Cell-based Drug Delivery Systems Research Articles

Platelet-Drug Conjugates Engineered via One-step Fusion Approach for Metastatic and Postoperative Cancer Treatment.

The exploration of cell-based drug delivery systems for cancer therapy has gained growing attention. Approaches to engineering therapeutic cells with multidrug loading in an effective, safe, and precise manner while preserving their inherent biological properties remain of great interest. Here, we report a strategy to simultaneously load multiple drugs in platelets in a one-step fusion process. We demonstrate doxorubicin (DOX)-encapsulated liposomes conjugated with interleukin-15 (IL-15) could fuse with platelets to achieve both cytoplasmic drug loading and surface cytokine modification with a loading efficiency of over 70 % within minutes. Due to their inherent targeting ability to metastatic cancers and postoperative bleeding sites, the engineered platelets demonstrated a synergistic therapeutic effect to suppress lung metastasis and postoperative recurrence in mouse B16F10 melanoma tumor models.

Comparison of cell delivery and cell membrane camouflaged PLGA nanoparticles in the delivery of shikonin for colorectal cancer treatment

Inspired by the "natural camouflage" strategy, cell-based biomimetic drug delivery systems (BDDS) have shown great potential in cancer therapy. Red blood cell (RBC) delivery vehicles and red blood cell membrane (RBCm)-camouflaged vehicles were commonly used strategies for drug delivery. We prepared shikonin-encapsulated PLGA nanoparticles (PLGA/SK) with different surface charges to obtain both RBC delivery and RBCm-camouflaged PLGA NPs. The physicochemical properties, in vivo circulation and antitumor effects of these biomimetic preparations were studied. Since the positive PLGA NPs may affect the morphology and function of RBCs, the biomimetic preparations prepared by the negative PLGA NPs showed better in vitro stability. However, positive PLGA NP-based biomimetic preparations exhibited longer circulation time and higher tumor region accumulation, leading to stronger anti-tumor effects. Meanwhile, the RBC delivery PLGA(+) NPs possessed better in vitro cytotoxicity, longer circulation time and higher tumor accumulation than RBCm-camouflaged PLGA(+) NPs. Collectively, RBC delivery vehicles possessed more potential than RBCm-camouflaged vehicles on drug delivery for tumor treatment, especially with positive NPs-loaded.

Functionalized and theranostic lipidic and tocosomal drug delivery systems: potentials and limitations in cancer photodynamic therapy

Photodynamic therapy (PDT) is a multidisciplinary area, which involves photophysics and photochemical sciences and plays an important role in cancer diagnosis and treatment. PDT involves a photo-activable drug called photosensitizer (PS), a specific wavelength of light and cellular compounds to produce toxic oxygen species in a much-localized way to destroy malignant tumors. Despite the various benefits of PDT, some PS-related limitations hinder its use as an ideal treatment option for cancer. To address these limitations (e.g., poor bioavailability, weak permeability, hydrophobicity, and aggregation), lipid-based and vesicular drug delivery systems have been employed. These carrier systems possess the ability to enhance the bioavailability, permeability, and solubility of the drug. Furthermore, they tend to load hydrophobic and lipophilic compounds and can be employed for an efficient and targeted drug delivery. The purpose of this review is to highlight the precise idea of PDT, the limitations of PDT related to PS, and the application of lipidic and tocosomal carriers in PDT for the treatment of various types of cancers. Liposomes, nanoliposomes, solid lipid nanoparticles, vesicular phospholipid gels, exosomes, transferosomes, and tocosomes are presented as commonly–employed vesicular drug carriers. Moreover, the amalgamation of cell-based drug delivery systems (CBDDS) with PDT holds considerable potential as an encouraging avenue in cancer treatment, especially in the context of immunotherapy.

Theoretical basis, state and challenges of living cell-based drug delivery systems.

The therapeutic efficacy of drugs is determined, to a certain extent, by the efficiency of drug delivery. The low efficiency of drug delivery systems (DDSs) is frequently associated with serious toxic side effects and can even prove fatal in certain cases. With the rapid development of technology, drug delivery has evolved from using traditional frameworks to using nano DDSs (NDDSs), endogenous biomaterials DDSs (EBDDSs), and living cell DDSs (LCDDSs). LCDDSs are receiving widespread attention from researchers at present owing to the unique advantages of living cells in targeted drug delivery, including their excellent biocompatibility properties, low immunogenicity, unique biological properties and functions, and role in the treatment of diseases. However, the theoretical basis and techniques involved in the application of LCDDSs have not been extensively summarized to date. Therefore, this review comprehensively summarizes the properties and applications of living cells, elaborates the various drug loading approaches and controlled drug release, and discusses the results of clinical trials. The review also discusses the current shortcomings and prospects for the future development of LCDDSs, which will serve as highly valuable insights for the development and clinical transformation of LCDDSs in the future.

Knowledge Gaps in Generating Cell-Based Drug Delivery Systems and a Possible Meeting with Artificial Intelligence.

Cell-based drug delivery systems are new strategies in targeted delivery in which cells or cell-membrane-derived systems are used as carriers and release their cargo in a controlled manner. Recently, great attention has been directed to cells as carrier systems for treating several diseases. There are various challenges in the development of cell-based drug delivery systems. The prediction of the properties of these platforms is a prerequisite step in their development to reduce undesirable effects. Integrating nanotechnology and artificial intelligence leads to more innovative technologies. Artificial intelligence quickly mines data and makes decisions more quickly and accurately. Machine learning as a subset of the broader artificial intelligence has been used in nanomedicine to design safer nanomaterials. Here, how challenges of developing cell-based drug delivery systems can be solved with potential predictive models of artificial intelligence and machine learning is portrayed. The most famous cell-based drug delivery systems and their challenges are described. Last but not least, artificial intelligence and most of its types used in nanomedicine are highlighted. The present Review has shown the challenges of developing cells or their derivatives as carriers and how they can be used with potential predictive models of artificial intelligence and machine learning.

"Zombie" Macrophages for Targeted Drug Delivery to Treat Acute Pneumonia.

A cell-based drug delivery system has emerged as a promising drug delivery platform. Due to their innate inflammatory tropism, natural and engineered macrophages have exhibited targeted accumulation in inflammatory tissues, which has allowed targeted delivery of medicine for the treatment of a variety of inflammatory diseases. Nevertheless, live macrophages may take up the medicine and metabolize it during preparation, storage, and in vivo delivery, sometimes causing unsatisfactory therapeutic efficacy. In addition, live macrophage-based drug delivery systems are usually freshly prepared and injected, due to the poor stability that does not allow storage. "Off-the-shelf" products would be indeed conducive to the timely therapy of acute diseases. Herein, a cryo-shocked macrophage-based drug delivery system was developed via supramolecular conjugation of cyclodextrin (CD)-modified "zombie" macrophages and adamantane (ADA)-functionalized nanomedicine. "Zombie" macrophages exhibited a much better storage stability over time than their counterpart live macrophage drug carriers and maintained cell morphology, membrane integrity, and biological functions. In an acute pneumonia mouse model, "zombie" macrophages carried quercetin-loaded nanomedicine, hand-in-hand, to the inflammatory lung tissues and effectively alleviated the inflammation in mice.

Living Leukocyte-Based Drug Delivery Systems.

Leukocytes play a vital role in immune responses, including defending against invasive pathogens, reconstructing impaired tissue, and maintaining immune homeostasis. When the immune system is activated in vivo, leukocytes accomplish a series of orderly and complex regulatory processes. While cancer and inflammation-related diseases like sepsis are critical medical difficulties plaguing humankind around the world, leukocytes have been shown to largely gather at the focal site,and significantly contribute toinflammation and cancer progression. Therefore, the living leukocyte-baseddrug delivery systems have attracted considerable attention in recent years due to the innate and specific targeting effect, low immunogenicity, improved therapeutic efficacy, and low reverse effect. In this review, the recent advances in the development of living leukocyte-based drug delivery systems including macrophages, neutrophils, and lymphocytes as promising treatment strategies for cancer and inflammation-related diseases are introduced. The advantages, current challenges, and limitations of these delivery systems are also discussed, as well as perspectives on the future development of precision and targeted therapy in the clinics are provided. Collectively, it is expected that such kind of living cell-based drug delivery system is promising to improve or even revolutionize the treatments of cancers and inflammation-related diseases in the clinics.

Cell-Based Drug Delivery Systems with Innate Homing Capability as a Novel Nanocarrier Platform.

Nanoparticle-based drug delivery systems have been designed to treat various diseases. However, many problems remain, such as inadequate tumor targeting and poor therapeutic outcomes. To overcome these obstacles, cell-based drug delivery systems have been developed. Candidates for cell-mediated drug delivery include blood cells, immune cells, and stem cells with innate tumor tropism and low immunogenicity; they act as a disguise to deliver the therapeutic payload. In drug delivery systems, therapeutic agents are encapsulated intracellularly or attached to the surface of the plasma membrane and transported to the desired site. Here, we review the pros and cons of cell-based therapies and discuss their homing mechanisms in the tumor microenvironment. In addition, different strategies to load therapeutic agents inside or on the surface of circulating cells and the current applications for a wide range of disease treatments are summarized.

Cell-Based Drug Delivery Systems Participate in the Cancer Immunity Cycle for Improved Cancer Immunotherapy.

Immunotherapy aims to activate the cancer patient's immune system for cancer therapy. The whole process of the immune system against cancer referred to as the "cancer immunity cycle", gives insight into how drugs can be designed to affect every step of the anticancer immune response. Cancer immunotherapy such as immune checkpoint inhibitor (ICI) therapy, cancer vaccines, as well as small molecule modulators has been applied to fight various cancers. However, the effect of immunotherapy in clinical applications is still unsatisfactory due to the limited response rate and immune-related adverse events. Mounting evidence suggests that cell-based drug delivery systems (DDSs) with low immunogenicity, superior targeting, and prolonged circulation have great potential to improve the efficacy of cancer immunotherapy. Therefore, with the rapid development of cell-based DDSs, understanding their important roles in various stages of the cancer immunity cycle guides the better design of cell-based cancer immunotherapy. Herein, an overview of how cell-based DDSs participate in cancer immunotherapy at various stages is presented and an outlook on possible challenges of clinical translation and application in future development.

A cell-mimicking platelet-based drug delivery system as a potential carrier of dimethyl fumarate for multiple sclerosis

Dimethyl fumarate (DMF), is one of the lately approved therapeutic agents for the multiple sclerosis (MS) treatment. Despite the beneficial effects, DMF also suffers from low penetration into brain.In this study, we designed a precise drug delivery system of DMF to cross BBB for MS management. The novelty of this study is developing a cell based biomimetic vehicle for specific drug delivery to the inflamed area in peripheral and CNS. DMF-loaded platelet-based nanoparticle as a cell-based drug delivery system was developed and compared with chitosan nanogel and platelet membrane coated chitosan nanogel. Prepared nanoparticles were characterized for particle size, morphology, release characteristics, and drug loading parameters. In the optimum condition, all nanoparticles were prepared in desirable nano-size and showed appropriate loading parameters. The neuropharmacokinetic evaluation was performed by determining the brain uptake of DMF, and brain uptake clearance for passage from BBB. Results from in vivo study demonstrated that the brain concentration of nanoparticles was higher than the free drug solution. The brain uptake clearance and AUC (0-∞) brain of DMF-loaded platelet nanoparticle were higher than platelet membrane coated chitosan nanogel and chitosan nanogel. The results demonstrated that platelet nanoparticles can be proposed as a potential biomimetic carrier for MS management.

Advances in Hybrid Vesicular-based Drug Delivery Systems: Improved Biocompatibility, Targeting, Therapeutic Efficacy and Pharmacokinetics of Anticancer Drugs.

