Target Site Accumulation Research Articles

Nanomedicine Advancements in Cancer Therapy: A Scientific Review

Cancer nanomedicines, characterized by submicrometer-sized formulations, aim to optimize the biodistribution of anticancer drugs by minimizing off-target effects, reducing toxicity, enhancing target site accumulation, and improving overall efficacy. Numerous nanomedicines have been developed to improve the effectiveness and safety of traditional anticancer treatments. These include formulations with carbon nanotubes, nanodiamonds, enzyme-responsive nanoparticles for controlled drug release, dendrimers as nanoparticle drug carriers, quantum dot nanocarrier systems for precise drug delivery, solid lipid nanoparticles, and polymeric nanoparticles designed for targeted drug delivery. Additionally, nanotechnology has been explored in cancer treatment through gene therapy. Despite these advances, the complex nature of carrier materials and functional integration presents challenges in preparing these candidates for clinical translation. Nanotechnology, with its unique features at the nanoscale, offers novel possibilities for developing cancer therapies while increasing efficacy and safety. Although only a few nanotherapeutics have obtained clinical approval, exciting uses for nanotechnology are on the horizon. Nanoparticles possess unique transport, biological, optical, magnetic, electrical, and thermal capabilities due to their small size within the light wavelength spectrum. This results in high surface area-to-volume ratios, allowing for the incorporation of various supporting components in addition to active medicinal substances. These properties aid in solubilization, degradation protection, delayed release, immune response evasion, tissue penetration, imaging, targeted distribution, and triggered activation. In summary, the future of nanomedicine holds promise for introducing innovative platforms in cancer treatment. The research presented underscores the potential for nanoparticles to revolutionize anticancer therapies, enhancing the overall therapeutic approach.

An updated review on liposomes

Liposomes, tiny bubbles made from the same material as a cell membrane, are considered the most successful nanocarriers for drug delivery. They are biocompatible and stable, encapsulating both hydrophilic and lipophilic drugs and protecting them from degradation. Liposomes are the most commonly used drug delivery vehicles due to their high drug trapping capacity and efficiency. These offer controlled release, targeted drug delivery, increased therapeutic efficacy, and reduced dosing frequency. Liposome-based drug formulations have been approved for clinical use and are the subject of extensive research. Recent liposomal formulations aim to reduce toxicity and increase target site accumulation. With numerous advantages, liposomes prove their uniqueness in safe drug delivery in various areas of pharmacy and medicine. We will keep an eye on overall updated review on liposomes classification, their structural components, mechanism of action, stability, method of preparation, their evaluation tests and applications.

Herbal Theranostics: Controlled, Targeted Delivery and Imaging of Herbal Molecules.

Modern medicine relies on a small number of key biologics, which can be found in nature but require further characterization and purification before they can be used. Since the herbal remedy is given through a dated and ineffective method of drug administration, its effectiveness is diminished. The novel form of medicine delivery has the potential to increase the effectiveness of herbal substances while decreasing their side effects. This is the main idea behind utilising different ways of drug delivery in herbal treatments. Several benefits arise from novel formulations of herbal compounds as compared to their conventional counterparts. These include enhanced penetrating ability into tissues, constant delivery of effective doses, and resistance to physical and chemical degradation. Controlled and targeted delivery that include herbal components allow for more traditional dosing while simultaneously increasing their efficacy. Enhancing the biodistribution and target site accumulation of systemically administered herbal medicines is the goal of nanomedicine formulations. The field of nanotheranostics has made significant advancements in the development of herbal compounds by combining diagnostic and therapeutic functions on a single nanoscale platform. It is critically important to create a theranostic nanoplatform that is derived from plants and is intrinsically "all-in-one" for single molecules. In addition to examining the mechanistic approach to nanoparticle synthesis, this review highlights the therapeutic effects of nanoscale phytochemical delivery systems. Furthermore, we have evaluated the scope for future advancements in this field, discussed several nanoparticles that have been developed recently for herbal imaging, and provided experimental evidence that supports their usage.

