Targeted Drug Delivery Efficiency Research Articles

Tumor Microenvironment ROS/pH Cascade-Responsive Supramolecular Nanoplatform with ROS Regeneration Property for Enhanced Hepatocellular Carcinoma Therapy.

The low targeted drug delivery efficiency, including poor tumor accumulation and penetration and uncontrolled drug release, leads to the failure of cancer therapy. Herein, a multifunctional supramolecular nanoplatform loading triptolide (TPL/PBAETK@GA NPs) was fabricated via the host-guest interaction between glycyrrhetinic-acid-modified poly(ethylene glycol)-adamantanecarboxylic acid moiety and reactive oxygen species (ROS)/pH cascade-responsive copolymer poly(β-amino esters)-thioketal (TK)-β-cyclodextrin. TPL/PBAETK@GA NPs could accumulate in hepatocellular carcinoma (HCC) tissue effectively, mediated by nanoscale advantage and GA' recognition to specific receptors. The elevated concentration of ROS in tumor microenvironment (TME) quickly breaks the TK linkages, causing the detachment of shell (cyclodextrin) CD layer. Then, the accompanying negative-to-positive charge-reversal of NPs was realized via the PBAE moiety protonation under the slightly acidic TME, significantly enhancing the NPs' cellular internalization. Remarkably, the pH-responsive endo/lysosome escape of PBAE core triggered intracellular TPL burst release, promoting the cancer cell apoptosis, autophagy, and intracellular ROS generation, leading to the self-amplification of ROS in TME. Afterward, the ROS positive-feedback loop was generated to further promote size-shrinkage and charge-reversal of NPs. Both in vitro and in vivo tests verified that TPL/PBAETK@GA NPs produced a satisfactory anti-HCC therapy outcome. Collectively, this study offers a potential appealing paradigm to enhance TPL-based HCC therapy outcomes via multifunctionalized supramolecular nanodrugs.

Collapsing behavior of spark-induced cavitation bubble in rigid tube

The phenomenon of cavitation within tubes is a common scenario in the fields of medicine and industry. This paper focuses on the effects of rigid circular tube length, diameter and the distance of bubble - tube port on the behavior of bubble in tube. The low-voltage discharge technique was utilized to induce a cavitation bubble in deionized water. The effects of rigid tube lengths, diameters, and bubble-tube port distances on the morphology of bubbles are observed using high-speed camera. It has been found that as the length of the rigid tube increases, so does the period, and this effect is more pronounced in tubes with smaller diameters. Conversely, the cavitation bubble period decreased and then stabilized as the tube diameter increased, the ratio of tube radius and the bubble radius exceeds 4.8, the period of bubble in tube is similar to that of bubble in free field. Further analysis of the influence of tube characteristics on microjets reveals that a pair of oppositely microjets were formed along the tube axis by the bubble near the midpoint of the tube axis. Moreover, when the non-dimensional tube length η < 3.5, the increase tube diameter results in a decrease microjet velocity. It has also been observed that as the bubble gradually approaches the interior of the tube, the velocity of microjets directed inward decreases. Additionally, the smaller the diameter of the tube, the greater the bubble-tube port distance required for the microjets to reach the same level of velocity as bubble near the center of the tube axis. These findings hold theoretical implications for improvement of targeted drug delivery efficiency in medicine and enhance the operational efficiency of inertial micropumps in industries.

A neutrophil-mediated carrier regulates tumor stemness by inhibiting autophagy to prevent postoperative triple-negative breast cancer recurrence and metastasis

Recurrence and metastasis after resection are still the main challenges in clinical treatment of breast cancer. Residual tumor and cancer stem-like cells are the primary culprits of recurrence and metastasis. Recent research studies indicate that autophagy is a cytoprotective mechanism of tumors, which maintains the stemness of cancer cells and promotes tumor proliferation and metastasis. Here, we constructed a “Trojan horse” using neutrophils as the carrier (PH-RL@NEs) to prevent the recurrence and metastasis of postoperative breast cancer. Neutrophils, as a “Trojan horse,” can quickly respond to postoperative inflammation and accurately deliver drugs to the residual tumor site. The inflammation-triggered “Trojan horse” was then opened to release the liposomes containing the chemotherapeutic drug paclitaxel (PTX) and the autophagy inhibitor hydroxychloroquine (HCQ). We found that HCQ could effectively inhibit tumor cell autophagy, interfere with tumor epithelial-mesenchymal transition, and reduce the tumor stem cell-like population. In the orthotopic 4T1 postoperative recurrence models, PTX and HCQ synergistically killed tumors and regulated the stemness of tumor cells, thereby significantly inhibiting tumor recurrence and metastasis. Our work proved that the inhibition of autophagy to reduce tumor stemness is feasible and effective, which opens up a new prospect for postoperative tumor treatment. Statement of significanceThe present study aimed to solve the issues of postoperative recurrence and metastasis of breast cancer and low efficiency of drug administration after surgery. For this purpose, we constructed neutrophils containing hydroxychloroquine (HCQ) and paclitaxel (PTX) co-loaded liposomes (PH-RL@NEs), which for the first time regulated the stemness of tumor cells by inhibiting autophagy, thereby inhibiting postoperative recurrence and metastasis of breast cancer cells. The results showed that PH-RL@NEs enhanced the targeted drug delivery efficiency, with the help of postoperative inflammation chemotaxis of neutrophils. HCQ effectively inhibited autophagy of tumor cells and reduced tumor stem cell-like cells, thus improving the therapeutic effect in the 4T1 in situ postoperative recurrence model.

Prediction of airway deformation effect on pulmonary air-particle dynamics: A numerical study

Most existing whole lung models neglect the airway deformation kinematics and assume the lung airways are static. However, neglecting the airway deformation effect on pulmonary air-particle flow dynamics significantly limits the modeling capability under disease-specific lung conditions. Therefore, a novel elastic truncated whole-lung (TWL) modeling framework has been developed to simulate the disease-specific airway deformation kinematics simultaneously with pulmonary air-particle flow dynamics using one-way coupled Euler–Lagrange method plus the dynamic mesh method. Specifically, the deformation kinematics of the elastic TWL model was calibrated with clinical data and pulmonary function test results for both healthy lung and lungs with chronic obstructive pulmonary diseases (COPDs). The transport dynamics of spherical sub micrometer and micrometer particles were investigated. Results show that noticeable differences in air-particle flow predictions between static and elastic lung models can be found, which demonstrates the necessity to model airway deformation kinematics in whole-lung models. The elastic TWL model predicted lower deposition fraction in mouth-throat regions and higher deposition fraction in lower airways. The effect of disease-specific airway deformation kinematics on particle transport and deposition in the whole lung was investigated, with a focus on the targeted drug delivery efficiency in small airways from generation (G8) to alveoli as the designated lung sites for COPD treatment using inhalation therapy. Simulation results indicate that with the exacerbation of COPD disease conditions, the highest delivery efficiency of the inhaled drug particles decreases which indicates that delivering aerosolized medications to small airways to treat COPD is more challenging for patients with severe disease conditions.

Flow topology and targeted drug delivery in cardiovascular disease

Targeted drug delivery is a promising technique to direct the drug to the specific diseased region. Nanoparticles have provided an attractive approach for this purpose. In practice, the major focus of targeted delivery has been on targeting cell receptors. However, the complex fluid mechanics in diseased biomedical flows questions if a sufficient number of nanoparticles can reach the desired region. In this paper, we propose that hidden topological structures in cardiovascular flows identified with Lagrangian coherent structures (LCS) control drug transport and provide valuable information for optimizing targeted drug delivery efficiency. We couple image-based computational fluid dynamics (CFD) with continuum transport models to study nanoparticle transport in coronary artery disease. We simulate nanoparticle transport as well as the recently proposed shear targeted drug delivery system that couples micro-carriers with nanoparticle drugs. The role of the LCS formed near the stenosed artery in controlling drug transport is discussed. Our results motivate the design of smart micro-needles guided by flow topology, which could achieve optimal drug delivery efficiency.

Novel nanococktail of a dual PI3K/mTOR inhibitor and cabazitaxel for castration-resistant prostate cancer.

Prognosis of castration-resistant prostate cancer (CRPC) carries is poor, and no effective therapeutic regimen is yet known. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway played a predominant role and may be a promising molecular target for CRPC. However, the toxicity of the dual PI3K inhibitors in clinical trials limits their clinical efficacy for CRPC. To solve this problem, we employed a highly integrated precision nanomedicine strategy to molecularly and physically target CRPC through synergistic effects, enhanced targeted drug delivery efficiency, and reduced unwanted side-effects. Gedatolisib (Ge), a potent inhibitor of PI3K/mTOR, was formulated into our disulfied-crosslinked micelle plateform (NanoGe), which exhibits excellent water solubility, small size (23.25±2 nm), excellent stability with redox stimulus-responsive disintegration, and preferential uptake at tumor sites. NanoGe improved the anti-neoplastic effect of free Ge by 53 times in PC-3M cells and 13 times in C4-2B cells though its enhanced uptake via caveolae- and clathrin-mediated endocytic pathways and the subsequent inhibition of the PI3K/mTOR pathway, resulting in Bax/Bcl-2 dependent apoptosis. In an animal xenograft model, NanoGe showed superior efficacy than free Ge, and synergized with nanoformulated cabazitaxel (NanoCa) as a nanococktail format to achieve a cure rate of 83%. Taken together, our results demonstrate the potency of NanoGe in combination with NanoCa is potent against prostate cancer.

Biomedical Micro-/Nanomotors: From Overcoming Biological Barriers to In Vivo Imaging.

Self-propelled micro- and nanomotors (MNMs) have shown great potential for applications in the biomedical field, such as active targeted delivery, detoxification, minimally invasive diagnostics, and nanosurgery, owing to their tiny size, autonomous motion, and navigation capacities. To enter the clinic, biomedical MNMs request the biodegradability of their manufacturing materials, the biocompatibility of chemical fuels or externally physical fields, the capability of overcoming various biological barriers (e.g., biofouling, blood flow, blood-brain barrier, cell membrane), and the in vivo visual positioning for autonomous navigation. Herein, the recent advances of synthetic MNMs in overcoming biological barriers and in vivo motion-tracking imaging techniques are highlighted. The challenges and future research priorities are also addressed. With continued attention and innovation, it is believed that, in the future, biomedical MNMs will pave the way to improve the targeted drug delivery efficiency.

Helium-Oxygen Mixture Model for Particle Transport in CT-Based Upper Airways.

The knowledge of respiratory particle transport in the extra-thoracic pathways is essential for the estimation of lung health-risk and optimization of targeted drug delivery. The published literature reports that a significant fraction of the inhaled aerosol particles are deposited in the upper airways, and available inhalers can deliver only a small amount of drug particles to the deeper airways. To improve the targeted drug delivery efficiency to the lungs, it is important to reduce the drug particle deposition in the upper airways. This study aims to minimize the unwanted aerosol particle deposition in the upper airways by employing a gas mixture model for the aerosol particle transport within the upper airways. A helium–oxygen (heliox) mixture (80% helium and 20% oxygen) model is developed for the airflow and particle transport as the heliox mixture is less dense than air. The mouth–throat and upper airway geometry are extracted from CT-scan images. Finite volume based ANSYS Fluent (19.2) solver is used to simulate the airflow and particle transport in the upper airways. Tecplot software and MATLAB code are employed for the airflow and particle post-processing. The simulation results show that turbulence intensity for heliox breathing is lower than in the case of air-breathing. The less turbulent heliox breathing eventually reduces the deposition efficiency (DE) at the upper airways than the air-breathing. The present study, along with additional patient-specific investigation, could improve the understanding of particle transport in upper airways, which may also increase the efficiency of aerosol drug delivery.

Targeted Exosomes for Drug Delivery: Biomanufacturing, Surface Tagging, and Validation.

Exosomes hold great potential to deliver therapeutic reagents for cancer treatment due to its inherent low antigenicity. However, several technical barriers, such as low productivity and ineffective cancer targeting, need to be overcome before wide clinical applications. The present study aims at creating a new biomanufacturing platform of cancer-targeted exosomes for drug delivery. Specifically, a scalable, robust, high-yield, cell line based exosome production process is created in a stirred-tank bioreactor, and an efficient surface tagging technique is developed to generate monoclonal antibody (mAb)-exosomes. The in vitro characterization using transmission electron microscopy, NanoSight, and western blotting confirm the high quality of exosomes. Flow cytometry and confocal laser scanning microscopy demonstrate that mAb-exosomes have strong surface binding to cancer cells. Furthermore, to validate the targeted drug delivery efficiency, romidepsin, a histone deacetylase inhibitor, is loaded into mAb-exosomes. The in vitro anti-cancer toxicity study shows high cytotoxicity of mAb-exosome-romidepsin to cancer cells. Finally, the in vivo study using tumor xenograft animal model validates the cancer targeting specificity, anti-cancer efficacy, and drug delivery capability of the targeted exosomes. In summary, new techniques enabling targeted exosomes for drug delivery are developed to support large-scale animal studies and to facilitate the translation from research to clinics.

Enhanced cancer therapy with pH-dependent and aptamer functionalized doxorubicin loaded polymeric (poly D, L-lactic-co-glycolic acid) nanoparticles

Aptamer based drug delivery systems are gaining the importance in anticancer therapy due to their targeted drug delivery efficiency without harming the normal cells. The present work formulated the pH-dependent aptamer functionalized polymer-based drug delivery system against human lung cancer. The prepared aptamer functionalized doxorubicin (DOX) loaded poly (D, L-lactic-co-glycolic acid) (PLGA), poly (N-vinylpyrrolidone) (PVP) nanoparticles (APT-DOX-PLGA-PVP NPs) were spherical in shape with an average size of 87.168 nm. The crystallography and presence of the PLGA (poly (D, L-lactic-co-glycolic acid)) and DOX (doxorubicin) in APT-DOX-PLGA-PVP NPs were indicated by the X-ray diffraction (XRD), Fourier transforms infrared spectroscopy (FTIR), and 1H and 13C nuclear magnetic resonance spectrometer (NMR). The pH-dependent aptamer AS1411 based drug release triggered the cancer cell death was evidenced by cytotoxicity assay, flow cytometry, and fluorescent microscopic imaging. In addition, the cellular uptake of the DOX was determined and the apoptosis-related signaling pathway in the A549 cells was studied by Western blot analysis. Further, the in vivo study revealed that mice treated with APT-DOX-PLGA-PVP NPs were significantly recovered from cancer as evident by mice weight and tumor size followed by the histopathological study. It was reported that the APT-DOX-PLGA-PVP NPs induced the apoptosis through the activation of the apoptosis-related proteins. Hence, the present study revealed that the APT-DOX-PLGA-PVP NPs improved the therapeutic efficiency through the nucleolin receptor endocytosis targeted drug release.

Quantitative Deep Tissue Imaging of Target Engagement in Intact Live Animals

Targeted drug delivery in cancer treatment has been a major area of development in the past decades. However, there is a great need in preclinical studies to not only assess the drug distribution but also monitor and quantify target engagement in vivo to ensure maximal drug delivery efficacy. Macroscopic Fluorescence Lifetime Imaging of Förster Resonance Energy Transfer (MFLI‐FRET) is a unique deep imaging methodology to monitor in vivo receptor‐target interactions in pre‐clinical studies. Overall, we demonstrated that MFLI‐FRET enables real time in vivo information on receptor ligand engagement in deep tissues, conversely to current commercial systems.In this study, we capitalized on the homodimeric nature of the transferrin receptor (TfR) to quantify transferrin (Tf) internalization into cancer cells by measuring FRET between receptor‐bound Tf‐labeled donor and acceptor near‐infrared (NIR) fluorophore pairs. We found a strong correlation between FRET levels and Tf internalization into tumor cells despite the significant heterogeneity of tumors regarding their size and cellular density. In contrast, no correlation between MFLI‐FRET and TfR levels was observed, underscoring the insufficient link between receptor density and intracellular drug delivery. We present data strongly supporting that receptor expression and tumor drug delivery cannot be estimated via ex vivo immunohistochemistry but that drug delivery is highly correlated with FRET imaging. Additionally, we compared results of in vivo MFLI‐FRET imaging with intensity‐based FRET (using the IVIS pre‐clinical optical imaging system). Intensity‐based imaging failed to provide reliable and consistent results, showing significantly higher FRET quantification in negative control samples. Hence, MFLI provides the ability to measure receptor engagement in critical organs associated with targeted drug delivery efficiency, such as the liver, xenografts and bladder, without disrupting their native environment. Such unique capabilities enable the quantitative assessment of receptor engagement in relevant in vivo heterogeneous systems as well as providing crucial intra‐ and inter‐ specimen validation. Overall, we demonstrate that MFLI‐FRET enables real time in vivo information on receptor ligand engagement in deep tissues, conversely to current commercial systems. MFLI‐FRET is well positioned to play a critical role in accelerating the optimization of targeted drug delivery efficacy in pre‐clinical studies. Furthermore, this method should find broad applicability in molecular imaging both in vitro and in vivo, and could be extended to applications as diverse as image guided‐surgery or optical tomography.Support or Funding InformationThe study was funded by NIH grants R01EB019443 and R01CA207725.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Lipid composition has significant effect on targeted drug delivery properties of NGR-modified liposomes