Anticancer drugs and diagnostics can be transported in nanoscale vesicles that provide a flexible platform. A hybrid nanoparticle, a nano assembly made up of many types of nanostructures, has the greatest potential to perform these two activities simultaneously. Nanomedicine has shown the promise of vesicular carriers based on lipopolymersomes, lipid peptides, and metallic hybrid nano-vesicle systems. However, there are significant limitations that hinder the clinical implementation of these systems at the commercial scale, such as low productivity, high energy consumption, expensive setup, long process durations, and the current cancer therapies described in this article. Combinatorial hybrid systems can be used to reduce the above limitations. A greater therapeutic index and improved clinical results are possible with hybrid nanovesicular systems, which integrate the benefits of many carriers into a single structure. Due to their unique properties, cell-based drug delivery systems have shown tremendous benefits in the treatment of cancer. Nanoparticles (NPs) can benefit significantly from the properties of erythrocytes and platelets, which are part of the circulatory cells and circulate for a long time. Due to their unique physicochemical properties, nanomaterials play an essential role in cell-based drug delivery. Combining the advantages of different nanomaterials and cell types gives the resulting delivery systems a wide range of desirable properties. NPs are nextgeneration core-shell nanostructures that combine a lipid shell with a polymer core. The fabrication of lipid-polymer hybrid NPs has recently undergone a fundamental shift, moving from a two-step to a one-step technique based on the joint self-assembly of polymers and lipids. Oncologists are particularly interested in this method as a combinatorial drug delivery platform because of its two-in-one structure. This article addresses various preparative methods for the preparation of hybrid nano-vesicular systems. It also discusses the cellular mechanism of hybrid nano-vesicular systems and describes the thorough knowledge of various hybrid vesicular systems.

Vesicles of yeast cell wall-sitagliptin to alleviate neuroinflammation in Alzheimer's disease

A cell-based drug delivery system based on yeast-cell wall loaded with sitagliptin, a drug with an anti-inflammatory effect, was developed to control neuroinflammation associated with Alzheimer's disease. The optimized nanoparticles had a spherical shape with a negative surface charge, and were shown to be less toxic than the carrier and sitagliptin. Moreover, the nanoparticles caused anti-inflammatory effects against tumor necrosis factor-alpha in mice model of neuroinflammation. The pharmacokinetics study showed the brain concentration of drug in the nanoparticles group was much higher than in the control group. To evaluate the effect of P-glycoprotein on brain entry of sitagliptin, the experiment was repeated with verapamil, as a P-glycoprotein inhibitor. Brain concentration of the nanoparticles group remained approximately unchanged, proving the “Trojan Horse” effect of the developed nanocarriers. The results are promising for using yeast-cell wall as a carrier for targeted delivery to immune cells for the management of inflammation.

Bioinspired and Biomimetic Nanomedicines for Targeted Cancer Therapy.

Undesirable side effects and multidrug resistance are the major obstacles in conventional chemotherapy towards cancers. Nanomedicines provide alternative strategies for tumor-targeted therapy due to their inherent properties, such as nanoscale size and tunable surface features. However, the applications of nanomedicines are hampered in vivo due to intrinsic disadvantages, such as poor abilities to cross biological barriers and unexpected off-target effects. Fortunately, biomimetic nanomedicines are emerging as promising therapeutics to maximize anti-tumor efficacy with minimal adverse effects due to their good biocompatibility and high accumulation abilities. These bioengineered agents incorporate both the physicochemical properties of diverse functional materials and the advantages of biological materials to achieve desired purposes, such as prolonged circulation time, specific targeting of tumor cells, and immune modulation. Among biological materials, mammalian cells (such as red blood cells, macrophages, monocytes, and neutrophils) and pathogens (such as viruses, bacteria, and fungi) are the functional components most often used to confer synthetic nanoparticles with the complex functionalities necessary for effective nano-biointeractions. In this review, we focus on recent advances in the development of bioinspired and biomimetic nanomedicines (such as mammalian cell-based drug delivery systems and pathogen-based nanoparticles) for targeted cancer therapy. We also discuss the biological influences and limitations of synthetic materials on the therapeutic effects and targeted efficacies of various nanomedicines.

Cell-based carrier for targeted hitchhiking delivery.

