Vectors For Targeted Delivery Research Articles

Therapeutic efficacy of an alpha-particle emitter labeled anti-GD2 humanized antibody against osteosarcoma-a proof of concept study.

Current treatments for osteosarcoma (OS) have a poor prognosis, particularly for patients with metastasis and recurrence, underscoring an urgent need for new targeted therapies to improve survival. Targeted alpha-particle therapy selectively delivers cytotoxic payloads to tumors with radiolabeled molecules that recognize tumor-associated antigens. We have recently demonstrated the potential of an FDA approved, humanized anti-GD2 antibody, hu3F8, as a targeted delivery vector for radiopharmaceutical imaging of OS. The current study aims to advance this system for alpha-particle therapy of OS. The hu3F8 antibody was radiolabeled with actinium-225, and the safety and therapeutic efficacy of the [225Ac]Ac-DOTA-hu3F8 were evaluated in both orthotopic murine xenografts of OS and spontaneously occurring OS in canines. Significant antitumor activity was proven in both cases, leading to improved overall survival. In the murine xenograft's case, tumor growth was delayed by 16-18days compared to the untreated cohort as demonstrated by bioluminescence imaging. The results were further validated with magnetic resonance imaging at 33days after treatment, and microcomputed tomography and planar microradiography post-mortem. Histological evaluations revealed radiation-induced renal toxicity, manifested as epithelial cell karyomegaly and suggestive polyploidy in the kidneys, suggesting rapid recovery of renal function after radiation damage. Treatment of the two canine patients delayed the progression of metastatic spread, with an overall survival time of 211 and 437days and survival beyond documented metastasis of 111 and 84days, respectively. This study highlights the potential of hu3F8-based alpha-particle therapy as a promising treatment strategy for OS.

Targeted delivery of PROTAC-based prodrug activated by bond-cleavage bioorthogonal chemistry for microneedle-assisted cancer therapy

Proteolysis-targeting chimera (PROTAC) is emerging as a new strategy to degrade target proteins in a precise way by taking advantage of the cellular ubiquitin-proteasome system. However, the potential cytotoxicity of PROTAC should be avoided to mitigate the off-target degradation of proteins in healthy tissues or cells. To address this issue, we herein present a strategy to cage a PROTAC with 4-(vinyloxy) benzyl carbonate (MZ1-O), which can be eliminated through a 3,6-dimethyl-1,2,4,5-tetrazine (Tz)-mediated inverse electron-demand Diels-Alder (iEDDA) reaction to generate a BRD4 (bromodomain-containing protein 4) degrader, MZ1. We further propose a dissolvable microneedle-assisted strategy for site-specific activation of MZ1-O that is delivered by a targeted delivery vector through systemic route in vivo, and demonstrate such a bioorthogonal strategy is efficient and precise for tumor treatment. Our study suggests that the bioorthogonal activation of PROTAC-based prodrug offers a highly specific and precise approach for cancer therapy.

Gold Complexes in Anticancer Therapy: From New Design Principles to Particle-Based Delivery Systems.

The discovery of the medicinal properties of gold complexes has fuelled the design and synthesis of new anticancer metallodrugs, which have received special attention due to their unique modes of action. Current research in the development of gold compounds with therapeutic properties is predominantly focused on the molecular design of drug leads with superior pharmacological activities, e.g., by introducing targeting features. Moreover, intensive research aims at improving the physicochemical properties of gold compounds, such as chemical stability and solubility in the physiological environment. In this regard, the encapsulation of gold compounds in nanocarriers or their chemical grafting onto targeted delivery vectors could lead to new nanomedicines that eventually reach clinical applications. Herein, we provide an overview of the state-of-the-art progress of gold anticancer compounds, andmore importantly we thoroughly revise the development of nanoparticle-based delivery systems for gold chemotherapeutics.

Gold Complexes in Anticancer Therapy: From New Design Principles to Particle‐Based Delivery Systems

AbstractThe discovery of the medicinal properties of gold complexes has fuelled the design and synthesis of new anticancer metallodrugs, which have received special attention due to their unique modes of action. Current research in the development of gold compounds with therapeutic properties is predominantly focused on the molecular design of drug leads with superior pharmacological activities, e.g., by introducing targeting features. Moreover, intensive research aims at improving the physicochemical properties of gold compounds, such as chemical stability and solubility in the physiological environment. In this regard, the encapsulation of gold compounds in nanocarriers or their chemical grafting onto targeted delivery vectors could lead to new nanomedicines that eventually reach clinical applications. Herein, we provide an overview of the state‐of‐the‐art progress of gold anticancer compounds, andmore importantly we thoroughly revise the development of nanoparticle‐based delivery systems for gold chemotherapeutics.

Mesoporous biophotonic carbon spheres with tunable curvature for intelligent drug delivery

Abstract Mesoporous carbon spheres (MCSs) are widely used in the field of pollutants adsorption, energy storage and various biomedicine applications such as targeted delivery vector, phototherapy sensitizers, bioimaging contrast agents, etc. Current synthetic strategies including soft templating and hard templating methods generally have the limits of using expensive surfactants or lack of control over the pore structures. Therefore, the complex and uncontrollable pore structures limit its further clinical application. Herein, we proposed a new synthetic strategy to control the uniformity of pore channel arrangement in MCSs which can modulate the photonic property and the corresponding light controlled drug release property in intelligent drug delivery. The as obtained MCSs with relative uniform pore channel arrangement and long pore channels are demonstrated to have the best NIR light-induced drug release performance. This work provides not only new synthetic method to modulate pore structure characteristics and biophotonic property of MCSs, but also uniform MCSs as novel delivery platforms with advanced controlled release performance.

Synthesis and characterization of curcumin-loaded pH/reduction dual-responsive folic acid modified carboxymethyl cellulose-based microcapsules for targeted drug delivery

In the present study, an eco-friendly, biodegradable, biocompatible, non-immunogenic, non-toxic polysaccharide, carboxymethyl cellulose (CMC), derivatived from renewable biomass cellulose, was used for designing and fabrication a folic acid modified pH and reduction dual-responsive carboxymethyl cellulose-based microcapsules (FA-PRCMCs). The curcumin (CUR)-loaded microcapsules (FA-PRCMCs@CUR) were prepared via a quick, efficient and environment-friendly sonochemical method, and were employed for the targeted delivery and pH/reduction dual-stimuli-responsive release of CUR. The excess CUR and ethyl acetate phases could be recycled and reused after preparation of FA-PRCMCs@CUR to avoid wasting resources and polluting the environment. The obtained FA-PRCMCs showed good biocompatibility and targeting in anti-tumor evaluation and endocytosis evaluation in vitro. FA-PRCMCs could effectively reduce the unnecessary damage to normal cells by chemotherapy drugs, and improve the utilization of chemotherapy drugs to reduce therapy costs. FA-PRCMCs could be used as smart targeted delivery vectors and have great clinical application potential.

Constructing of pH and reduction dual-responsive folic acid-modified hyaluronic acid-based microcapsules for dual-targeted drug delivery via sonochemical method

In this study, an eco-friendly, biodegradable, biocompatible, non-immunogenic, non-toxic polysaccharide hyaluronic acid (HA) was used to design and fabrication folic acid (FA)-modified pH and reduction-responsive HA-base microcapsules (FA-PRMCs). The microcapsules loaded with curcumin (CUR) are fabricated by a fast, economical and environmentally friendly sonochemical method. Ethyl acetate as the core solvent phase loaded with curcumin can be recycled and reused repeatedly. The obtained microcapsules showed good biocompatibility and targeting in anti-tumor evaluation and endocytosis evaluation in vitro. The responsive release characteristics of microcapsules could avoid side effects on normal tissues. As a low-cost intelligent targeted delivery vector, FA-PRMCs have great clinical application potential in the future.

Enhanced gene transfection of macrophages by photochemical internalization: Potential for gene-directed enzyme prodrug therapy of gliomas.

Drawn by tumor synthesis of chemo-attractive factors, macrophages are frequently found in and around glioblastomas and play an important role both in augmenting as well as inhibiting tumor growth. Patient-derived macrophages have the potential, therefore, to act as targeted delivery vectors for a variety of anti-cancer treatments. Among these is ex vivo gene transfection and re-injection back into the patient of macrophages to target residual tumors. In this study, photochemical internalization (PCI) is investigated as a technique for the non-viral transfection of the cytosine deaminase (CD) prodrug activating gene into macrophages. The CD gene encodes an enzyme that converts the nontoxic antifungal agent, 5-fluorocytosine (5-FC), into 5-fluorouracil (5-FU) - a potent chemotherapeutic agent. PCI (photosensitizer + light treatment) mediated CD gene transfection of rat alveolar Ma cells was carried out in vitro. CD gene transfected NR8383 macrophages were co-cultured with F98 rat glioma cells in the presence or absence of 5-FC. Cell viability was assayed using the MTS colorimetric assay. Compared to the glioma cells, NR8383 demonstrated enhanced resistance to the toxic effects of 5-FU. PCI greatly increased the transfection efficiency of the CD gene in NR8383 cells. The viability of F98 cells was significantly inhibited by coculture with CD transfected NR8383 macrophages and 5-FC. Although gene insertion into macrophages has proven difficult, the results presented here show that non-viral transfection of the CD gene into these immune cells can be enhanced via PCI. CD transfected NR8383 cells could efficiently convert 5-FC to 5-FU and export the drug, producing a pronounced bystander toxic effect on adjacent non-transfected glioma cells. Compared to single treatment, repetitive PCI-induced transfection was more efficient at low CD plasmid concentration.

