Approach For Targeted Delivery Research Articles

Novel Techniques Targeting Fibroblasts after Ischemic Heart Injury.

The great plasticity of cardiac fibroblasts allows them to respond quickly to myocardial injury and to contribute to the subsequent cardiac remodeling. Being the most abundant cell type (in numbers) in the heart, and a key participant in the several phases of tissue healing, the cardiac fibroblast is an excellent target for treating cardiac diseases. The development of cardiac fibroblast-specific approaches have, however, been difficult due to the lack of cellular specific markers. The development of genetic lineage tracing tools and Cre-recombinant transgenics has led to a huge acceleration in cardiac fibroblast research. Additionally, the use of novel targeted delivery approaches like nanoparticles and modified adenoviruses, has allowed researchers to define the developmental origin of cardiac fibroblasts, elucidate their differentiation pathways, and functional mechanisms in cardiac injury and disease. In this review, we will first characterize the roles of fibroblasts in the different stages of cardiac repair and then examine novel techniques targeting fibroblasts post-ischemic heart injury.

Targeted delivery approaches for synthesis of plant based nanoparticles as anticancer chemotherapeutics

Natural resources, with their immense structural variety, continue to be a vital source of fresh, novel chemical entities with therapeutic usefulness. Current therapy regimens require selective drug targeting to increase action on cancer cells while reducing harm to normal cells. Modified medications and drug delivery systems based on nanotechnology are being developed and launched into the market for better cancer therapy and management, with promising outcomes. This study highlights nanotechnology-based drug delivery vehicles as well as a few targeted delivery methodologies for the manufacture of plant-based nanoparticles that can be further investigated for the creation of more anticancer medications.

Sympathetic Neurostress Drives Osteoblastic Exosomal MiR-21 Transfer to Disrupt Bone Homeostasis and Promote Osteopenia.

Innervation and extracellular vesicle secretion co-exist in the local tissue microenvironment for message transfer, but whether they are interconnected to regulate organ homeostasis remains unknown. Sympatho-adrenergic activation is implicated in stress-induced depression and leads to bone loss, but the mechanisms and therapeutics are incompletely elucidated. Here, it is revealed that sympathetic neurostress through the β1/2 -adrenergic receptor (β1/2-AR) signaling triggers the transcription response of a microRNA, miR-21, in osteoblasts, which is transferred to osteoclast progenitors via exosomes for dictating osteoclastogenesis. After confirming that miR-21 deficiency retards the β1/2-AR agonist isoproterenol (ISO)-induced osteopenia, it is shown that the pharmacological inhibition of exosome release by two clinically-relevant drugs, dimethyl amiloride and omeprazole, suppresses osteoblastic miR-21 transfer and ameliorates bone loss under both ISO and chronic variable stress (CVS)-induced depression conditions. A targeted delivery approach to specifically silence osteoblastic miR-21 is further applied, which is effective in rescuing the bone remodeling balance and ameliorating ISO- and CVS-induced osteopenias. These results decipher a previously unrecognized paradigm that neural cues drive exosomal microRNA communication to regulate organ homeostasis and help to establish feasible strategies to counteract bone loss under psychological stresses.

Receptor-Mediated Targeted Delivery of Surface-ModifiedNanomedicine in Breast Cancer: Recent Update and Challenges.

Breast cancer therapeutic intervention continues to be ambiguous owing to the lack of strategies for targeted transport and receptor-mediated uptake of drugs by cancer cells. In addition to this, sporadic tumor microenvironment, prominent restrictions with conventional chemotherapy, and multidrug-resistant mechanisms of breast cancer cells possess a big challenge to even otherwise optimal and efficacious breast cancer treatment strategies. Surface-modified nanomedicines can expedite the cellular uptake and delivery of drug-loaded nanoparticulate constructs through binding with specific receptors overexpressed aberrantly on the tumor cell. The present review elucidates the interesting yet challenging concept of targeted delivery approaches by exploiting different types of nanoparticulate systems with multiple targeting ligands to target overexpressed receptors of breast cancer cells. The therapeutic efficacy of these novel approaches in preclinical models is also comprehensively discussed in this review. It is concluded from critical analysis of related literature that insight into the translational gap between laboratories and clinical settings would provide the possible future directions to plug the loopholes in the process of development of these receptor-targeted nanomedicines for the treatment of breast cancer.

Nucleic Acid-Based Treatments Against COVID-19: Potential Efficacy of Aptamers and siRNAs.

