Tumor Drug Delivery Research Articles

A Review of High Intensity Focused Ultrasound Focal Therapy Results Using the MRI Ultrasound Fusion

To provide its therapeutic effects, High-Intensity Focused Ultrasound (HIFU) treatment makes use of ultrasonic waves that are transmitted through tissue medium. This non-invasive technology shows capacity for a variety of medical applications, including tumor ablation, vascular coagulation, and gene and drug delivery. Nonetheless, there are many problems that can arise from using this technology. The goal of this research was to examine the effectiveness of focused HIFU treatment for prostate cancer by employing an MRI-US fusion platform to pinpoint the precise location of the tumor and administer the therapy. Focal HIFU treatment for locally advanced prostate cancer is a prospective case series employed in this article. There must not be a Gleason 5 signal on the prostatic biopsy and the focal lesion must be less than 20 mm in size on multiparametric Magnetic Resonance Imaging (MRI) for inclusion. The first half of the series were treated with traditional HIFU focused treatment, whereas the second half were treated using an MRI-US fusion platform. Requirement for salvage treatment was used as the major outcome measure of treatment efficacy. Results of supplementary interest were Prostate Specific Antigen (PSA) change, intraoperative morbidity, postoperative clinical outcome, and tumor resurgence in follow-up biopsies.

Stroma-targeted nanoparticles that remodel stromal alignment to enhance drug delivery and improve the antitumor efficacy of Nab-paclitaxel in pancreatic ductal adenocarcinoma models

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. A dense desmoplastic and specifically aligned stroma plays integral roles in the progression of PDAC, and inhibits drug penetration to impede treatment. However, direct depletion of stromal components for PDAC therapy interferes with the stromal balance, possibly accelerating tumor progression. Specific fiber alignment of the extracellular matrix, the most significant type of stroma topology in PDAC, is an important feature of PDAC and often overlooked. Here, we found that the alignment of collagen fibers, as determined by second harmonic generation (SHG) imaging, negatively correlated with pancreatic cancer prognosis. We report an integrated, two-step strategy for PDAC treatment, utilizing pretreatment with polymer-lipid-peptide nanoparticles that deliver inhibitors of lysyl oxidase like 2 (LOXL2) and discoidin domain receptor 1 (DDR1), followed by treatment with albumin-bound-paclitaxel (Nab-paclitaxel). The LOXL2 and DDR1 inhibitors intervene with collagen crosslinking and matrix metallopeptidase 1 (MMP1) expression to remodel stromal alignment without decreasing the collagen content, thus facilitating the transport of Nab-paclitaxel through the stromal barrier to enhance drug penetration and accumulation in the PDAC tumor tissue. Through this mechanism, the combined strategy resulted in significant antitumor efficacy in PDAC orthotopic xenograft mice. The current work highlights the key role of stromal alignment in therapeutics transport through stromal barriers. The strategy of remodeling stromal alignment may represent a promising approach for improving drug delivery in other stroma-rich tumors and fibrosis-related diseases.

Abstract 749: SimBioSys TumorScope accurately models and predicts response to neoadjuvant therapy in breast cancer - Validation study