Intestinal probiotics E. coli Nissle 1917 as a targeted vehicle for delivery of p53 and Tum-5 to solid tumors for cancer therapy

Traditional cancer therapies, such as surgery treatment, radiotherapy, and chemotherapy, often fail to completely eliminate tumor cells in an anaerobic microenvironment of tumor regions.In contrast to these traditional cancer therapies, the use of targeted delivery vectors to deliver anticancer genes or antitumor drugs to hypoxic areas in tumors is the most clinically promising cancer treatment with rapid development in recent years. In this study, E.coli Nissle 1917 (EcN), an intestinal probiotic, was utilized as a targeted transport vector to deliver p53 and Tum-5 protein to tumor hypoxic regions. The tumor-targeting characteristics of EcN were investigated using luciferase LuxCDABE operon, and the results demonstrated that EcN could specifically accumulate in the solid tumor areas of SMMC-7721 tumor-bearing BALB/c nude mice. The Tum 5-p53 bifunctional proteins were initially constructed and then delivered to solid tumor regions by using the targeted transporter EcN for cancer therapy. The antitumor effect and safety of three engineered bacteria, namely, EcN (Tum-5), EcN (p53), and EcN (Tum 5-p53), were also examined. The calculated tumor volume and tumor weight indicated that these three engineered bacteria could inhibit the growth of human hepatoma SMMC-7721 cells, and the antitumor effect of EcN (Tum 5-p53) expressing the Tum 5-p53 fusion protein was significantly better than those of EcN (Tum-5) and EcN (p53) alone. Immunofluorescence demonstrated that the expression of Ki-67, a nuclear proliferation-related protein, was inhibited in the tumor areas of the groups treated with the engineered bacteria, whereas the expression of caspase-3 was upregulated. The expression trends of Ki-67 and caspase-3 were consistent with the different antitumor efficacies of these three engineered bacteria. EcN did not elicit obvious side effects on mice. This research not only provids a foundation for tumor-targeted therapy but also contributes greatly to the development of antitumor agents and anticancer proteins.

Signed, Sealed, Delivered: Conjugate and Prodrug Strategies as Targeted Delivery Vectors for Antibiotics.

Innate and developed resistance mechanisms of bacteria to antibiotics are obstacles in the design of novel drugs. However, antibacterial prodrugs and conjugates have shown promise in circumventing resistance and tolerance mechanisms via directed delivery of antibiotics to the site of infection or to specific species or strains of bacteria. The selective targeting and increased permeability and accumulation of these prodrugs not only improves efficacy over unmodified drugs but also reduces off-target effects, toxicity, and development of resistance. Herein, we discuss some of these methods, including sideromycins, antibody-directed prodrugs, cell penetrating peptide conjugates, and codrugs.

Glycosylated Reversible Addition-Fragmentation Chain Transfer Polymers with Varying Polyethylene Glycol Linkers Produce Different Short Interfering RNA Uptake, Gene Silencing, and Toxicity Profiles.

Achieving efficient and targeted delivery of short interfering (siRNA) is an important research challenge to overcome to render highly promising siRNA therapies clinically successful. Challenges exist in designing synthetic carriers for these RNAi constructs that provide protection against serum degradation, extended blood retention times, effective cellular uptake through a variety of uptake mechanisms, endosomal escape, and efficient cargo release. These challenges have resulted in a significant body of research and led to many important findings about the chemical composition and structural layout of the delivery vector for optimal gene silencing. The challenge of targeted delivery vectors remains, and strategies to take advantage of nature's self-selective cellular uptake mechanisms for specific organ cells, such as the liver, have enabled researchers to step closer to achieving this goal. In this work, we report the design, synthesis, and biological evaluation of a novel polymeric delivery vector incorporating galactose moieties to target hepatic cells through clathrin-mediated endocytosis at asialoglycoprotein receptors. An investigation into the density of carbohydrate functionality and its distance from the polymer backbone is conducted using reversible addition-fragmentation chain transfer polymerization and postpolymerization modification.

Intracellular delivery of messenger RNA by recombinant PP7 virus-like particles carrying low molecular weight protamine.

BackgroundCell-penetrating peptides (CPPs) have been widely used as carriers to transport different molecules into living cells, whereas messenger RNAs (mRNAs) have been utilized as target molecules for the prevention and treatment of various diseases. However, the instability of CPPs and mRNAs has limited their application. Bacteriophage PP7 virus-like particles (VLPs) may protect peptides and RNAs from degradation through displaying foreign peptides on their surface and encapsidating RNA linked with the pac site.ResultsIn this study, the cDNA of the PP7 coat protein single-chain dimer carrying low molecular weight protamine (LMWP) and the cDNA of green fluorescent protein (GFP) were inserted into two multiple cloning sites of pETDuet-1, respectively. PP7 VLPs carrying the LMWP peptide and GFP mRNA were subsequently expressed in Escherichia coli BL21 (DE3) with high yield and thermal stability, and were easily purified. The VLPs were also non-replicative, non-infectious, and non-toxic. Moreover, they penetrated the mouse prostate cancer cells RM-1 after 24 h incubation. Last, PP7 VLPs carrying the LMWP could encapsidate the GFP mRNA, which was translated into mature protein in mammalian cells.ConclusionsRecombinant PP7 VLPs can be used simultaneously as a targeted delivery vector for both peptides and mRNA due to their abilities to package RNA and display peptides.Electronic supplementary materialThe online version of this article (doi:10.1186/s12896-016-0274-9) contains supplementary material, which is available to authorized users.

Mesoporous Silica Nanoparticles: A Potential Targeted Delivery Vector for Reproductive Biology?

Over the last decade, biomedical nanotechnology has revolutionized existing approaches for the prevention, diagnosis and treatment of a variety of medical conditions, including cancer, microbial and viral infections, and chronic internal diseases. This innovative approach has also given rise to a number of sensitive tools to investigate the specific mechanisms underlying these conditions. Accumulation of evidence for the improved performance of nanomaterial-based techniques over conventional research and therapeutic approaches will inevitably promote the rapid dissemination of nanobiotechnological ‘vision’ to a growing number of research and clinical disciplines, including reproductive biology, which has until recently received only scant attention.

Therapeutic siRNAs and nonviral systems for their delivery

Gene-directed therapy with small interfer-ring RNA (siRNA) has a tremedous potential and in the future will undoubtly occupy one of the leading positions among other therapeutic methods. The lack of efficient and targeted delivery vectors delays the successful implementation of this method in clinic. To develop such systems, one needs a comprehansive insight into the processes of interactions between siRNAs, its delivery systems and an organism. This review covers properties of therapeutic siRNAs and non-viral systems for their delivery.

Bone marrow derived mesenchymal stem cells incorporate into the prostate during regrowth.

BackgroundProstate cancer recurrence involves increased growth of cancer epithelial cells, as androgen dependent prostate cancer progresses to castrate resistant prostate cancer (CRPC) following initial therapy. Understanding CRPC prostate regrowth will provide opportunities for new cancer therapies to treat advanced disease.Methodology/Principal FindingsElevated chemokine expression in the prostate stroma of a castrate resistant mouse model, Tgfbr2fspKO, prompted us to look at the involvement of bone marrow derived cells (BMDCs) in prostate regrowth. We identified bone marrow cells recruited to the prostate in GFP-chimeric mice. A dramatic increase in BMDC recruitment for prostate regrowth occurred three days after exogenous testosterone implantation. Recruitment led to incorporation of BMDCs within the prostate epithelia. Immunofluorescence staining suggested BMDCs in the prostate coexpressed androgen receptor; p63, a basal epithelial marker; and cytokeratin 8, a luminal epithelial marker. A subset of the BMDC population, mesenchymal stem cells (MSCs), were specifically found to be incorporated in the prostate at its greatest time of remodeling. Rosa26 expressing MSCs injected into GFP mice supported MSC fusion with resident prostate epithelial cells through co-localization of β-galactosidase and GFP during regrowth. In a human C4-2B xenograft model of CRPC, MSCs were specifically recruited. Injection of GFP-labeled MSCs supported C4-2B tumor progression by potentiating canonical Wnt signaling. The use of MSCs as a targeted delivery vector for the exogenously expressed Wnt antagonist, secreted frizzled related protein-2 (SFRP2), reduced tumor growth, increased apoptosis and potentiated tumor necrosis.Conclusions/SignificanceMesenchymal stem cells fuse with prostate epithelia during the process of prostate regrowth. MSCs recruited to the regrowing prostate can be used as a vehicle for transporting genetic information with potential therapeutic effects on castrate resistant prostate cancer, for instance by antagonizing Wnt signaling through SFRP2.