Despite significant efforts, there are currently no approved treatments for COVID-19. However, biotechnological approaches appear to be promising in the treatment of the disease. Accordingly, nucleic acid-based treatments including aptamers and siRNAs are candidates that might be effective in COVID-19 treatment. Aptamers can hamper entry and replication stages of the SARS-CoV-2 infection, while siRNAs can cleave the viral genomic and subgenomic RNAs to inhibit the viral life cycle and reduce viral loads. As a conjugated molecule, aptamer–siRNA chimeras have proven to be dual-functioning antiviral therapy, acting both as virus-neutralizing and replication-interfering agents as well as being a siRNA targeted delivery approach. Previous successful applications of these compounds against various stages of the pathogenesis of diseases and viral infections, besides their advantages over other alternatives, might provide sufficient rationale for the application of these nucleic acid-based drugs against the SARS-CoV-2. However, none of them are devoid of limitations. Here, the literature was reviewed to assess the plausibility of using aptamers, siRNAs, and aptamer–siRNA chimeras against the SARS-CoV-2 based on their previously established effectiveness, and discussing challenges lie in applying these molecules.

Emerging targeted drug delivery strategies toward ovarian cancer.

Ovarian cancer is a high-mortality malignancy in women. The contemporary clinical chemotherapy with classic cytotoxic drugs, targeted molecular inhibitors would mostly fail when ovarian cancer cells become drug-resistant or metastasize through the body or when patients bare no more toleration because of strong adverse effects. The past decade has spotted varying targeted delivery systems including antibody-drug conjugates (ADCs), peptide/folate/aptamer-drug conjugates, polymer-drug conjugates, ligand-functionalized nanomedicines, and dual-targeted nanomedicines that upgrade ovarian cancer chemo- and molecular therapy effectively in preclinical/clinical settings via endowing therapeutic agents selectivity and bypassing drug resistance as well as lessening systemic toxicity. The targeted delivery approaches further provide means to potentiate emergent treatment modalities such as molecular therapy, gene therapy, protein therapy, photodynamic therapy, dual-targeting therapy and combination therapy for ovarian cancer. This review highlights up-to-date development of targeted drug delivery strategies toward advanced, metastatic, relapsed, and drug resistant ovarian cancers.

Biocompatible copper sulfide-based nanocomposites for artery interventional chemo-photothermal therapy of orthotropic hepatocellular carcinoma.

Transcatheter arterial embolization has been considered as a promising targeted delivery approach for hepatocellular carcinoma (HCC). Currently, chemoembolization was the main treatment for unresectable HCC. However, the traditional chemoembolization treatment suffers from undesirable therapeutic effects and serious side-effects. In this study, the doxorubicin (DOX)-encapsulated and near-infrared (NIR)–responsible copper sulfide (CuS)–based nanotherapeutics was developed for magnetic resonance imaging (MRI)–guided chemo-photothermal therapy of HCC tumor in rats. The DOX-loaded CuS nanocomposites (DOX@BSA-CuS) demonstrated distinct NIR-triggered drug release behavior and high photothermal effect. In an orthotopic HCC rat model, DOX@BSA-CuS nanocomposites were selectively delivered to the tumor site via the intra-arterial transcatheter. The proposed DOX@BSA-CuS nanocomposites plus NIR laser irradiation exhibited significant tumor growth suppression performance. Moreover, the treatment progress can be monitored by MRI images. Finally, the preliminary toxicity estimate suggested the negligible side-effect of DOX@BSA-CuS nanocomposites during the therapeutic process. These results suggest the clinical translational potential possibility for imaging-guided arterial embolization with DOX@BSA-CuS nanocomposites for the treatment of HCC.

Onco-Receptors Targeting in Lung Cancer via Application of Surface-Modified and Hybrid Nanoparticles: A Cross-Disciplinary Review

