Drug Targeting: Organ-Specific Strategies, Volume 12
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Although interaction identified in our PPI networks can be affected by the different normalization methods utilized by different platforms for our microarray data. In this study, we mainly focus on the comparison of regeneration PPI networks constructed for different organs. As a result, we were able to integrate data from different platforms for the comparison.
Several hub proteins were related to cell proliferation, cell cycle, and angiogenesis. For instance, H2afx, which regulates the G1-to-S-phase transition of the cell cycle, was identified to be a hub protein of the PPI networks of cerebellum, fin, and retina regeneration [ 21 ]. Another hub protein identified in all four regenerative PPI networks was Hdac1, which interacts with retinoblastoma tumor-suppressor protein, forming a complex that is key in the control of cell proliferation and differentiation [ 22 ].
Rb1 protein recruits chromatin-modifying enzymes and prevents the transcription of multiple cell cycle genes [ 23 ]. It is an inhibitor of the cell cycle and stabilizes constitutive heterochromatin to maintain the overall chromatin structure during regeneration [ 23 ]. The identification of these hub proteins partially validates our constructed PPI networks. Further analysis was performed to compare the four constructed regenerative PPI networks as follows: i identification of core proteins, which are a set of proteins obtained from overlaps across all four regenerative PPI networks, and ii further identification of core PPI networks, which correspond to those PPI networks associated with these core proteins in each organ regeneration network.
As a result, core proteins were observed in the four regenerative networks. The number of edges of the four core PPI networks was for heart, for cerebellum, for fin, and for retina, respectively. The figures and complete lists for core networks are included and illustrated in S2 File and the GO biological processes of the core proteins are recorded in S3 File.
Since there might also exist specialized molecular functions during the regeneration process of different organs, organ-specific proteins were identified by taking the relative complement set of each regenerative PPI network with respect to other three PPI networks see S4 File for a complete list of organ-specific proteins.
In other words, an organ-specific protein is a unique protein that only exists in the regenerative PPI network of a particular organ. The top three enriched pathways are shown in order with their corresponding proteins see S5 File for complete pathway classification of both the core and organ-specific proteins.
In contrast, the primary pathways of the organ-specific proteins of the heart were the integrin signaling and the FGF signaling pathways. FGF is a family of growth factors, with members involved in angiogenesis, wound healing, embryonic development, and various endocrine signaling pathways. The primary pathway for cerebellum-specific proteins was identified as Wnt signaling.
Wnt signaling has been recognized for its role in embryonic development control, including body axis patterning, cell fate specification, cell proliferation, and cell migration. It was reported that stimulation of Wnt signaling increases the number of neurogenic progenitors, which react to injury by proliferating and generating neuroblasts that migrate to the lesion site to repair damaged tissue in zebrafish cerebellum [ 26 , 27 ].
The primary pathways of the organ-specific proteins for fin regeneration were angiogenesis and Wnt signaling. Angiogenesis is a normal and vital process in growth, development, wound healing, and in the formation of granulation tissue, whereas Wnt signaling has been reported to regulate the nerve reconstruction and blastema cell proliferation in fin regeneration experiments [ 28 , 29 ].
These pathways are related to neurons, indicating an influence on the regeneration of optic neurons. These pathways may play important roles during the regeneration processes, and further investigation of the zebrafish regeneration mechanism will be discussed in the Discussion section. In this study, we propose a multi-step recalled-blastema-like formation model and attempt to classify the roles of the primary pathways both in core proteins and organ-specific proteins based on this model.
Blastema is generally defined as a group of cells that gives rise to an organ or part in either normal development or regeneration. The first step in regeneration is the injury response step. The second step is de-differentiation, where blastema can be derived from the de-differentiation of various functional cell types, such as skeletal muscle, dermis, and cartilage [ 32 ].
The next step is the recalled-blastema-like formation step. Broadly speaking, fibroblasts from the connective tissue migrate across the injured surface to meet at the center of the wound and then multiply to form a blastema. A blastema is a proliferative mass of morphologically similar cells that can develop into the structures lost after trauma. The fourth step is the differentiation of recalled-blastema-like formation and pattern formation step.
Drug Targeting: Organ-specific Strategies (Methods and Principles in Medicinal Chemistry)
The model whereby blastema tissue differentiates into epithelial, chondrogenic, and osteogenic tissues is highly regarded in studies of wound repair [ 34 ]. Pattern formation is the reproducible generation of complex and self-regulating patterns, where Wnt signaling was proposed to play a dual role: as an activator during the process, and as an inhibitor after the process [ 35 ]. Although the datasets are limited to within five days after injury and while differentiation and pattern formation might not occur within these five days, we use this step to select candidate proteins for differentiation and pattern formation.
The last step is the recovery step, which can be considered the termination step of regeneration. Map3k7, which controls cellular functions of transcriptional regulation and apoptosis, was identified as a core protein in all four regenerative core PPI networks. Map3k7 may be crucial to the regeneration of zebrafish organs due to its regulation of apoptosis and cell survival [ 25 , 36 ].
Based on our result, Map3k7 might play a role in preventing wound deterioration through regulation of apoptosis and cell survival as part of the injury response during zebrafish organ regeneration Fig. We proposed a multiple-step recalled-blastema-like formation model, including injury response, de-differentiation, recalled-blastema-like formation, differentiation, and pattern formation steps. The length of the arrows in the figure indicates duration of activities during the regeneration process.
Map3k7 removes excessively damaged cells and also augments the survival of slightly damaged cells in the injury response step. In the second step, a source of recalled-blastema-like formation is produced by Mapk1 and Mapk3, which promote proliferation and de-differentiation in undamaged cells, which is induced by impaired tissue. In the third step, Smad2 and Smad7 act as antagonists while Smurf2 promotes the expression of Smad7.
They coordinate the accumulation of stem cells and recalled-blastema-like formation to prepare for differentiation and pattern formation in the next step. Jun and Smad3 regulate the G1 phase of the cell cycle and mediate cell fate while Skib and Spaw regulate pattern formation. The last step can be viewed as termination of the regeneration process. Amongst the regenerative core proteins identified through our regenerative PPI networks, we also observed two other mitogen-activated protein kinases: Mapk3 and Mapk1, also known as Erk1 and Erk2.
As the downstream proteins of Map3k7, Mapk3 and Mapk1 participate in the regulation of a large variety of processes including cell adhesion, cell cycle progression, cell migration, cell survival, differentiation, metabolism, proliferation, and transcription [ 37 ]. The source of stem cells comes from the de-differentiation and proliferation of unimpaired cells, and Mapk1 and Mapk3 have been reported to support the regulation of cell proliferation during liver and nerve regeneration [ 38 , 39 ].
They have also been reported to mediate de-differentiation of hepatocytes through the epithelial-mesenchymal transition [ 40 ]. Both Mapk1 and Mapk3 were observed as core proteins, indicating that, in zebrafish organ regeneration, Mapk1 and Mapk3 may play a role in blastema de-differentiation to develop into the structures lost after trauma Fig. Smad2 expression within the blastema was increased during tail regeneration in the leopard gecko, while Smad7 regulates blastema formation at the early stage of zebrafish fin regeneration, indicating indispensable roles for Smad2 and Smad7 in the zebrafish blastema [ 41 , 42 ].
It was also reported that mice lacking exon 1 of the Smad7 gene exhibited reduced neural stem and progenitor cell quiescence and proliferation in the lateral ventricles, indicating that Smad7 regulates stem cell activity [ 43 ]. Thus, Smad7 may act as a regulator for zebrafish recalled-blastema-like formation alongside the antagonist Smad2 and enhancer Smurf2; and we speculate that Smad2, