Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications

Abstract

In recent years, the use of nanomedicine formulations for therapeutic and diagnostic applications has increased exponentially. Many different systems and strategies have been developed for drug targeting to pathological sites, as well as for visualizing and quantifying important (patho-) physiological processes. In addition, ever more efforts have been undertaken to combine diagnostic and therapeutic properties within a single nanomedicine formulation. These so-called nanotheranostics are able to provide valuable information on drug delivery, drug release and drug efficacy, and they are considered to be highly useful for personalizing nanomedicine-based (chemo-) therapeutic interventions.

Figure 1

Nanomedicine systems and strategies. A-E: Examples of clinically relevant nanotherapeutics and nanotheranostics. Liposomes and liposomal bilayers are depicted in gray, polymers and polymer-coatings in green, linkers allowing for drug release and for sheddable stealth coatings in blue, targeting ligands in yellow, antibodies in purple, imaging agents in orange, and conjugated or entrapped (chemo-) therapeutic agents in red. F-J: Drug targeting strategies. F: Upon the i.v. injection of a standard low-molecular-weight (chemo-) therapeutic drug, which is often rapidly cleared from the blood, only low levels of the agent accumulate at the target site, while localization to healthy non-target tissues tends to be high. G: Upon using a passively targeted nanomedicine formulation, by means of the EPR effect, the accumulation of drugs in tumors and in tumor cells can be substantially increased, while their localization in healthy organs and tissues can be attenuated. H: Active targeting to internalization-prone cell surface receptors (over-) expressed by cancer cells aims to improve the cellular uptake of nanomedicine formulations. This is particularly useful for the intracellular delivery of agents which are poorly internalized by cells, such as DNA and siRNA. I: Active targeting to receptors (over-) expressed by angiogenic endothelial cells can on the one hand aim to increase drug delivery to tumor endothelium, thereby eradicating tumor blood vessels, and depriving tumor cells of oxygen and nutrients (I-1). On the other hand, reasoning that tumor blood vessels are continuously exposed to long-circulating nanomedicines, endothelial cell targeting might also be useful for improving the overall tumor accumulation of chemotherapeutic drugs (I-2) J: Stimuli-responsive nanomedicines can be triggered to release their contents by externally applied stimuli, such as hyperthermia and ultrasound. This can be done either upon (EPR-mediated) accumulation at the target site (J-1), or while the formulations are still present in the circulation (J-2). Image reproduced, with permission, from [8,31].

Figure 2

Therapeutic, diagnostic and theranostic applications of nanomedicines. A-C: PSMA-targeted PLA/PLGA-nanoparticles containing docetaxel (DTXL-TNP) were extensively optimized from a formulation point of view, their efficacy was evaluated in three different mouse tumor models (B), and their pharmacokinetics were assessed in mice, rats, monkeys and humans. In addition, initial responses in patients with lung cancer metastases and tonsillar tumors were monitored (C). D-F: Multilamellar liposomes containing cytarabine and daunorubicin (CPX-351) were extensively evaluated in vitro and in vivo, to identify the optimal ratio for synergistic drug efficacy (E). Liposomes containing an optimal ‘ratiometric’ mixture of 5:1 cytarabine vs. daunorubicin were subsequently evaluated in patients suffering from relapsed and refractorary acute myeloid leukemia, showing prolonged presence of drugs and metabolites in blood (F), and a significant number of complete responses in pretreated patients. G-I: Gadomer-17 is a polylysine dendrimer containing 24 gadolinium complexes. It is significantly larger it is highly useful for DCE-MRI, MR lymphography and MR angiography, enabling the visualization of tumor blood vessels and coronary arteries in animal models and in patients (H-I). J-L: Carboxydextran-coated iron oxide nanoparticles (Resovist) have been employed for MR angiography and stem cell tracking in preclinical models (K), as well as for visualizing metastatic liver lesions in patients (L). M-P: HPMA-based polymeric nanomedicines can be functionalized both with drugs and with imaging agents, enabling the in vivo visualization of their circulating properties and tumor accumulation in tumor-bearing mice and rats (N), as well as their ability to target solid tumors and metastases in patients (O). P-R: Liposomes, such as Doxil, can also be easily co-loaded with drugs and imaging agents. In HNSCC-bearing nude rats, Doxil co-functionalized with the beta- and gamma-emitter rhenium-186 not only enabled the monitoring of tumor accumulation using 3D SPECT-CT and 2D gamma-scintigraphy (Q), but also the combination of radionuclide therapy with chemotherapy. Technetium-99m-labeled Doxil can be used to visualize and quantify tumor accumulation in patients, suffering e.g. from different types of sarcomas (R), thereby enabling patient preselection and (more) personalized nano-chemotherapeutic treatments. Images are adapted, with permission, from [30,32-34,38-42,50-52].

Figure 3

Rationale for image-guided and personalized nanomedicine. By combining non-invasive imaging information on the target site accumulation (1^st selection step) and therapeutic efficacy (2^nd patient selection step) of theranostics nanomedicines, patients can be preselected. They can then either be assigned to nanomedicine treatment (in case of moderate to high tumor accumulation and proper antitumor efficacy), or to conventional/alternative chemotherapeutic interventions (in case of low tumor accumulation and/or improper efficacy). In addition, during the first patient selection step, patients presenting with high levels of nanomedicine accumulation in potentially endangered healthy organs can be excluded from nanomedicine treatment, to attenuate the incidence and/or intensity of side effects. Image reproduced, with permission, from [9].