Lung cancer is among the most prevalent and leading causes of death worldwide. The major reason for high mortality is the late diagnosis of the disease, and in most cases, lung cancer is diagnosed at fourth stage in which the cancer has metastasized to almost all vital organs. The other reason for higher mortality is the uptake of the chemotherapeutic agents by the healthy cells, which in turn increases the chances of cytotoxicity to the healthy body cells. The complex pathophysiology of lung cancer provides various pathways to target the cancerous cells. In this regard, upregulated onco-receptors on the cell surface of tumor including epidermal growth factor receptor (EGFR), integrins, transferrin receptor (TFR), folate receptor (FR), cluster of differentiation 44 (CD44) receptor, etc. could be exploited for the inhibition of pathways and tumor-specific drug targeting. Further, cancer borne immunological targets like T-lymphocytes, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and dendritic cells could serve as a target site to modulate tumor activity through targeting various surface-expressed receptors or interfering with immune cell-specific pathways. Hence, novel approaches are required for both the diagnosis and treatment of lung cancers. In this context, several researchers have employed various targeted delivery approaches to overcome the problems allied with the conventional diagnosis of and therapy methods used against lung cancer. Nanoparticles are cell nonspecific in biological systems, and may cause unwanted deleterious effects in the body. Therefore, nanodrug delivery systems (NDDSs) need further advancement to overcome the problem of toxicity in the treatment of lung cancer. Moreover, the route of nanomedicines’ delivery to lungs plays a vital role in localizing the drug concentration to target the lung cancer. Surface-modified nanoparticles and hybrid nanoparticles have a wide range of applications in the field of theranostics. This cross-disciplinary review summarizes the current knowledge of the pathways implicated in the different classes of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. Furthermore, it focuses specifically on the significance and emerging role of surface functionalized and hybrid nanomaterials as drug delivery systems through citing recent examples targeted at lung cancer treatment.

Targeted knockdown of the adenosine A2A receptor by lipid NPs rescues the chemotaxis of head and neck cancer memory T cells

In solid malignancies, including head and neck squamous cell carcinoma (HNSCC), the immunosuppressive molecule adenosine, which accumulates in the tumor, suppresses cytotoxic CD8+ T cell functions including chemotaxis and tumor infiltration. Adenosine functions through binding to the adenosine A2A receptor (A2AR) present on T cells. In order to increase T cell migration into the tumor, the negative effect of adenosine must be abrogated. Systemic drug treatments targeting A2AR are available; however, they could lead to negative toxicities due to the broad expression of this receptor. Herein, we developed a lipid nanoparticle (NP)-based targeted delivery approach to knock down A2AR in T cells in order to increase their chemotaxis in the presence of adenosine. By using flow cytometry, immunofluorescence, qRT-PCR, and 3D-chemotaxis, we demonstrated that CD45RO-labeled nanoparticles delivering ADORA2A gene-silencing-RNAs decreased ADORA2A mRNA expression and rescued the chemotaxis of HNSCC CD8+ memory T cells. Overall, the data indicate that targeting the adenosine signaling pathway with lipid NPs is successful at suppressing the inhibitory effect of adenosine on the chemotaxis of HNSCC memory T cells, which could ultimately help increase T cell infiltration into the tumor.

Nanoparticles Targeting Receptors on Breast Cancer for Efficient Delivery of Chemotherapeutics.

The journey of chemotherapeutic drugs from the site of administration to the site of action is confronted by several factors including low bioavailability, uneven distribution in major organs, limited accessibility of drug molecules to the distant tumor tissues, and lower therapeutic indexes. These unavoidable features of classical chemotherapeutics necessitate an additional high, repetitive dose of drugs to obtain maximum therapeutic responses with the result of unintended adverse side effects. An erratic tumor microenvironment, notable drawbacks of conventional chemotherapy, and multidrug-resistant mechanisms of breast cancer cells warrant precisely designed therapeutics for the treatment of cancers. In recent decades, nanoparticles have been deployed for the delivery of standard anticancer drugs to maximize the therapeutic potency while minimizing the adverse effects to increase the quality and span of life. Several organic and inorganic nanoplatforms that have been designed exploiting the distinctive features of the tumor microenvironment and tumor cells offer favorable physicochemical properties and pharmacokinetic profiles of a parent drug, with delivery of higher amounts of the drug to the pathological site and its controlled release, thereby improving the balance between its efficacy and toxicity. Advances to this front have included design and construction of targeted nanoparticles by conjugating homing devices like peptide, ligand, and Fab on the surface of nanomaterials to navigate nanoparticledrug complexes towards the target tumor cell with minimal destruction of healthy cells. Furthermore, actively targeting nanoparticles can facilitate the delivery and cellular uptake of nanoparticle-loaded drug constructs via binding with specific receptors expressed aberrantly on the surface of a tumor cell. Herein, we present an overview of the principle of targeted delivery approaches, exploiting drug-nanoparticle conjugates with multiple targeting moieties to target specific receptors of breast cancer cells and highlighting therapeutic evaluation in preclinical studies. We conclude that an understanding of the translational gap and challenges would show the possible future directions to foster the development of novel targeted nanotherapeutics.

Epigenetics in Breast Cancer Therapy-New Strategies and Future Nanomedicine Perspectives.