Application of Nanoparticles: Diagnosis, Therapeutics, and Delivery of Insulin/Anti-Diabetic Drugs to Enhance the Therapeutic Efficacy of Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic metabolic disorder of carbohydrates, lipids, and proteins due to a deficiency of insulin secretion or failure to respond to insulin secreted from pancreatic cells, which leads to high blood glucose levels. DM is one of the top four noncommunicable diseases and causes of death worldwide. Even though great achievements were made in the management and treatment of DM, there are still certain limitations, mainly related to the early diagnosis, and lack of appropriate delivery of insulin and other anti-diabetic agents. Nanotechnology is an emerging field in the area of nanomedicine and NP based anti-diabetic agent delivery is reported to enhance efficacy by increasing bioavailability and target site accumulation. Moreover, theranostic NPs can be used as diagnostic tools for the early detection and prevention of diseases owing to their unique biological, physiochemical, and magnetic properties. NPs have been synthesized from a variety of organic and inorganic materials including polysaccharides, dendrimers, proteins, lipids, DNA, carbon nanotubes, quantum dots, and mesoporous materials within the nanoscale size. This review focuses on the role of NPs, derived from organic and inorganic materials, in the diagnosis and treatment of DM.

Nanomedicine approaches for treatment of hematologic and oncologic malignancies.

Cancer is a leading cause of death worldwide. Nowadays, the therapies are inadequate and spur demand for improved technologies. Rapid growth in nanotechnology and novel nanomedicine products represents an opportunity to achieve sophisticated targeting strategies and multi-functionality. Nanomedicine is increasingly used to develop new cancer diagnosis and treatment methods since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs, thereby reducing their toxicity. Cancer nanotechnology and cancer immunotherapy are two parallel themes that have emerged over the last few decades while searching for a cure for cancer. Immunotherapy is revolutionizing cancer treatment, as it can achieve unprecedented responses in advanced-stage patients, including complete cures and long-term survival. A deeper understanding of the human immune system allows the establishment of combination regimens in which immunotherapy is combined with other treatment modalities (as in the case of the nanodrug Ferumoxytol). Furthermore, the combination of gene therapy approaches with nanotechnology that aims to silence or express cancer-relevant genes via one-time treatment is gradually progressing from bench to bedside. The most common example includes lipid-based nanoparticles that target VEGF-Α and KRAS pathways. This review focuses on nanoparticle-based platforms utilized in recent advances aiming to increase the efficacy of currently available cancer therapies. The insights provided and the evidence obtained in this paper indicate a bright future ahead for immuno-oncology applications of engineering nanomedicines.

Discovery of a Redox-Activatable Chemical Probe for Detection of Cyclooxygenase-2 in Cells and Animals.

Cyclooxygenase-2 (COX-2) expression is up-regulated in inflammatory tissues and many premalignant and malignant tumors. Assessment of COX-2 protein in vivo, therefore, promises to be a powerful strategy to distinguish pathologic cells from normal cells in a complex disease setting. Herein, we report the first redox-activatable COX-2 probe, fluorocoxib Q (FQ), for in vivo molecular imaging of pathogenesis. FQ inhibits COX-2 selectively in purified enzyme and cell-based assays. FQ exhibits extremely low fluorescence and displays time- and concentration-dependent fluorescence enhancement upon exposure to a redox environment. FQ enters the cells freely and binds to the COX-2 enzyme. FQ exhibits high circulation half-life and metabolic stability sufficient for target site accumulation and demonstrates COX-2-targeted uptake and retention in cancer cells and pathologic tissues. Once taken up, it undergoes redox-mediated transformation into a fluorescent compound fluorocoxib Q-H that results in high signal-to-noise contrast and differentiates pathologic tissues from non-pathologic tissues for real-time in vivo imaging.

Monitoring EPR Effect Dynamics during Nanotaxane Treatment with Theranostic Polymeric Micelles.

Cancer nanomedicines rely on the enhanced permeability and retention (EPR) effect for efficient target site accumulation. The EPR effect, however, is highly heterogeneous among different tumor types and cancer patients and its extent is expected to dynamically change during the course of nanochemotherapy. Here the authors set out to longitudinally study the dynamics of the EPR effect upon single‐ and double‐dose nanotherapy with fluorophore‐labeled and paclitaxel‐loaded polymeric micelles. Using computed tomography‐fluorescence molecular tomography imaging, it is shown that the extent of nanomedicine tumor accumulation is predictive for therapy outcome. It is also shown that the interindividual heterogeneity in EPR‐based tumor accumulation significantly increases during treatment, especially for more efficient double‐dose nanotaxane therapy. Furthermore, for double‐dose micelle therapy, tumor accumulation significantly increased over time, from 7% injected dose per gram (ID g–1) upon the first administration to 15% ID g–1 upon the fifth administration, contributing to more efficient inhibition of tumor growth. These findings shed light on the dynamics of the EPR effect during nanomedicine treatment and they exemplify the importance of using imaging in nanomedicine treatment prediction and clinical translation.

Theranostics Nanomedicine: Recent Advancement, Applications and Challenges

Many advancements have been made in treatment and diagnosis tools with the progress in modern medicine and technology. Theronostics are multifunctional nanomaterials that combine therapeutic as well as imaging functions. Theranostic nanomedicines are used for checking drug release and efficacy. The amalgamation of diagnostic and therapeutic agents within a single system provides the target site localization and accumulation of nanomedicines in organs.It provides a transition from conventional medicine to personalized medicine. Many different types of nanomedicines have been evaluated over the years. Theragnostics approach includes pharmacogenomics, personalized medicine and imaging to develop efficient new targeted therapies which will help in better and optimize drug selection along with monitoring the therapy response to increase drug safety and efficacy. This review summarizes the recent development and various nanocarriers developed for nanotheranostics, includes inorganic Nanoparticles, Polymeric, dendrimers, micelles, liposomes, metallic, and carbon nanotubes.

Evaluating the effect of clofazimine against Mycobacterium tuberculosis given alone or in combination with pretomanid, bedaquiline or linezolid

In recent years, clofazimine (CFZ) has been regaining prominence for the treatment of tuberculosis. However, it shows limited efficacy as a single drug and optimal combination partners have not been identified. Therefore, the objective of our analysis was to evaluate the efficacy of CFZ-containing two-drug regimens with pretomanid (PMD), bedaquiline (BDQ) or linezolid (LZD) by: (i) determining their pharmacodynamic (PD) mode of interaction against Mycobacterium tuberculosis (Mtb) strain H37Rv in log- phase and acid-phase metabolic states, and against Mtb strain 18b in a non-replicating persister (NRP) metabolic state; (ii) predicting bacterial cell kill of the drugs alone and in combination; and (iii) evaluating the relationship between the interaction mode and the extent of bacterial cell kill. The results of our Greco universal response surface analysis showed that CFZ was at least additive with a clear trend towards synergy when combined with PMD, BDQ and LZD against Mtb in all explored metabolic states under in vitro checkerboard assay conditions. The results further showed that all two-drug combination regimens exerted greater bacterial kill than any of the drugs alone. CFZ alone showed the least antimicrobial efficacy amongst the evaluated drugs, and there was a lack of correlation between the mode of interaction and the extent of bacterial kill. However, we may underestimate the effect of CFZ in this screening approach owing to limited in vitro study duration and neglect of target site accumulation. Clofazimine; Pretomanid; Bedaquiline; Linezolid; Combination chemotherapy; Mycobacterium tuberculosis.

Optical imaging of the whole-body to cellular biodistribution of clinical-stage PEG-b-pHPMA-based core-crosslinked polymeric micelles