The Asn-Gly-Arg (NGR) motif has previously been demonstrated to specifically bind to CD13, which is selectively overexpressed in tumor vasculature and some tumor cells (e.g. HT1080). It was reported that NGR-modified stealth liposomes (NGR-SL) could be prepared with different lipid composition, such as 1,2-dipalmitoyl-sn-glycero-phosphatidylcholine (DPPC), hydrogenated soy posphatidylcholine (HSPC) and soy posphatidylcholine (SPC). In the present study, NGR-modified liposomes were prepared with DPPC, HSPC, SPC or the mixture of HSPC and SPC. The resultant liposomes with different lipid composition were compared in terms of cell uptake, antitumor efficacy and targeted drug delivery efficiency using HT1080 tumor model. It was found that NGR-SL composed of the mixture of HSPC and SPC was able to improve targeted drug delivery efficiency to tumor producing the most significant antitumor activity. Collectively, the NGR-modified liposomes composed of the mixture of HSPC and SPC are promising carriers for the treatment of tumor. Besides NGR ligand, lipid composition could also significantly affect the targeted delivery efficiency to the tumor.

Assessing the barriers to image‐guided drug delivery

Imaging has become a cornerstone for medical diagnosis and the guidance of patient management. A new field called image-guided drug delivery (IGDD) now combines the vast potential of the radiological sciences with the delivery of treatment and promises to fulfill the vision of personalized medicine. Whether imaging is used to deliver focused energy to drug-laden particles for enhanced, local drug release around tumors, or it is invoked in the context of nanoparticle-based agents to quantify distinctive biomarkers that could risk stratify patients for improved targeted drug delivery efficiency, the overarching goal of IGDD is to use imaging to maximize effective therapy in diseased tissues and to minimize systemic drug exposure in order to reduce toxicities. Over the last several years, innumerable reports and reviews covering the gamut of IGDD technologies have been published, but inadequate attention has been directed toward identifying and addressing the barriers limiting clinical translation. In this consensus opinion, the opportunities and challenges impacting the clinical realization of IGDD-based personalized medicine were discussed as a panel and recommendations were proffered to accelerate the field forward.

Increased Tumor Cisplatin Levels in Heated Tumors in Mice after Administration of Thermosensitive, Large Unilamellar Vesicles Encapsulating Cisplatin

Hyperthermia (HT)-dependent cisplatin (CDDP) release and tumor CDDP level increase after the administration of thermosensitive, large unilamellar vesicles (LUVs: LUV-1 and LUV-2) and a thermosensitive, small unilamellar vesicle (SUV: SUV-1) were examined in comparison with those following administration of a non-thermosensitive LUV (LUV-3) and a CDDP solution (Sol) in tumor bearing mice. The LUV-1 and LUV-2 released CDDP at a faster rate than SUV-1 when incubated in saline at temperatures between 41 and 44°C. The blood CDDP levels after liposome administration were higher than those after Sol administration. The systemic clearance of LUV-2 was slightly larger than those of the other liposomes. The tumor CDDP levels after thermosensitive liposome administration were increased in response to HT in comparison to LUV-3 or Sol. The increased ratio for LUV-1 was the largest. The ratio of the area under the tumor CDDP level versus time curve (AUC) for LUV-1 + HT to the AUC for Sol + HT was ~5. The results indicate that (?) the tumor-CDDP level increase after thermosensitive liposome administration is due to CDDP release from the liposome in the blood at or adjacent to the heated tumor, (2) the increase is highly dependent on the heat sensitivity and systemic stability of the liposome, and (3) LUV, such as LUV-1, exhibit higher heat sensitivity and larger, targeted drug delivery efficiency than SUV.