Simple SummaryDespite advances in cancer treatment, difficult-to-treat tumor subtypes remain a challenge. New multidisciplinary approaches can help overcome current obstacles posed by tumor heterogeneity, activation and enrichment of cancer stem cells, and acquired drug resistance development. Epigenome modulation, currently unsuccessful in solid tumors due to epigenetic drug instability, toxicity, and off-target effects, might be enabled by implementing nano-based delivery strategies aiming to improve breast cancer patient outcomes.Epigenetic dysregulation has been recognized as a critical factor contributing to the development of resistance against standard chemotherapy and to breast cancer progression via epithelial-to-mesenchymal transition. Although the efficacy of the first-generation epigenetic drugs (epi-drugs) in solid tumor management has been disappointing, there is an increasing body of evidence showing that epigenome modulation, in synergy with other therapeutic approaches, could play an important role in cancer treatment, reversing acquired therapy resistance. However, the epigenetic therapy of solid malignancies is not straightforward. The emergence of nanotechnologies applied to medicine has brought new opportunities to advance the targeted delivery of epi-drugs while improving their stability and solubility, and minimizing off-target effects. Furthermore, the omics technologies, as powerful molecular epidemiology screening tools, enable new diagnostic and prognostic epigenetic biomarker identification, allowing for patient stratification and tailored management. In combination with new-generation epi-drugs, nanomedicine can help to overcome low therapeutic efficacy in treatment-resistant tumors. This review provides an overview of ongoing clinical trials focusing on combination therapies employing epi-drugs for breast cancer treatment and summarizes the latest nano-based targeted delivery approaches for epi-drugs. Moreover, it highlights the current limitations and obstacles associated with applying these experimental strategies in the clinics.

Mitochondrial-induced Epigenetic Modifications: From Biology to Clinical Translation.

Mitochondria are maternally inherited semi-autonomous organelles that play a central role in redox balance, energy metabolism, control of integrated stress responses, and cellular homeostasis. The molecular communication between mitochondria and the nucleus is intricate and bidirectional in nature. Though mitochondrial genome encodes for several key proteins involved in oxidative phosphorylation, several regulatory factors encoded by nuclear DNA are prominent contributors to mitochondrial biogenesis and function. The loss of synergy between this reciprocal control of anterograde (nuclear to mitochondrial) and retrograde (mitochondrial to nuclear) signaling, triggers epigenomic imbalance and affects mitochondrial function and global gene expressions. Recent expansions of our knowledge on mitochondrial epigenomics have offered novel perspectives for the study of several non-communicable diseases including cancer. As mitochondria are considered beacons for pharmacological interventions, new frontiers in targeted delivery approaches could provide opportunities for effective disease management and cure through reversible epigenetic reprogramming. This review focuses on recent progress in the area of mitochondrial-nuclear cross-talk and epigenetic regulation of mitochondrial DNA methylation, mitochondrial micro RNAs, and post-translational modification of mitochondrial nucleoid-associated proteins that hold major opportunities for targeted drug delivery and clinical translation.

Targeted, Site-Specific, Delivery Vehicles of Therapeutics for COVID-19 Patients. Brief Review.

Definitive pharmacological therapies for COVID-19 have yet to be identified. Several hundred trials are ongoing globally in the hope of a solution. However, nearly all treatments rely on systemic delivery but COVID-19 damages the lungs preferentially. The use of a targeted delivery approach is reviewed where engineered products are able to reach damaged lung tissue directly, which includes catheter-based and aerosol-based approaches. In this review we have outlined various target directed approaches which include microbubbles, extracellular vesicles including exosomes, adenosine nanoparticles, novel bio-objects, direct aerosol targeted pulmonary delivery and catheter-based drug delivery with reference to their relative effectiveness for the specific lesions. Currently several trials are ongoing to determine the effectiveness of such delivery systems alone and in conjunction with systemic therapies. Such approaches may prove to be very effective in the controlled and localized COVID-19 viral lesions in the lungs and potential sites. Moreover, localized delivery offered a safer delivery mode for such drugs which may have systemic adverse effects.