Core-crosslinked polymeric micelles (CCPM) based on PEG-b-pHPMA-lactate are clinically evaluated for the treatment of cancer. We macroscopically and microscopically investigated the biodistribution and target site accumulation of CCPM. To this end, fluorophore-labeled CCPM were intravenously injected in mice bearing 4T1 triple-negative breast cancer (TNBC) tumors, and their localization at the whole-body, tissue and cellular level was analyzed using multimodal and multiscale optical imaging. At the organism level, we performed non-invasive 3D micro-computed tomography-fluorescence tomography (μCT-FLT) and 2D fluorescence reflectance imaging (FRI). At the tissue and cellular level, we performed extensive immunohistochemistry, focusing primarily on cancer, endothelial and phagocytic immune cells. The CCPM achieved highly efficient tumor targeting in the 4T1 TNBC mouse model (18.6 %ID/g), with values twice as high as those in liver and spleen (9.1 and 8.9 %ID/g, respectively). Microscopic analysis of tissue slices revealed that at 48 h post injection, 67% of intratumoral CCPM were localized extracellularly. Phenotypic analyses on the remaining 33% of intracellularly accumulated CCPM showed that predominantly F4/80+ phagocytes had taken up the nanocarrier formulation. Similar uptake patterns were observed for liver and spleen. The propensity of CCPM to primarily accumulate in the extracellular space in tumors suggests that the anticancer efficacy of the formulation mainly results from sustained release of the chemotherapeutic payload in the tumor microenvironment. In addition, their high uptake by phagocytic immune cells encourages potential use for immunomodulatory anticancer therapy. Altogether, the beneficial biodistribution, efficient tumor targeting and prominent engagement of PEG-b-pHPMA-lactate-based CCPM with key cell populations underline the clinical versatility of this clinical-stage nanocarrier formulation.

Nanomedicine and drug delivery systems in cancer and regenerative medicine.

Nanomedicine and drug delivery technologies play a prominent role in modern medicine, facilitating better treatments than conventional drugs. Nanomedicine is being increasingly used to develop new methods of cancer diagnosis and treatment, since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs, thereby reducing their toxicity. Regenerative medicine provides another area where innovative drug delivery technology is being studied for improved tissue regeneration. Drug delivery systems can protect therapeutic proteins and peptides against degradation in biological environments and deliver them in a controlled manner. Similarly, the combination of drug delivery systems and stem cells can improve their survival, differentiation, and engraftment. The present review summarizes the most important steps carried-out by the group of Prof Blanco-Prieto in nanomedicine and drug delivery technologies. Throughout her scientific career, she has contributed to the area of nanomedicine to improve anticancer therapy. In particular, nanoparticles loaded with edelfosine, doxorubicin, or methotrexate have demonstrated great anticancer activity in preclinical settings of lymphoma, glioma, and pediatric osteosarcoma. In regenerative medicine, a major focus has been the development of drug delivery systems for brain and cardiac repair. In this context, several microparticle-based technologies loaded with biologics have demonstrated efficacy in clinically relevant animal models such as monkeys and pigs. The latest research by this group has shown that drug delivery systems combined with cell therapy can achieve a more complete and potent regenerative response. Cutting-edge areas such as noninvasive intravenous delivery of cardioprotective nanomedicines or extracellular vesicle-based therapies are also being explored. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Imaging-assisted anticancer nanotherapy.

Cancer nanomedicines are submicrometer-sized formulations designed to improve the biodistribution of anticancer drugs, resulting in less off-target localization, altered toxicity profiles, improved target site accumulation and enhanced efficacy. Together, these beneficial features have resulted in the regulatory approval of about a dozen nanomedicines for the treatment of solid and hematological malignancies. In recent years, significant progress has been made in combining nanomedicines with imaging, to better understand key aspects of the tumor-targeted drug delivery process, and to address the high inter- and intra-individual heterogeneity in the Enhanced Permeability and Retention (EPR) effect. Strategies explored in this regard have included the use of traditional imaging techniques, companion diagnostics and nanotheranostics. Preclinically, integrating imaging in nanomedicine and drug delivery research has enabled the non-invasive and quantitative assessment of nanocarrier biodistribution, target site accumulation and (triggered) drug release. Clinically, imaging has been emerging as a promising tool for patient stratification, which is urgently needed to improve the translation of cancer nanomedicines. We here summarize recent progress in imaging-assisted anticancer nanotherapy and we discuss future strategies to improve the performance of cancer nanomedicines in patients.

Nuclear imaging approaches facilitating nanomedicine translation.

