Clinical Translation Of Nanomedicine Research Articles

Meta-Analysis of Nanoparticle Delivery to Tumors Using a Physiologically Based Pharmacokinetic Modeling and Simulation Approach.

Numerous studies have engineered nanoparticles with different physicochemical properties to enhance the delivery efficiency to solid tumors, yet the mean and median delivery efficiencies are only 1.48% and 0.70% of the injected dose (%ID), respectively, according to a study using a nonphysiologically based modeling approach based on published data from 2005 to 2015. In this study, we used physiologically based pharmacokinetic (PBPK) models to analyze 376 data sets covering a wide range of nanomedicines published from 2005 to 2018 and found mean and median delivery efficiencies at the last sampling time point of 2.23% and 0.76%ID, respectively. Also, the mean and median delivery efficiencies were 2.24% and 0.76%ID at 24 h and were decreased to 1.23% and 0.35%ID at 168 h, respectively, after intravenous administration. While these delivery efficiencies appear to be higher than previous findings, they are still quite low and represent a critical barrier in the clinical translation of nanomedicines. We explored the potential causes of this poor delivery efficiency using the more mechanistic PBPK perspective applied to a subset of gold nanoparticles and found that low delivery efficiency was associated with low distribution and permeability coefficients at the tumor site (P < 0.01). We also demonstrate how PBPK modeling and simulation can be used as an effective tool to investigate tumor delivery efficiency of nanomedicines.

The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs.

The regulatory approval of Onpattro, a lipid nanoparticle-based short interfering RNA drug for the treatment of polyneuropathies induced by hereditary transthyretin amyloidosis, paves the way for clinical development of many nucleic acid-based therapies enabled by nanoparticle delivery.

Abstract 3899: Nanoparticle reduces hepatotoxicity of cancer treatment by controlled release and Kupffer cell uptake

Abstract Background: One of the major concerns in cancer treatment and clinical translation of many anti-cancer compounds has been their potential toxicities, especially hepatotoxicity. Nanoparticle (NP) holds great potential to solve the problem, as many clinical studies have not shown increased hepatotoxicity for nanotherapeutics with higher accumulation in the liver. However, there are few studies investigating how nanoparticle assists in reducing hepatotoxicity. Herein, we demonstrated that nanoformulation of known hepatotoxic anti-cancer compounds showed lower hepatotoxicity than their small molecule counterparts. Importantly, we demonstrated that slower drug release is associated with reduced hepatotoxicity. We also showed that that Kupffer cell uptake in the liver reduce nanotherapeutics’ hepatotoxicity. Methods: Two different antineoplastic drugs with high hepatotoxicity, SN-38 and wortmannin (Wtmn), were encapsulated into lipid shell-PLGA core nanoparticles separately. NP release kinetics were controlled by adjusting lipids/polymer ratio for fast (Fast-NPs), medium (Medium-NPs) and slow drug release profile (Slow-NPs), respectively. Hepatotoxicity of NPs or free drugs was analyzed by assessing serum ALT and AST levels post intravenous injection at ½ MTD in CD-1 mice. IHC staining of HO-1 and Mn-SOD was also used to show liver damage. In vitro hepatotoxicity of primary hepatocytes after Kupffer cell uptake was assessed by MTS assay and LDH assay. In vivo macrophage depletion was achieved using clodrosome. Results: Nanoformulations of SN-38 and Wtmn showed lower ALT and AST levels than their small molecule counterparts 12 h and 24 h post treatment. The liver damage was further confirmed with IHC staining of Mn-SOD and HO-1. To address the effect of drug release kinetics on hepatotoxicity, we showed that over 90% of drugs were released within 24 h in Fast-NP. While the release rate of Slow-NPs was 66.8% for SN-38 and 67.5% for Wtmn. We showed that Slow-NPs of Wtmn resulted in minimal increase of ALT and AST levels. Compared to the baseline in untreated mice, the ALT level was 2.3-fold for Slow-NPs, 4.4-fold for Medium-NPs and 6-fold for fast-NPs; meanwhile, the AST level was 1.6-fold, 2.5-fold and 3.6-fold, respectively. To assess the effect of Kupffer cell uptake in hepatotoxicity, we found that the toxicity of the nanotherapeutics for primary hepatocytes significantly reduced after Kupffer cell uptake in vitro. We further confirmed it in vivo by depleting Kupffer cells in CD-1 mice. We demonstrated that ALT and AST levels of nanotherapeutics significantly increased to the levels comparable to free drugs after Kupffer cell depletion. Conclusions: We demonstrate that nanoparticle reduces hepatotoxicity of cancer treatment by controlled release and Kupffer cell uptake. Our work bridges an important knowledge in nanoparticle drug delivery and clinical translation of nanomedicine. Citation Format: Yu Mi, Feifei Yang, Andrew Z. Wang. Nanoparticle reduces hepatotoxicity of cancer treatment by controlled release and Kupffer cell uptake [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3899.

Encapsulating maytansinoid in pH-sensitive nanocarriers: The importance of using extremely potent cytotoxic agents and fast release for nanomedicine to achieve tumor elimination

The clinical translation of nanomedicine is hindered by the low delivery efficiency, and consequently drug concentration in tumor sites falls short of the therapeutic effective range which leads to poor clinical outcomes. One important lesson learned from the development of antibody-drug-conjugates (ADCs) is that to achieve significant clinical benefits, extremely potent cytotoxic agents and cleavable linkers should be used. By encapsulating maytansinoid, AP3, which is 100–1,000 times more potent than most conventional small molecule anticancer drugs, in pH-sensitive acetalated dextran-polyethylene glycol (PEG) (ADP) nanocarriers, even with only 1% drug loading, we were able to eradicate tumors in 50% of tested animals with negligible side effects, while free AP3 only showed marginal efficacy and severe liver damages. This study suggests that besides improving the low efficiency of nano-delivery systems, the potency of drug to be delivered is also critical to the clinical outcomes of nanomedicine. Our results also showed that ADP nanoparticles (NPs) were able to expand the narrow therapeutic window of maytansinoids in a similar manner to the ADCs.

Understanding the Chemical Nature of Nanoparticle-Protein Interactions.

The formation of a protein corona has been considered a pitfall in the clinical translation of nanomedicines. Hence, interdisciplinary studies on corona characterization are critically essential. A deep understanding of the formation of hard and soft protein coronas upon in vivo administration of nanoparticles is vital. The protein corona gives the nanoplatform a new biological identity. Furthermore, the control of and mechanistic understanding of corona formation as it is regulated by the physicochemical properties of nanoparticles is crucial for developing safe nanomedicines. A growing number of analytical techniques have been developed in the past decade for examining NP-protein interactions, contributing to a better understanding of protein corona formation on the surface of nanoparticles. In this Review, we summarize the latest developments in the in vivo and in vitro study of dynamic protein corona formation. Insights derived from techniques used to visualize, quantify, and define protein coronas, as well as the methods for examining the kinetics and structural changes of coronal proteins, are discussed. The potential challenges and future perspectives in the study of protein corona formation and its effects on biological behavior and applications of therapeutic nanomaterials are also provided.

Alliance with EPR Effect: Combined Strategies to Improve the EPR Effect in the Tumor Microenvironment.

The use of nanomedicine for cancer treatment takes advantage of its preferential accumulation in tumors owing to the enhanced permeability and retention (EPR) effect. The development of cancer nanomedicine has promised highly effective treatment options unprecedented by standard therapeutics. However, the therapeutic efficacy of passively targeted nanomedicine is not always satisfactory because it is largely influenced by the heterogeneity of the intensity of the EPR effect exhibited within a tumor, at different stages of a tumor, and among individual tumors. In addition, limited data on EPR effectiveness in human hinders further clinical translation of nanomedicine. This unsatisfactory therapeutic outcome in mice and humans necessitates novel approaches to improve the EPR effect. This review focuses on current attempts at overcoming the limitations of traditional EPR-dependent nanomedicine by incorporating supplementary strategies, such as additional molecular targeting, physical alteration, or physiological remodeling of the tumor microenvironment. This review will provide valuable insight to researchers who seek to overcome the limitations of relying on the EPR effect alone in cancer nanomedicine and go “beyond the EPR effect”.

Ultrasmall Noble Metal Nanoparticles: Breakthroughs and Biomedical Implications.

As a bridge between individual atoms and large plasmonic nanoparticles, ultrasmall (core size <3 nm) noble metal nanoparticles (UNMNPs) have been serving as model for us to fundamentally understand many unique properties of noble metals that can only be observed at an extremely small size scale. With decades'efforts, many significant breakthroughs in the synthesis, characterization and functionalization of UNMNPs have laid down a solid foundation for their future applications in the healthcare. In this review, we aim to tightly correlate these breakthroughs with their biomedical applications and illustrate how to utilize these breakthroughs to address long-standing challenges in the clinical translation of nanomedicines. In the end, we offer our perspective on the remaining challenges and opportunities at the frontier of biomedical-related UNMNPs research.

Clinical translation of nanomedicine: New opportunities in image-guided cancer diagnostics and surgery

Clinical translation of nanomedicine: New opportunities in image-guided cancer diagnostics and surgery

Phytochemicals as Dynamic Surface Ligands To Control Nanoparticle-Protein Interactions.

The rapid formation of the protein corona on to the nanoparticle (NP) surface is the key that confers biological identity to NPs and subsequently dictates their fate both in vitro and in vivo. Despite significant efforts, the inability to control the spontaneous interaction of serum proteins with the administered NPs remains a major constraint in clinical translation of nanomedicines. The ligands present on the NP surface offer promise in controlling their biological interactions; however, their influence on the NP–protein interaction is not well-understood. The current study investigates the potential of phytochemical-capped silver nanoparticles (AgNPs) toward allowing a control over NP interactions with the human serum albumin (HSA), the most abundant protein in the biological fluids. Specifically, we demonstrate the ability of curcumin (Cur) and epigallocatechin-3-gallate (EGCG) to independently act as reducing agents to produce phytochemical-capped AgNPs that show biologically desirable interactions with HSA. The key finding of our study is that the phytochemical-capped AgNPs initially interact with HSA more strongly compared to the citrate-stabilized AgNPs; however, the resultant NP–HSA complexes are less stable in the case of the former, which causes a lesser degree of changes in the protein conformation during interactions. Further, the choice of the phytochemical allows control over NP–HSA interactions, such that Cur- and EGCG-capped AgNPs interacted with HSA in a static versus dynamic manner, respectively. The diversity of the functional groups present in natural phytochemicals and their potential as in situ capping ligands during synthesis offer new opportunities in controlling the interactions of NPs with complex biological fluids, with implications in nanodiagnostics and nanomedicine.

Current developments and applications of microfluidic technology toward clinical translation of nanomedicines.

Nanoparticulate drug delivery systems hold great potential for the therapy of many diseases, especially cancer. However, the translation of nanoparticulate drug delivery systems from academic research to industrial and clinical practice has been slow. This slow translation can be ascribed to the high batch-to-batch variations and insufficient production rate of the conventional preparation methods, and the lack of technologies for rapid screening of nanoparticulate drug delivery systems with high correlation to the in vivo tests. These issues can be addressed by the microfluidic technologies. For example, microfluidics can not only produce nanoparticles in a well-controlled, reproducible, and high-throughput manner, but also create 3D environments with continuous flow to mimic the physiological and/or pathological processes. This review provides an overview of the microfluidic devices developed to prepare nanoparticulate drug delivery systems, including drug nanosuspensions, polymer nanoparticles, polyplexes, structured nanoparticles and theranostic nanoparticles. We also highlight the recent advances of microfluidic systems in fabricating the increasingly realistic models of the in vivo milieu for rapid screening of nanoparticles. Overall, the microfluidic technologies offer a promise approach to accelerate the clinical translation of nanoparticulate drug delivery systems.

Research advances in gold nanoparticle-mediated tumor radiosensitization

Nanotechnology has been extensively applied in the diagnosis and treatment of cancer, and is currently a major focus of research worldwide. Among the various nanomaterials, gold nanoparticles (GNPs) are of particular interest to many researchers due to their superior properties of low cytotoxicity, good biocompatibility, and preferential accumulation in tumors (the enhanced permeability and retention effect), which in turn gives GNPs a potential application in cancer diagnostics, imaging, photothermal therapy, and radiotherapy. Many published studies have shown that GNPs can be used as a new ideal radiosensitizer, and therefore understanding the radiosensitizing effects of GNPs both in vitro and in vivo will be of great significance in the clinical translation of nanomedicine. Key words: Gold nanoparticles; Physical properties; Radiosensitization; Clinical application