Stable Immune Response Induced by Intradermal DNA Vaccination by a Novel Needleless Pyro-Drive Jet Injector

DNA vaccination can be applied to the treatment of various infectious diseases and cancers; however, technical difficulties have hindered the development of an effective delivery method. The efficacy of a DNA vaccine depends on optimal antigen expression by the injected plasmid DNA. The pyro-drive jet injector (PJI) is a novel system that allows for adjustment of injection depth and may, thus, provide a targeted delivery approach for various therapeutic or preventative compounds. Herein, we investigated its potential for use in delivering DNA vaccines. This study evaluated the optimal ignition powder dosage, as well as its delivery effectiveness in both rat and mouse models, while comparing the results of the PJI with that of a needle syringe delivery system. We found that the PJI effectively delivered plasmid DNA to intradermal regions in both rats and mice. Further, it efficiently transfected plasmid DNA directly into the nuclei, resulting in higher protein expression than that achieved via needle syringe injection. Moreover, results from animal ovalbumin (OVA) antigen induction models revealed that animals receiving OVA expression plasmids (pOVA) via PJI exhibited dose-dependent (10 μg, 60 μg, and 120 μg) production of anti-OVA antibodies; while only low titers (< 1/100) of OVA antibodies were detected when 120 μg of pOVA was injected via needle syringe. Thus, PJI is an effective, novel method for delivery of plasmid DNA into epidermal and dermal cells suggesting its promise as a tool for DNA vaccination.

Development of an intravaginal ring for the topical delivery of Aurora kinase A inhibitor, MLN8237.

Human papilloma virus (HPV) is the main culprit in cervical cancers. Although the HPV vaccine is now available, the slow and gradual process for HPV cancers to form means little will change, even for vaccinated individuals. This warrants the development of new therapeutic strategies in both the newly diagnosed and recurrent patients. We have previously shown that Alisertib (MLN8237), an Aurora A kinase inhibitor, potently and selectively kills HPV-positive cervical cancer cells. However, Alisertib is known for its unfavorable side effects when administered systemically. A targeted delivery approach is therefore warranted. The topical delivery of drugs to the cervix for the treatment of cervical cancer is an underexplored area of research that has the potential to significantly improve therapeutic outcome. Here, we design a novel topical drug delivery system for localized delivery in the vaginal tract using intravaginal silicone rings loaded with Alisertib. We assessed the suitability of the drug for the application and delivery method and develop a high-performance liquid chromatography method, then show that the vaginal rings were effective at releasing Alisertib over an extended period of time. Furthermore, we showed that Alisertib-loaded vaginal rings did not induce overt inflammation in the mouse vaginal tract. Our work has major translational implications for the future development of vaginal ring devices for the topical treatment of cervical cancer.

Abstract 983: Antibody-drug conjugates of NAMPT inhibitors: Discovery, optimization, and preclinical characterization

Abstract Nicotinamide phosphoribosyltransferase (NAMPT) regulates the biosynthesis of NAD from nicotinamide via a salvage biosynthetic pathway. Inhibition of NAMPT depletes cellular NAD levels leading to disruption of energy metabolism and cell death. Non-targeted small molecule NAMPT inhibitors have demonstrated poor tolerability in clinical trials and in preclinical models, including cardiac and retinal toxicities in rats. In an effort to improve the therapeutic window of this drug class, we pursued a targeted-delivery approach using antibody-drug conjugates. Through a medicinal chemistry effort, we identified novel NAMPT inhibitors that incorporate chemical functionality in the solvent-exposed terminus to allow construction of enzyme-cleavable drug linkers. Additionally, we applied a pyridinium-based linker strategy that allows for traceless linker attachment through a conserved nicotinamide-mimetic moiety of NAMPT inhibitors. Candidate molecules were evaluated for NAMPT binding affinity and cellular cytotoxicity as free drugs, and for cellular cytotoxicity as ADCs with the alternate linker strategies. Comparisons across inhibitors and linker strategies provide insight into optimal design of cleavable drug linkers for this class of drugs. In vitro, the ADCs deplete NAD and lead to downstream ATP depletion in a time-dependent manner. In vivo evaluation using human tumor xenografts shows translation of the pharmacodynamic effect resulting in tumor regression in models of Hodgkin lymphoma, non-Hodgkin lymphoma, and acute myeloid leukemia. Toxicology studies in Sprague Dawley rats demonstrate excellent tolerability at active doses, with no observable cardiac or retinal toxicities at the highest tested doses in single- and multi-dose regimens. These findings detail the development of a novel payload class and optimized linker strategy for use with antibody-drug conjugates, and demonstrate a preclinical efficacy and safety profile to support continued efforts toward clinical therapeutics. Citation Format: Chris Neumann, Kathleen C. Olivas, Kung Pern Wang, Andrew B. Waight, David W. Meyer, Luke V. Loftus, Margo C. Zaval, Martha E. Anderson, Steven Jin, Julia H. Cochran, Jessica K. Simmons, Paul G. Pittman, Fu Li, Michelle L. Ulrich, Abbie Wong, Weiping Zeng, Robert P. Lyon, Peter D. Senter. Antibody-drug conjugates of NAMPT inhibitors: Discovery, optimization, and preclinical characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 983.

Layer-by-layer nanoparticles for novel delivery of cisplatin and PARP inhibitors for platinum-based drug resistance therapy in ovarian cancer.

Advanced staged high‐grade serous ovarian cancer (HGSOC) is the leading cause of gynecological cancer death in the developed world, with 5‐year survival rates of only 25–30% due to late‐stage diagnosis and the shortcomings of platinum‐based therapies. A Phase I clinical trial of a combination of free cisplatin and poly(ADP‐ribose) polymerase inhibitors (PARPis) showed therapeutic benefit for HGSOC. In this study, we address the challenge of resistance to platinum‐based therapy by developing a targeted delivery approach. Novel electrostatic layer‐by‐layer (LbL) liposomal nanoparticles (NPs) with a terminal hyaluronic acid layer that facilitates CD44 receptor targeting are designed for selective targeting of HGSOC cells; the liposomes can be formulated to contain both cisplatin and the PARPi drug within the liposomal core and bilayer. The therapeutic effectiveness of LbL NP‐encapsulated cisplatin and PARPi alone and in combination was compared with the corresponding free drugs in luciferase and CD44‐expressing OVCAR8 orthotopic xenografts in female nude mice. The NPs exhibited prolonged blood circulation half‐life, mechanistic staged drug release and targeted codelivery of the therapeutic agents to HGSOC cells. Moreover, compared to the free drugs, the NPs resulted in significantly reduced tumor metastasis, extended survival, and moderated systemic toxicity.

Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

Spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody–drug conjugates and other targeted delivery approaches. Unfortunately, it is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive. As a result, the design and synthesis of more acid-stable and linker functional group-equipped analogs that retain the low picomolar potency of the parent natural product requires more efficient and step-economical synthetic access. Using uniquely enabling direct complex fragment coupling crotyl- and alkallylsilylation reactions, we report a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is characterized by GI50 values in the low picomolar range, and a proof-of-concept result that the C(15) acetate may be replaced with linker functional group-bearing esters with only minimal reductions in potency.

ADME Considerations for the Development of Biopharmaceutical Conjugates Using Cleavable Linkers.

The recent approval of trastuzumab emtansine (Kadcyla®) and brentuximab vedotin (Adcetris ®) has spurred tremendous investment in new approaches for the targeted delivery of pharmaceutical agents. Targeted delivery approaches, such as Antibody Drug Conjugates (ADCs), typically rely on an endogenous or exogenous "trigger" that results in the release of the pharmacologically active agent at the intended site of action. Lysosomal and intracellular triggers include proteolytic cleavage, glycolytic cleavage, phosphatase cleavage, hydrolytic cleavage, and reductive cleavage. Recent work has also illustrated that exogenous triggers and extracellular enzymes can be harnessed to result in linker cleavage at the site of action. As these linker technologies have grown, so also has our understanding of the biophysical parameters that drive exposure and stability. The growth in targeted delivery approaches has also driven advancement in bioanalytical strategies for assessing the distribution, processing, and metabolism of these agents. This review provides a systematic overview of each of these areas, particularly focusing on recent advancements in the field that has the potential to expand the scope of therapeutic areas that ADCs and other targeted delivery approaches can be designed to address.

Targeted Delivery of STAT-3 Modulator to Breast Cancer Stem-Like Cells Downregulates a Series of Stemness Genes.

Cancer stem cells are known to be controlled by pathways that are dormant in normal adult cells, for example, PTEN, which is a negative regulator of transcription factor STAT3. STAT3 regulates genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of enormous clinical significance. Studies on breast cancer stem cells (BCSC) have been also significantly correlated with STATs. We describe here for the first time a novel strategy to selectively target CSCs and to induce downregulation of STAT3 downstream target genes reducing expression of series of "stem-ness genes" in treated tumors. In vitro and in vivo experiments were performed to evaluate functional activity with gene and protein expression studies. The results of the study indicate that this targeted delivery approach deactivates STAT3 causing a reduction of CD44+/CD24- CSC populations with aptly tracked gene and protein regulations of "stemness" characteristics. Mol Cancer Ther; 17(1); 119-29. ©2017 AACR.