Abstract Neoadjuvant Therapy (NAT) for breast cancer results in higher rates of breast conservation surgery. Importantly, there is data supporting the use of multiple NAT regimens, with little guidance as to which one would be most effective for a given patient. Thus, tools that can accurately predict patient outcome before cancer treatment can provide guidance during treatment planning and increase the chances of therapy success. Here we present the first biophysical modelling platform, TumorScope (TS), capable of constructing a 3D model of the tumor microenvironment by integrating models for tumor morphology, metabolism, drug delivery and behavior, and vascularity. Thereby allowing visualization of response to multiple NATs for a given tumor. TS integrates patient data to create an in-silico tumor model capturing the tumor response trajectory, volume, dimensions, pathological complete response (pCR), residual cancer burden and tumor morphology, and risk of recurrence (ROR). To illustrate the clinical applicability and to validate TS we performed a single center validation study. Previously acquired pre-treatment standard of care (SOC) diagnostic data (demographics, drug regimen, imaging (DCE MRI), and pathology) was used as TS inputs. Using this baseline data only, TS predicted weekly volumetric response through the treatment time and used simulated residual volume to predict pCR and assessed the ROR. The validation was performed using ground truth from post treatment assessment of pCR, radiographic volumes extracted from MRIs and ROR information. A chart review was performed to identify consecutive patients who had received NAT and had a corresponding pre-treatment MRI at University of Cincinnati. A validation set was generated from this list and data processed through TS (n=81, after excluding 9 patients with poor quality DCE-MRIs). TS predicted pCR was predefined as a residual tumor volume < 0.01 cm3 or a 99.9% or greater reduction in tumor volume. Performance metrics of TS were calculated. TS response (pCR vs. residual) prediction accuracy had an area under the curve (AUC) =0.912 with sensitivity and specificity of 88.9% and 92.5%, respectively. The performance was robust across all subtypes. Using SOC diagnostic data TS predicted the reduction in tumor volume with a median absolute volumetric error of 3.4% vs radiographic volume from pre-surgery DCE MRIs (n=59). TS prognostic ROR (High vs Low) had a hazard ratio [HR] 12.705, p=0.01 which was comparable as a prognostic indicator to actual pCR which had a [HR] 5.81, p=0.08. In summary, TS accurately predicts patient-specific response to NAT in early breast cancer using only baseline SOC pre-treatment data. This approach to a comprehensive view of the tumor represents a major step-forward in personalized clinical decision making. The results from this study will be used in a multi-center meta-analysis of TS performance characteristics. Citation Format: Gregory H. Norris, John Pfeiffer, Yuhan Zhang, Hope R. Esslinger, The SimBioSys Team, Vinita Takiar. SimBioSys TumorScope accurately models and predicts response to neoadjuvant therapy in breast cancer - Validation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 749.

EPCT-03. Working together to accelerate the preclinical to clinical translation of drug delivery systems for children’s brain tumours

Children's brain tumours are the biggest cancer killer in children and young adults. Several techniques, such as intra-cerebrospinal fluid chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems, electric field therapy, and intra-arterial and intra-nasal chemotherapy, have the potential to transform the treatment of brain tumours in children. However, there have been very few clinical trials to evaluate these. In 2021, the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) and the ITCC (Innovative Therapies for Children with Cancer) brain tumour group established a Clinical Trials Working Group comprising international researchers and clinicians to address this issue. This partnership highlighted the main challenges in preclinical to clinical translation of paediatric CNS drug delivery as: (1) a lack of specific funding for prototype development and/or scale-up for clinical trials; (2) difficulties in navigating the regulatory landscape; (3) lack of accurate preclinical models; and (4) increased need for multi-centric working. In response to this, we ran a hybrid workshop in November 2021 on ‘Clinical Trial Readiness for CNS Drug Delivery’. At this workshop, around 50 delegates (comprising clinicians, researchers, trial regulatory experts, policy makers, and representatives from funding organisations, brain tumour charities and industry) came together to discuss issues around funding, preclinical models and regulatory processes. We have established speciality-specific working groups to build on the workshop discussions, with the aim of producing recommendations around the use of preclinical models and drug delivery techniques according to brain tumour type. We have also used the workshop presentations and discussions to create a ‘Roadmap’ document for preclinical to clinical translation, which will be freely shared with the neuro-oncology research community. We continue to liaise with funders and regulatory bodies to address the changes that are needed in these areas. If you would like to join our network, contact: cbtddc@nottingham.ac.uk

A phase 1, first-in-human, dose-escalation and biomarker trial of liposomal gemcitabine (FF-10832) in patients with advanced solid tumors.