A Strategy for Adenovirus Vector Targeting with a Secreted Single Chain Antibody

BackgroundSuccessful gene therapy will require targeted delivery vectors capable of self-directed localization. In this regard, the use of antibodies or single chain antibody fragments (scFv) in conjunction with adenovirus (Ad) vectors remains an attractive means to achieve cell-specific targeting. However, a longstanding barrier to the development of Ad vectors with genetically incorporated scFvs has been the biosynthetic incompatibility between Ad capsid proteins and antibody-derived species. Specifically, scFv require posttranslational modifications not available to Ad capsid proteins due to their cytoplasmic routing during protein synthesis and virion assembly.Methodology/Principal FindingsWe have therefore sought to develop scFv-targeted Ad vectors using a secreted scFv that undergoes the requisite posttranslational modifications and is trafficked for secretion. Formation of the scFv-targeted Ad vector is achieved via highly specific association of the Ad virion and a targeting scFv employing synthetic leucine zipper-like dimerization domains (zippers) that have been optimized for structural compatibility with the Ad capsid and for association with the secreted scFv. Our results show that zipper-containing Ad fiber molecules trimerize and incorporate into mature virions and that zippers can be genetically fused to scFv without ablating target recognition. Most importantly, we show that zipper-tagged virions and scFv provide target-specific gene transfer.Conclusions/SignificanceThis work describes a new approach to produce targeted Ad vectors using a secreted scFv molecule, thereby avoiding the problem of structural and biosynthetic incompatibility between Ad and a complex targeting ligand. This approach may facilitate Ad targeting using a wide variety of targeting ligands directed towards a variety of cellular receptors.

Dendrimers and the Double Helix - From DNA Binding Towards Gene Therapy

This article focuses on the ability of dendritic molecules to interact with nucleic acids and hence deliver them into cells. Dendritic molecules have branched structures which are made by an iterative, layer-by-layer synthesis. The control applied in their synthesis means that dendrimers are well-defined nanoscale molecular species - ideal for interacting with nanoscale bio-targets such as DNA/RNA. Binding and delivery of genetic material into cells in vivo holds out the prospect of gene therapy, and we will consider the potential advantages of dendritic vectors in this field of nanomedicine. As this article illustrates, the synthetic versatility of dendritic molecules has enabled the synthesis of a wide array of DNA binders and delivery vehicles, with different advantages. This versatility forms the basis for optimism that the dendritic approach may well yield active, highly targeted delivery vectors, suitable for in vivo application in gene therapy.

Effects of camptothecin on tumor cell proliferation and angiogenesis when coupled to a bombesin analog used as a targeted delivery vector

The camptothecin-bombesin conjugate termed DC-51-43, as a novel targeted drug delivery system, was examined in over 10 human tumor cell lines and shows a potent antiproliferative activity. This conjugate has also demonstrated its antitumor activity in our previous experiments. In our present study, we evaluate this conjugate for its antiangiogenic activity by in-vitro and in-vivo experiments. The camptothecin-bombesin conjugate and free camptothecin show potent in-vitro inhibitory activities of cell adhesion to various extracellular matrix components and integrins alphaVbeta3 and alphaVbeta5, not beta1/alphabeta1. This conjugate displays inhibitory activity to cell migration and invasion at concentrations of 10 micromol/l or above. This conjugate is also effective against in-vitro capillary-like tube formation of endothelial cells (at 40 micromol/l), and in-vivo angiogenesis as seen by blocking the spread of host mice endothelial cells into matrigel plugs. These experimental results support the fact that the camptothecin-bombesin conjugate has therapeutic activities against angiogenesis. By binding to bombesin receptor-expressing sites, this bombesin analog, consisting of 11 amino acids, is potentially a novel delivery vector for nonspecific cytotoxic agents.