Nanomedicine approaches can effectively modulate the biodistribution and bioavailability of therapeutic agents, improving their therapeutic index. However, despite the ever-increasing amount of literature reporting on preclinical nanomedicine, the number of nanotherapeutics receiving FDA approval remains relatively low. Several barriers exist that hamper the effective preclinical evaluation and clinical translation of nanotherapeutics. Key barriers include insufficient understanding of nanomedicines' in vivo behavior, inadequate translation from murine models to larger animals, and a lack of patient stratification strategies. Integrating quantitative non-invasive imaging techniques in nanomedicine development offers attractive possibilities to address these issues. Among the available imaging techniques, nuclear imaging by positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are highly attractive in this context owing to their quantitative nature and uncontested sensitivity. In basic and translational research, nuclear imaging techniques can provide critical quantitative information about pharmacokinetic parameters, biodistribution profiles or target site accumulation of nanocarriers and their associated payload. During clinical evaluation, nuclear imaging can be used to select patients amenable to nanomedicine treatment. Here, we review how nuclear imaging-based approaches are increasingly being integrated into nanomedicine development and discuss future developments that will accelerate their clinical translation.

Balancing Passive and Active Targeting to Different Tumor Compartments Using Riboflavin-Functionalized Polymeric Nanocarriers.

Riboflavin transporters (RFTs) and the riboflavin carrier protein (RCP) are highly upregulated in many tumor cells, tumor stem cells, and tumor neovasculature, which makes them attractive targets for nanomedicines. Addressing cells in different tumor compartments requires drug carriers, which are not only able to accumulate via the EPR effect but also to extravasate, target specific cell populations, and get internalized by cells. Reasoning that antibodies are among the most efficient targeting systems developed by nature, we consider their size (∼10-15 nm) to be ideal for balancing passive and active tumor targeting. Therefore, small, short-circulating (10 kDa, ∼7 nm, t1/2 ∼ 1 h) and larger, longer-circulating (40 kDa, ∼13 nm, t1/2 ∼ 13 h) riboflavin-targeted branched PEG polymers were synthesized, and their biodistribution and target site accumulation were evaluated in mice bearing angiogenic squamous cell carcinoma (A431) and desmoplastic prostate cancer (PC3) xenografts. The tumor accumulation of the 10 kDa PEG was characterized by rapid intercompartmental exchange and significantly improved upon active targeting with riboflavin (RF). The 40 kDa PEG accumulated in tumors four times more efficiently than the small polymer, but its accumulation did not profit from active RF-targeting. However, RF-targeting enhanced the cellular internalization in both tumor models and for both polymer sizes. Interestingly, the nanocarriers' cell-uptake in tumors was not directly correlated with the extent of accumulation. For example, in both tumor models the small RF-PEG accumulated much less strongly than the large passively targeted PEG but showed significantly higher intracellular amounts 24 h after iv administration. Additionally, the size of the polymer determined its preferential uptake by different tumor cell compartments: the 10 kDa RF-PEGs most efficiently targeted cancer cells, whereas the highest uptake of the 40 kDa RF-PEGs was observed in tumor-associated macrophages. These findings imply that drug carriers with sizes in the range of therapeutic antibodies show balanced properties with respect to passive accumulation, tissue penetration, and active targeting. Besides highlighting the potential of RF-mediated (cancer) cell targeting, we show that strong tumor accumulation does not automatically mean high cellular uptake and that the nanocarriers' size plays a critical role in cell- and compartment-specific drug targeting.

Rediscovering the therapeutic use of glucocorticoids in rheumatoid arthritis.

This review will focus on new information obtained on how to apply glucocorticoids in the treatment of rheumatoid arthritis, aiming at an optimal risk-benefit ratio. Moreover, advances in the development of new preparations such as liposomal glucocorticoids will be discussed. In early rheumatoid arthritis, treatment regimens with a disease-modifying drug and initially medium-dose glucocorticoids (>7.5 but ≤30 mg prednisone equivalent) are noninferior compared with regimens with disease-modifying drugs and initially high-dose glucocorticoids (>30 mg prednisone equivalent) and have repeatedly been proven to be more effective than methotrexate monotherapy. Use of glucocorticoids following such a scheme during a period of 6 months to 2 years was not associated with increased mortality, nor with substantial bone loss if bone protective measures had been taken. New drug delivery systems, and in particular long-circulating liposomes, aiming at enhancing the biodistribution and the target site accumulation of glucocorticoids and thereby improving the balance between their efficacy and toxicity, are promising; more results on the effects in rheumatoid arthritis patients are expected to be reported during the years to come. Combination therapy including methotrexate and glucocorticoids should be the initial treatment in patients with early rheumatoid arthritis. Treatment regimens including medium-dose glucocorticoids are noninferior compared with regimens with initially high-dose glucocorticoids. Studies on new glucocorticoid preparations and new drug delivery systems improving the balance between efficacy and toxicity of glucocorticoid therapy are ongoing.