3097 Background: FF-10832 is a stable liposomal formulation of gemcitabine (GEM) shown to overcome resistance through increased plasma stability and enhanced tumor drug delivery. Macrophage uptake and immune activation in the tumor microenvironment (TME) play a role in the superior efficacy of FF-10832 compared to GEM, with selective, marrow-sparing biodistribution contributing to an improved safety profile. Methods: A 3+3 design determined the safety, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended Phase 2 dose (RP2D). FF-10832 was administered IV once or twice per cycle on a 28 or 21-day schedule until disease progression or unacceptable toxicity. Circulating immune cell populations were measured over time by flow cytometry. Results: Patients (pts) [n = 73, 26M/47F; median age, 64 (range, 26–84); # prior therapies, 3 (1–11); prior GEM, 60%] received FF-10832 on Day 1 and 15 Q28 days (1.2–30 mg/m2), Day 1 and 8 Q21 days (12–23 mg/m2), or Day 1 only Q28 or 21 days (30–55 mg/m2); median # cycles = 2 (1–14) & time on study = 8.3 (4–60) weeks. Common drug-related adverse events were Grade (Gr) ≤2 rash (22%), nausea (22%, 1 Gr 3), and pyrexia (21%, 2 Gr 3). Dose-limiting Gr ≥3 cellulitis/skin ulcers were observed at ≥23 mg/m2 with twice per cycle dosing and those regimens discontinued. Dose frequency was reduced to Day 1 only, which was well-tolerated without significant skin toxicity. Gr ≥3 thrombocytopenia and pneumonitis were observed at 55 mg/m2 Q21 days and the MTD confirmed at 40 (Q21) and 48 mg/m2 (Q28). Median OS = 25.3 (95%CI: 16–27.1) weeks and PFS = 9.6 (95%CI: 7.9–17.6) weeks. Three of 35 evaluable pts achieved a partial response (PR): one pt with gallbladder cancer who previously progressed on GEM achieved a 50%↓ by Cycle 13 at 40 mg/m2 Q28 days & maintains response on study at 60 weeks; two pts with pancreatic cancer had ≥30%↓: one adenocarcinoma after 2 cycles at 4.8 mg/m2 Days 1 & 15 Q28 days, and one acinar cell after 7 cycles at 40 mg/m2 Q28 days who remains on study. Stable disease (SD) was observed in 16 pts; 9 for ≥20 weeks. AUC increased in proportion to dose without accumulation. An extended plasma t1/2 (hrs) for released (39) & total GEM (26) with a free fraction < 1% of total GEM concentrations suggests continuous release in the TME. Pts with PR or SD had dose and time-related log decreases in Ki67+ regulatory T cells relative to total CD4+ cells with increases in anti-tumor CD8+ cells, suggesting a shift to a more immunocompetent environment. Conclusions: FF-10832 was well-tolerated in heavily pre-treated pts with solid tumors, with evidence of anti-tumor activity in pts who progressed on prior GEM. Prolonged, continuous exposure and enhancement of anti-tumor immunity may contribute to improved efficacy. Expansion is ongoing in biliary tract cancer pts treated at the RP2D/schedule of 40 mg/m2 Day 1 of a 21-day cycle. Clinical trial information: NCT03440450.

A first-in-human phase 1 dose escalation study of FF-10850 (liposomal topotecan) in patients with advanced solid tumors.

3101 Background: FF-10850 (liposomal topotecan) was developed using a unique dihydrosphingomyelin-based carrier to enhance tumor drug delivery and retention, leading to improved efficacy and safety. Preclinical studies demonstrated superior anti-tumor activity with less myelosuppression compared to topotecan, with a pharmacokinetic (PK) profile supporting a twice-monthly dosing schedule. Methods: Accelerated titration followed by a 3+3 dose escalation design was used to determine the safety, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), PK, and recommended Phase 2 dose. FF-10850 was administered IV on Day 1 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Results: Patients (pts) [n = 29; 4M/25F; median age, 64 (range, 37–79) and # prior therapies, 4 (range, 1–8)] received FF-10850 at doses of 1, 2, 2.5, 3, 3.5 and 5 mg/m2; median # of cycles, 2 (range, 1–11). FF-10850 was well-tolerated at doses up to 2 mg/m2. Common drug-related adverse events (AEs) included anemia (83%, 51% Gr≥3), thrombocytopenia (62%, 35% Gr≥3), neutropenia (59%, 45% Gr≥3), nausea (38%), fatigue (24%, 7% Gr≥3), alopecia (24%), and hypokalemia (17%, 3% Gr≥3). Dose-limiting Gr≥3 thrombocytopenia, neutropenia, anemia, and fatigue were observed at doses ≥2.5 mg/m2. Eight pts required dose reductions due to AEs. The median time on study was 8.3 (1.6–45) weeks, with a median PFS of 9.4 weeks and median OS at least 26 weeks. Of 24 pts evaluable for response, two achieved a partial response (PR). One pt with ovarian cancer treated at 3.5 mg/m2 achieved a complete response in target lesions by Cycle 2 with stable non-target lesions, and maintained response for > 30 weeks (8 cycles) before progressing; dose was reduced in this pt to 2.6 mg/m2 at Cycle 2 due to Gr 4 thrombocytopenia. Another pt with refractory metastatic Merkel cell carcinoma tolerated therapy well at 2 mg/m2 and achieved a 48% reduction in target lesions that was maintained for > 30 weeks (8 cycles). Stable disease was observed in an additional 9 pts for ≥10 weeks (5 ovarian, 2 uterine and 2 cervical); five who maintained disease control for ≥24-45 weeks including one (ovarian) who had previously progressed on topotecan. An extended plasma t1/2 for topotecan of 25-30 hours was observed with no apparent dose-dependency or accumulation; < 1% of circulating topotecan was in the free (released) form. Conclusions: FF-10850 was well-tolerated up to 2 mg/m2 with anti-tumor activity demonstrated in heavily pre-treated pts with solid tumors including ovarian cancer, and an improved PK profile allowing less frequent dosing compared to topotecan. Expansion is ongoing in pts with ovarian and Merkel cell carcinoma at the RP2D of 2 mg/m2 IV on Day 1 & 15 of a 28-day cycle. Clinical trial information: NCT04047251.