Drug delivery systems aim at improving drug transport efficiency and therapeutic efficacy by rational design, and current research on conventional delivery systems brings new developments for disease treatment. Recently, studies on cell-based drug delivery systems are rapidly emerging, which shows great advantages in comparison to conventional drug delivery system. The system uses cells as carriers to delivery conventional drugs or nanomedicines and shows good biocompatibility and enhanced targeting efficiency, beneficial from self component and its physiological function. The construction methodology of cell-based carrier determines the effect on the physiological functions of transporting cell and affects its clinical application. There are different strategies to prepare cell-based carrier, such as direct internalization or surface conjugation of drugs or drug loaded materials. Thus, it is necessary to fully understand the advantages and disadvantages of different strategies for constructing cell-based carrier and then to seek the appropriate construction methodology for achieving better therapeutic results based on disease characterization. We here summarize the application of different types of cell-based carriers reported in recent years and further discuss their applications in disease therapy and the dilemmas faced in clinical translation. We hope that this summary can accelerate the process of clinical translation by promoting the technology development of cell-based carrier.

In vitro analysis of genome-engineered muscle-derived stem cells for autoregulated anti-inflammatory and antifibrotic activity.

Traumatic muscle injury leads to chronic and pathologic fibrosis in skeletal muscles, primarily driven through upregulation of transforming growth factor-β1 (TGF-β1). Cell-based therapies, such as injection of muscle-derived stem cells (MDSCs),have shown promise in muscle repair. However, injected MDSCs in injured skeletal muscle can differentiate into myofibroblasts under the influence of TGF-β1, and contribute to the development of fibrosis, limiting their regenerative potential. In this study, we created a "smart" cell-based drug delivery system using CRISPR-Cas9 to genetically engineer MDSCs capable of sensing TGF-β1 and producing an antifibrotic biologic, decorin. These gene-edited smart cells, capable of inhibiting fibrosis in a dose-dependent and autoregulating manner, show anti-inflammatory and antifibrotic properties in vitro, without changing the expression of myogenic and stem cell markers as well as their cell proliferation and myogenic differentiation. Additionally, differentiation down a fibrotic lineage is reduced or eliminated in response to TGF-β1. Our results show that gene editing can be used to successfully create smart stem cells capable of producing biologic drugs with antifibrotic capabilities in a controlled and localized manner. This system provides a tool for cell-based drug delivery as the basis for a novel therapeutic approach for a variety of diseases.

Blood cells as supercarrier systems for advanced drug delivery

In recent years, drug delivery has emerged as a more and more popular drug administration means for the improvement of pharmacokinetics, minimization of side effects, and enhancement of clinical outcomes. However, rapid clearance from the blood flow by immune systems limits the performance of drugs injected into the blood circulation. Thus, a new avenue for drug delivery systems by using the blood cells has drawn increasing attention. Blood cells can protect the drugs from macrophage uptake, prolong their circulation time, and improve their biocompatibility and stability. Here, we review recent advances in the developments and applications of numerous blood cell-based drug delivery systems and those inspired by blood cells. We highlight examples of vascular drug delivery using carriers red blood cells, white blood cells as well as platelets. We expect that this review will provide a jumping-off point or an inspiration for further investigation in this area.

Combination of Nanomaterials in Cell-Based Drug Delivery Systems for Cancer Treatment.

Cell-based drug delivery systems have shown tremendous advantages in cancer treatment due to their distinctive properties. For instance, delivery of therapeutics using tumor-tropic cells like neutrophils, lymphocytes and mesenchymal stem cells can achieve specific tumor targeting due to the “Trojan Horse” effect. Other circulatory cells like erythrocytes and platelets can greatly improve the circulation time of nanoparticles due to their innate long circulation property. Adipocytes, especially cancer-associated adipocytes, play key roles in tumor development and metabolism, therefore, adipocytes are regarded as promising bio-derived nanoplatforms for anticancer targeted drug delivery. Nanomaterials are important participants in cell-based drug delivery because of their unique physicochemical characteristics. Therefore, the integration of various nanomaterials with different cell types will endow the constructed delivery systems with many attractive properties due to the merits of both. In this review, a number of strategies based on nanomaterial-involved cell-mediated drug delivery systems for cancer treatment will be summarized. This review discusses how nanomaterials can be a benefit to cell-based therapies and how cell-derived carriers overcome the limitations of nanomaterials, which highlights recent advancements and specific biomedical applications based on nanomaterial-mediated, cell-based drug delivery systems.