Nanoparticles for imaging: top or flop?

Nanoparticles are frequently suggested as diagnostic agents. However, except for iron oxide nanoparticles, diagnostic nanoparticles have been barely incorporated into clinical use so far. This is predominantly due to difficulties in achieving acceptable pharmacokinetic properties and reproducible particle uniformity as well as to concerns about toxicity, biodegradation, and elimination. Reasonable indications for the clinical utilization of nanoparticles should consider their biologic behavior. For example, many nanoparticles are taken up by macrophages and accumulate in macrophage-rich tissues. Thus, they can be used to provide contrast in liver, spleen, lymph nodes, and inflammatory lesions (eg, atherosclerotic plaques). Furthermore, cells can be efficiently labeled with nanoparticles, enabling the localization of implanted (stem) cells and tissue-engineered grafts as well as in vivo migration studies of cells. The potential of using nanoparticles for molecular imaging is compromised because their pharmacokinetic properties are difficult to control. Ideal targets for nanoparticles are localized on the endothelial luminal surface, whereas targeted nanoparticle delivery to extravascular structures is often limited and difficult to separate from an underlying enhanced permeability and retention (EPR) effect. The majority of clinically used nanoparticle-based drug delivery systems are based on the EPR effect, and, for their more personalized use, imaging markers can be incorporated to monitor biodistribution, target site accumulation, drug release, and treatment efficacy. In conclusion, although nanoparticles are not always the right choice for molecular imaging (because smaller or larger molecules might provide more specific information), there are other diagnostic and theranostic applications for which nanoparticles hold substantial clinical potential.

Absorption reconstruction improves biodistribution assessment of fluorescent nanoprobes using hybrid fluorescence-mediated tomography.

Aim: Fluorescence-mediated tomography (FMT) holds potential for accelerating diagnostic and theranostic drug development. However, for proper quantitative fluorescence reconstruction, knowledge on optical scattering and absorption, which are highly heterogeneous in different (mouse) tissues, is required. We here describe methods to assess these parameters using co-registered micro Computed Tomography (µCT) data and nonlinear whole-animal absorption reconstruction, and evaluate their importance for assessment of the biodistribution and target site accumulation of fluorophore-labeled drug delivery systems.Methods: Besides phantoms with varying degrees of absorption, mice bearing A431 tumors were imaged 15 min and 48 h after i.v. injection of a fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) using µCT-FMT. The outer shape of mice and a scattering map were derived using automated segmentation of the µCT data. Furthermore, a 3D absorption map was reconstructed from the trans-illumination data. We determined the absorption of five interactively segmented regions (heart, liver, kidney, muscle, tumor). Since blood is the main near-infrared absorber in vivo, the absorption was also estimated from the relative blood volume (rBV), determined by contrast-enhanced µCT. We compared the reconstructed absorption with the rBV-based values and analyzed the effect of using the absorption map on the fluorescence reconstruction.Results: Phantom experiments demonstrated that absorption reconstruction is possible and necessary for quantitative fluorescence reconstruction. In vivo, the reconstructed absorption showed high values in strongly blood-perfused organs such as the heart, liver and kidney. The absorption values correlated strongly with the rBV-based absorption values, confirming the accuracy of the absorption reconstruction. Usage of homogenous absorption instead of the reconstructed absorption map resulted in reduced values in the heart, liver and kidney, by factors of 3.5, 2.1 and 1.4, respectively. For muscle and subcutaneous tumors, which have a much lower rBV and absorption, absorption reconstruction was less important.Conclusion: Quantitative whole-animal absorption reconstruction is possible and can be validated in vivo using the rBV. Usage of an absorption map is important when quantitatively assessing the biodistribution of fluorescently labeled drugs and drug delivery systems, to avoid a systematic underestimation of fluorescence in strongly absorbing organs, such as the heart, liver and kidney.