Abstract No. 355 Percutaneous needle-based liquid ablation agent for tumor treatment and drug delivery

The purpose of the study was to determine whether a single percutaneous needle based injection of an ionic liquid with various therapeutics could be used to ablate normal and tumor tissue, incite inflammation, retain chemotherapy drugs within the ablation zone and achieve uniform delivery of drugs within tissue.

Applying quality by design approach for the determination of potent paclitaxel loaded poly(lactic acid) based implants for localized tumor drug delivery

In the present study, poly(lactic acid) (PLA) and poly(ethylene succinate) (PESu) or poly(ethylene glycol) (PEG) under the framework of quality by design, were blended to produce effective sustained-release matrices for Paclitaxel delivery. A complete physicochemical characterization including weight variation, thickness, water uptake, moisture absorption, moisture loss, and hydrolytic degradation under physiological conditions, was performed. Quality by design approach was applied to study the critical parameters. In vitro cancer toxicity was studied in human cancer cell lines including lung and breast adenocarcinoma. The developed Paclitaxel-loaded films can act as a promising alternative topical matrix as an implant for breast and lung cancer treatment.

Emerging Trends and Research Foci in Tumor Microenvironment of Pancreatic Cancer: A Bibliometric and Visualized Study.

BackgroundPancreatic cancer (PC) is a serious disease with high mortality. The tumor microenvironment plays a key role in the occurrence and development of PC. The purpose of this study is to analyze trends by year, country, institution, journal, reference and keyword in publications on the PC microenvironment and to predict future research hotspots.MethodsThe Web of Science Core Collection was used to search for publications. We analyzed the contributions of various countries/regions, institutes, and authors and identified research hotspots and promising future trends using the CiteSpace and VOSviewer programs. We also summarized relevant completed clinical trials.ResultsA total of 2,155 papers on the PC microenvironment published between 2011 and 2021 were included in the study. The number of publications has increased every year. The average number of citations per article was 32.69. The USA had the most publications, followed by China, and a total of 50 influential articles were identified through co-citation analysis. Clustering analysis revealed two clusters of keywords: basic research and clinical application. The co-occurrence cluster analysis showed glutamine metabolism, carcinoma-associated fibroblasts, oxidative phosphorylation as the highly concerned research topics of basic research in recently. The three latest hot topics in clinical application are liposomes, endoscopic ultrasound and photodynamic therapy.ConclusionThe number of publications and research interest have generally increased, and the USA has made prominent contributions to the study of the tumor microenvironment of PC. The current research hotspots mainly focus on energy metabolism in the hypoxic tumor microenvironment, cancer associated fibroblasts in regulating the tumor microenvironment, accurate diagnosis, drug delivery and new treatments.

513 Towards Obtaining One Billion Recordings Per Cubic Millimeter for the Validation of Focused Ultrasound Transducers: How Can Robust Systems Help With Translational Activities?