Abstract 174: Preclinical activity of new liposomal formulation of doxorubicin (TLD-1)

Abstract Background: InnoMedica is a young company with focus on clinical translation of nanomedicine. The company employs its own manufacturing technology that gives rise to a novel liposome platform. The platform allows for specific shaping of nanosurfaces. This leads to a myriad of different particle designs with highly distinct biological functions. In a first approach, the lead-formulation TLD-1 (targeted liposomal doxorubicin) was developed in order to ameliorate chemotherapeutic outcome for patients, taking into account the patterns of biodistribution in the entire organism as well as nanoparticle-cell interactions and subcellular localisation. Methods: Pharmacologic properties of TLD-1 were investigated in vitro and in vivo. Human ovarian cancer cells A2780 were cultured in both 2D and 3D settings and antineoplastic activity of different formulations of doxorubicin was measured by quantification of cell viability. The same formulations were also compared in three animal models of cancer including murine breast cancer 4T1, human breast cancer MDA-MB231, and A2780. MDA-MB231 and A2780 cells were grown in vitro and injected subcutaneously (sc) in immunodeficient mice (Athymic Nude-Foxn1nu). 4T1 cells were injected either sc or in the mammary fat pad of immunocompetent mice (BALB/c). The different drug products were injected intravenously twice weekly for a total of three weeks. Activity was determined with caliper measurements of tumor diameters every three days. Animal body weight was recorded as index of toxicity. Doxorubicin was determined in plasma and tissues by HPLC-MS. Results: In 2D and 3D cell culture assays, TLD-1 showed a marked increase in cytotoxicity compared to Caelyx and was close to free drug. In all three animal models, TLD-1 showed activity superior to that of free doxorubicin given at the same dose and compared well to Caelyx both in terms of activity and toxicity. Conclusions: A couple of nanoparticulate features of TLD-1 liposomes are believed to attribute to the difference in antitumor activity. Cytotoxicity data from cell culture experiments indicate that TLD-1 liposomes are readily taken up by cancer cells and release their drug load into the cytoplasm. Commercial liposomes as in Caelyx seem to largely remain outside of cancer cells. In sum, TLD-1 is a novel and highly active antineoplastic nanodrug that has the potential to outperform free drug as well as commercial liposomal formulations of doxorubicin. Citation Format: Massimo Broggini, Federica Guffanti, Roberta Affatato, Lavinia Morosi, Patrick Buschor, Christoph Matthieu, Florian Weiss, Andreas Konig, Peter Halbherr, Stefan Halbherr. Preclinical activity of new liposomal formulation of doxorubicin (TLD-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 174. doi:10.1158/1538-7445.AM2017-174

Strategies for Preparing Albumin-based Nanoparticles for Multifunctional Bioimaging and Drug Delivery.

Biosafety is the primary concern in clinical translation of nanomedicine. As an intrinsic ingredient of human blood without immunogenicity and encouraged by its successful clinical application in Abraxane, albumin has been regarded as a promising material to produce nanoparticles for bioimaging and drug delivery. The strategies for synthesizing albumin-based nanoparticles could be generally categorized into five classes: template, nanocarrier, scaffold, stabilizer and albumin-polymer conjugate. This review introduces approaches utilizing albumin in the preparation of nanoparticles and thereby provides scientists with knowledge of goal-driven design on albumin-based nanomedicine.

Microfluidics in Nanomedicine

Nanomedicine is the medical application of nanotechnology for the treatment and prevention of major ailments, including cancer and cardiovascular diseases. Despite the progress and potential of nanomedicines, many such materials fail to reach clinical trials due to critical challenges that include poor reproducibility in high-volume production that have led to failure in animal studies and clinical trials. Recent approaches using microfluidic technology have provided emerging platforms with great potential to accelerate the clinical translation of nanomedicine. Microfluidic technologies for nanomedicine development are reviewed in this chapter, together with a detailed discussion of microfluidic assembly, characterization and evaluation of nanomedicine, and a description of current challenges and future prospects. Keywords: microfluidics; nanotechnology; nanomedicine; biomimetic microsystem; clinical translation

Clinical Translation of Nanomedicine

Clinical Translation of Nanomedicine