient intracellular trafficking and subcellular targeting.
Section snippets
Endocytic routes and non-ligand targeted nanomedicines
Precise release of drugs in specific organs, tissues, and cells [22] has been the primary focus of nanoparticle-based therapeutic strategies. However, drug-loaded nanoparticles must overcome a number of transport barriers to reach their target [23]. Particularly for intracellular targeting, efficient translocation of nanoparticles across the plasma membrane barrier is a prerequisite. The plasma membrane is highly complex and provides an independent environment necessary to develop the normal
Receptor-mediated cellular internalization of ligand-targeted nanomedicines
The overexpression of receptors on the surface of target disease cells has been widely explored to improve the cellular uptake of nanoparticles as well as to minimize off-site toxicity. Representative examples of receptors known for active disease cell targeting include folate receptor (FR), transferrin receptor (TfR), epidermal growth factor receptor (EGFR), G-protein coupled receptor (GPCR), low-density lipoprotein receptor (LDLR), and lectins [92]. The receptor-mediated cellular
From endosomes/lysosomes to cytoplasm
Ligand-conjugated nanoparticles with specific tissue- or cellular-level targeting have already been successfully produced, and this novel paradigm combines with the EPR effect to increase intratumoral concentration of cytotoxic anticancer drugs. Many interesting therapeutic targets are localized in the intracellular compartments. This fact has triggered increasing efforts to develop sophisticated nanoparticle designs capable of precise navigation across physiological barriers and selective
Outlook
The success of nanoparticle-based carrier systems in human trials for the targeted delivery of therapeutic agents reflects the progress of nanomedicines towards the clinic. For the development of more potent nanomedicines, an in-depth understanding of cellular uptake mechanisms is of paramount importance. Nanoparticles enter the cells via a combination of different internalization routes. Depending on the size, shape and surface charge of the nanoparticles, a particular cellular internalization
Acknowledgments
This work was supported by the National Cancer Institute (NCI) (grant U54-CA151884), the National Heart, Lung, and Blood Institute (NHLBI) Program of Excellence in Nanotechnology (PEN) (contract #HHSN268201000045C), the National Institute of Biomedical Imaging and Bioengineering (NIBIB) R01 grant (EB015419-01), the National Research Foundation of Korea (K1A1A2048701), Movember Challenge Award from Prostate Cancer Foundation, and the David Koch–Prostate Cancer Foundation Award in
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This review is part of the 30th Anniversary Issue of the Journal of Controlled Release.