OBJECTIVES/GOALS: The first aim was to construct a controlled and high resolution FUS water tank characterization system with 1 micron step-sizes. The second aim was to create two unique standardized protocols for mapping the generated acoustic field from FUS transducers; protocol one maps the full 3D field while protocol two rapidly detects changes to the original plot. METHODS/STUDY POPULATION: To accomplish aim one, the focused ultrasound mapping platform was constructed with a water conditioning unit for water degassing and temperature control, a three-axis stage with 1 micron step-size capabilities, and a data plotting software. To measure the outcomes of aim one, the water temperature was monitored, and axis step sizes were measured through ten independent axis translation recordings. To accomplish aim two, FUS acquisitions were executed at different resolutions. For FUS localization at the cellular level, a 1-5 micron step size is required. Once the initial scan was performed, duplicate scans were executed to detect inherent perturbations or errors in the system. Once calculated, the best methods of detecting true changes to FUS signals are proposed. RESULTS/ANTICIPATED RESULTS: The FUS characterization system maintained water temperature and performed 1 micron step-sizes. While pre-existing platforms have demonstrated a resolution of one thousand recordings per cubic millimeter, the proposed system (time and computing power willing) can record one billion recordings per cubic millimeter. In practice, a resolution of 20 micron was sufficient for non-cellular level FUS characterizations. Successive 2D scans were reliably stacked to form a 3D rendering of the generated acoustic field with the average focal point intensity yielding a 1% coefficient of variation between identical scans. This inherent variation can be used as the threshold of significance for true change detection; to rapidly detect changes to the FUS signal, sampling can be performed at regions of high baseline values. DISCUSSION/SIGNIFICANCE: Focused ultrasound medical devices are gaining popularity for treatments including tumor ablation, neuromodulation, and drug delivery; however, the field lacks a standardized method to characterize these FUS transducers. The presented platform and protocols enable a rigorous and high quality translation through verification and validation.

Biophysical characterization and in vitro imaging of carbonized MOFs

Nanoparticles have been widely used in biological imaging and treatments of various diseases, especially for studies of tumors, due to their high efficiency in drug delivery and many other functions. Metal-organic frameworks have been an important research area in recent years because of advantages such as large apertures, adjustable structural compositions, adjustable sizes, multifunctionality, high drug loading, good biocompatibility and so on, and they show promise as multifunctional drug carriers. In this study, a carbonized MOF with photothermal therapeutic potential and dual-mode imaging capability was prepared. The biophysical properties of MIL-100 and C-MIL nanoparticles were determined, such as particle size, zeta potential and saturation magnetization strength. CCK-8 cell assays and mouse HE sections confirmed that C-MIL nanoparticles have good in vitro and in vivo biocompatibility. The solution temperature of C-MIL nanoparticles reached 58.1 °C during sustained laser irradiation at 808 nm, which confirmed the photothermal potential of the nanoparticles. Moreover, in biological imaging, C-MIL nanoparticles showed the ability to support in vitro nuclear magnetic and photoacoustic dual-mode imaging. C-MIL nanoparticles provide new options for tumor therapy, drug delivery and biological imaging.

Vascularized Lung Cancer Model for Evaluating the Promoted Transport of Anticancer Drugs and Immune Cells in an Engineered Tumor Microenvironment.

The tumor microenvironment (TME) is the environment around the tumor, including blood vessels, immune cells, fibroblasts, signaling molecules, and the extracellular matrix (ECM). Owing to its component interactions, the TME influences tumor growth and drug delivery in a highly complex manner. Although several vascularized cancer models are developed to mimic the TME in vitro, these models cannot comprehensively reflect blood vessel-tumor spheroid interactions. Here, a method for inducing controlled tumor angiogenesis by engineering the microenvironment is presented. The interstitial flow direction regulates the direction of capillary sprouting, showing that angiogenesis occurs in the opposite direction of flow, while the existence of lung fibroblasts affects the continuity and lumen formation of sprouted capillaries. The vascularized tumor model shows enhanced delivery of anticancer drugs and immune cells to the tumor spheroids because of the perfusable vascular networks. The possibility of capillary embolism using anticancer drug-conjugated liquid metal nanoparticles is investigated using the vascularized tumor model. This vascularized tumor platform can aid in the development of effective anticancer drugs and cancer immunotherapy.