Noninvasive Optical Imaging of Nanomedicine Biodistribution

Nanomedicines are sub-micrometer-sized carrier materials designed to improve the biodistribution of i.v. administered (chemo-) therapeutic agents. In recent years, ever more efforts in the nanomedicine field have employed optical imaging (OI) techniques to monitor biodistribution and target site accumulation. Thus far, however, the longitudinal assessment of nanomedicine biodistribution using OI has been impossible, due to limited light penetration (in the case of 2D fluorescence reflectance imaging; FRI) and to the inability to accurately allocate fluorescent signals to nonsuperficial organs (in the case of 3D fluorescence molecular tomography; FMT). Using a combination of high-resolution microcomputed tomography (μCT) and FMT, we have here set out to establish a hybrid imaging protocol for noninvasively visualizing and quantifying the accumulation of near-infrared fluorophore-labeled nanomedicines in tissues other than superficial tumors. To this end, HPMA-based polymeric drug carriers were labeled with Dy750, their biodistribution and tumor accumulation were analyzed using FMT, and the resulting data sets were fused with anatomical μCT data sets in which several different physiologically relevant organs were presegmented. The robustness of 3D organ segmentation was validated, and the results obtained using 3D CT-FMT were compared to those obtained upon standard 3D FMT and 2D FRI. Our findings convincingly demonstrate that combining anatomical μCT with molecular FMT facilitates the noninvasive assessment of nanomedicine biodistribution.

Nanotheranostics: combining non-invasive imaging with tumor-targeted drug delivery to individualize (chemo-) therapeutic interventions

Nanomedicine formulations aim to improve the biodistribution and the target site accumulation of systemically administered (chemo-) therapeutic agents. Various different passively and actively targeted nanomedicines have been evaluated over the years, based e.g. on liposomes, polymers, micelles and antibodies, and a significant amount of (pre-) clinical evidence has been obtained showing that these 5–200 nm-sized carrier materials are able to improve the therapeutic index of low-molecular-weight drugs. Besides for therapeutic purposes, however, nanomedicine formulations have also been more and more used for imaging applications, as well as, in recent years, for theranostic approaches, i.e. for systems and strategies in which disease diagnosis and therapy are combined. Potential applications of theranostic nanomedicine formulations range from the noninvasive assessment of the biodistribution and the target site accumulation of low-molecular-weight drugs, and the visualization of drug distribution and drug release at the target site, to the optimization of strategies relying on triggered drug release, and the prediction and real-time monitoring of therapeutic responses. Nanotheranostic systems are consequently considered to be highly suitable systems for (pre-) clinical implementation, not only because they might assist in better understanding various important aspects of the drug delivery process, and in developing better drug delivery systems, but also because they might contribute to realizing the potential of “personalized medicine”, and to establishing more effective and less toxic treatment regimens for individual patients.

Overcoming cellular multidrug resistance using classical nanomedicine formulations

Over the past few decades, many different types of nanomedicines have been evaluated, both in vitro and in vivo. In general, nanomedicines are designed to improve the in vivo properties of low-molecular-weight (chemo-) therapeutic drugs, i.e. their biodistribution and the target site accumulation, and to thereby improve the balance between their efficacy and toxicity. A significant number of studies have also addressed the in vitro properties of nanomedicines, showing e.g. their ability to overcome cellular multidrug resistance (MDR). Particularly promising results in this regard have been reported for ‘pharmacologically active’ carrier materials, such as Pluronics, which are able to directly inhibit drug efflux pumps and other cellular detoxification mechanisms. In the present report, we have set out to evaluate the ability of classical (and pharmacologically inactive) carrier materials to overcome MDR. To this end, four different drug-sensitive and drug-resistant cancer cell lines were treated with increasing concentrations of free doxorubicin, of polymer-bound doxorubicin, of micellar doxorubicin and of liposomal doxorubicin, and resistance indices (IC50 in resistant cells/IC50 in sensitive cells) were determined. In addition, the cellular uptake of the four formulations was evaluated using fluorescence microscopy. It was found that the carrier materials did manage to overcome MDR to some extent, but that the overall benefit was quite small; only for polymer-bound doxorubicin in A431 cells, a significant (4-fold) reduction in the resistance index was observed. These findings indicate that the ability of classical nanomedicines to overcome cellular MDR should not be overestimated.