Multistage targeted “Photoactive neutrophil” for enhancing synergistic photo-chemotherapy

Cell-based drug delivery system holds a great promise in anticancer treatment, due to its potential of maximizing therapeutic efficacy while minimizing adverse effects. However, current cell system can only deliver drugs in tumor lesions, but lack an ability to target subcellular locus of therapeutic actions, thereby compromising anticancer efficacy. Herein, we bioengineered living neutrophils as a novel type of “Photoactive neutrophil” (PAN) with capabilities of self-amplified multistage targeting and inflammation response for enhancing mitochondria-specific photo-chemotherapy. PAN encapsulated multifunctional nanocomplex (RA/Ce6) of RGD-apoptotic peptide conjugate (RA) decorated liposomal photosensitizer Ce6, and could overcome tumor barriers to selectively release RA/Ce6 within tumor. Consequently, RA/Ce6 actively entered cancer cells and accumulated in mitochondria to trigger combined photodynamic therapy (PDT) and RA-induced mitochondrial membrane disruption, resulting in enhanced therapeutic effects. Importantly, PAN exhibited inflammation amplified tumor targeting after PDT, and initiated combined photo-chemotherapy to suppress tumor growth without adverse effects, leading to prolonged mice survival. Therefore, PAN represents the first multistage targeted cell therapy, and brings new insights into cancer treatment.

Biomimetic cell-actuated artificial muscle with nanofibrous bundles

Biohybrid artificial muscle produced by integrating living muscle cells and their scaffolds with free movement in vivo is promising for advanced biomedical applications, including cell-based microrobotic systems and therapeutic drug delivery systems. Herein, we provide a biohybrid artificial muscle constructed by integrating living muscle cells and their scaffolds, inspired by bundled myofilaments in skeletal muscle. First, a bundled biohybrid artificial muscle was fabricated by the integration of skeletal muscle cells and hydrophilic polyurethane (HPU)/carbon nanotube (CNT) nanofibers into a fiber shape similar to that of natural skeletal muscle. The HPU/CNT nanofibers provided a stretchable basic backbone of the 3-dimensional fiber structure, which is similar to actin-myosin scaffolds. The incorporated skeletal muscle fibers contribute to the actuation of biohybrid artificial muscle. In fact, electrical field stimulation reversibly leads to the contraction of biohybrid artificial muscle. Therefore, the current development of cell-actuated artificial muscle provides great potential for energy delivery systems as actuators for implantable medibot movement and drug delivery systems. Moreover, the innervation of the biohybrid artificial muscle with motor neurons is of great interest for human-machine interfaces.

Primary Macrophage-Based Microrobots: An Effective Tumor Therapy In Vivo by Dual-Targeting Function and Near-Infrared-Triggered Drug Release.

Macrophages (MΦs) have the capability to sense chemotactic cues and to home tumors, therefore presenting a great approach to engineer these cells to deliver therapeutic agents to treat diseases. However, current cell-based drug delivery systems usually use commercial cell lines that may elicit an immune response when injected into a host animal. Furthermore, premature off-target drug release also remains an enormous challenge. Here, we isolated and differentiated MΦs from the spleens of BALB/c mice and developed dual-targeting MΦ-based microrobots, regulated by chemotaxis and an external magnetic field, and had a precise spatiotemporal controlled drug release at the tumor sites in response to the NIR laser irradiation. These microrobots were prepared by coloading citric acid (CA)-coated superparamagnetic nanoparticles (MNPs) and doxorubicin (DOX)-containing thermosensitive nanoliposomes (TSLPs) into the MΦs. CA-MNPs promoted a magnetic targeting function to the microrobots and also permitted photothermal heating in response to the NIR irradiation, triggering drug release from TSLPs. In vitro experiments showed that the microrobots effectively infiltrated tumors in 3D breast cancer tumor spheroids, particularly in the presence of the magnetic field, and effectively induced tumor cell death, further enhanced by the NIR laser irradiation. In vivo experiments confirmed that the application of the magnetic field and NIR laser could markedly inhibit the growth of tumors with a subtherapeutic dose of DOX and a single injection of the microrobots. In summary, the study proposes a strategy for the effective anticancer treatment using the developed microrobots.