A Single Short 'Tone Burst' Results in Optimal Drug Delivery to Tumours Using Ultrasound-Triggered Therapeutic Microbubbles.

Advanced drug delivery systems, such as ultrasound-mediated drug delivery, show great promise for increasing the therapeutic index. Improvements in delivery by altering the ultrasound parameters have been studied heavily in vitro but relatively little in vivo. Here, the same therapeutic microbubble and tumour type are used to determine whether altering ultrasound parameters can improve drug delivery. Liposomes were loaded with SN38 and attached via avidin: biotin linkages to microbubbles. The whole structure was targeted to the tumour vasculature by the addition of anti-vascular endothelial growth factor receptor 2 antibodies. Tumour drug delivery and metabolism were quantified in SW480 xenografts after application of an ultrasound trigger to the tumour region. Increasing the trigger duration from 5 s to 2 min or increasing the number of 5 s triggers did not improve drug delivery, nor did changing to a chirp trigger designed to stimulate a greater proportion of the microbubble population, although this did show that the short tone trigger resulted in greater release of free SN38. Examination of ultrasound triggers in vivo to improve drug delivery is justified as there are multiple mechanisms at play that may not allow direct translation from in vitro findings. In this setting, a short tone burst gives the best ultrasound parameters for tumoural drug delivery.

Normalizing tumor microenvironment with nanomedicine and metronomic therapy to improve immunotherapy

Nanomedicine offered hope for improving the treatment of cancer but the survival benefits of the clinically approved nanomedicines are modest in many cases when compared to conventional chemotherapy. Metronomic therapy, defined as the frequent, low dose administration of chemotherapeutics – is being tested in clinical trials as an alternative to the conventional maximum tolerated dose (MTD) chemotherapy schedule. Although metronomic chemotherapy has not been clinically approved yet, it has shown better survival than MTD in many preclinical studies. When beneficial, metronomic therapy seems to be associated with normalization of the tumor microenvironment including improvements in tumor perfusion, tissue oxygenation and drug delivery as well as activation of the immune system. Recent preclinical studies suggest that nanomedicines can cause similar changes in the tumor microenvironment. Here, by employing a mathematical framework, we show that both approaches can serve as normalization strategies to enhance treatment. Furthermore, employing murine breast and fibrosarcoma tumor models as well as ultrasound shear wave elastography and contrast-enhanced ultrasound, we provide evidence that the approved nanomedicine Doxil can induce normalization in a dose-dependent manner by improving tumor perfusion as a result of tissue softening. Finally, we show that pretreatment with a normalizing dose of Doxil can improve the efficacy of immune checkpoint inhibition.

Bioinspired adhesive microneedle patch with gemcitabine encapsulation for pancreatic cancer treatment

Gemcitabine is the standard therapeutic agent for pancreatic cancer (PC), while its side effects eliminating, stromal barrier overcoming, and efficiency improvement are still challenges in clinical application. Herein, inspired by the structures of octopus tentacles, we present a novel adhesive microneedle (MN) patch with gemcitabine encapsulation for the PC treatment. The MN patch with good biocompatibility, flexibility, and drug loading efficiency, was fabricated by using gelatin methacryloyl (GelMA) to replicate a top-down mold-based lithography. Benefitting from the octopus tentacles-mimicked surface microstructure, the resultant GelMA hydrogel MN patch is imparted with the ability to adhere to the irregular surfaces of tumors. With the anticancer drug gemcitabine encapsulating in the hydrogel, the MN patch is demonstrated to efficiently penetrate the tumor tissue, release gemcitabine with desired kinetics, and exhibit high anti-tumor efficiency both in vitro and in a mouse orthotopic tumor model. Thus, we believe that chemotheraputics-loaded MN patch will find practically valuable in drug delivery and treatment for hypovascular tumors with stromal barrier in clinical medicine.

Triculture Model of In Vitro BBB and its Application to Study BBB‐Associated Chemosensitivity and Drug Delivery in Glioblastoma (Adv. Funct. Mater. 10/2022)

Blood–Brain Barrier In article number 2106860, Kangwon Lee, Nakwon Choi, Hong Nam Kim, and co-workers fabricate a brain-on-a-chip platform to replicate the complicated glioblastoma multiforme microenvironment and the anatomical features and functionality of the in vivo blood–brain barrier, and demonstrate the influence of the glioblastoma multiforme microenvironment on tumor behavior and drug delivery.

Platelets for cancer treatment and drug delivery.

Extensive research is currently being conducted into a variety of bio-inspired biomimetic nanoparticles (NPs) with new cell simulation functions across the fields of materials science, chemistry, biology, physics, and engineering. Cells such as erythrocytes, platelets, and stem cells have been engineered as new drug carriers. The platelet-derived drug delivery system, which is a new targeted drug delivery system (TDDS), can effectively navigate the blood circulatory system and interact with the complex tumor microenvironment; it appears to outperform traditional anticancer drugs; hence, it has attracted considerable research interest. In this review, we describe innovative studies and outline the latest progress regarding the use of platelets as tumor targeting and drug delivery vehicles; we also highlight opportunities and challenges relevant to the manufacture of tumor-related platelet TDDSs.

Identification of an Aptamer With Binding Specificity to Tumor-Homing Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSCs) play a critical role in tumor growth and metastasis. Since they constantly infiltrate into the tumor tissue, these cells are considered as an ideal carrier for tumor-targeted drug delivery. We recently identified a DNA-based thioaptamer (T1) with tumor accumulating activity, demonstrated its potential on tumor targeting and drug delivery. In the current study, we have carried out structure-activity relationship analysis to further optimize the aptamer. In the process, we have identified a sequence-modified aptamer (M1) that shows an enhanced binding affinity to MDSCs over the parental T1 aptamer. In addition, M1 can penetrate into the tumor tissue more effectively by hitchhiking on MDSCs. Taken together, we have identified a new reagent for enhanced tumor-targeted drug delivery.

Towards controlled drug delivery in brain tumors with microbubble-enhanced focused ultrasound.

Brain tumors are particularly challenging malignancies, due to their location in a structurally and functionally distinct part of the human body - the central nervous system (CNS). The CNS is separated and protected by a unique system of brain and blood vessel cells which together prevent most bloodborne therapeutics from entering the brain tumor microenvironment (TME). Recently, great strides have been made through microbubble (MB) ultrasound contrast agents in conjunction with ultrasound energy to locally increase the permeability of brain vessels and modulate the brain TME. As we elaborate in this review, this physical method can effectively deliver a wide range of anticancer agents, including chemotherapeutics, antibodies, and nanoparticle drug conjugates across a range of preclinical brain tumors, including high grade glioma (glioblastoma), diffuse intrinsic pontine gliomas, and brain metastasis. Moreover, recent evidence suggests that this technology can promote the effective delivery of novel immunotherapeutic agents, including immune check-point inhibitors and chimeric antigen receptor T cells, among others. With early clinical studies demonstrating safety, and several Phase I/II trials testing the preclinical findings underway, this technology is making firm steps towards shaping the future treatments of primary and metastatic brain cancer. By elaborating on its key components, including ultrasound systems and MB technology, along with methods for closed-loop spatial and temporal control of MB activity, we highlight how this technology can be tuned to enable new, personalized treatment strategies for primary brain malignancies and brain metastases.

Controlled release of nitric oxide for enhanced tumor drug delivery and reduction of thrombosis risk

Platelets activation and hypercoagulation induced by tumor cell-specific thrombotic secretions such as tissue factor (TF) and cancer procoagulant (CP), microparticles (MPs), and cytokines not only increase cancer-associated thrombosis but also accelerate cancer progress. In addition, the tumor heterogeneity such avascular areas, vascular occlusion and interstitial fluid pressure still challenges efficient drug delivery into tumor tissue. To overcome these adversities, we herein present an antiplatelet strategy based on a proteinic nanoparticles co-assembly of l-arginine (LA) and photosensitizer IR783 for local NO release to inhibit the activation of tumor-associated platelets and normalize angiogenesis, suppressing thrombosis and increasing tumoral accumulation of the nanoagent. In addition, NIR-controlled release localizes the NO spatiotemporally to tumor-associated platelets and prevents undesirable systemic bleeding substantially. Moreover, NO can transform to more cytotoxic peroxynitrite to destroy cancer cells. Our study describes an antiplatelet-directed cancer treatment, which represents a promising area of targeted cancer therapy.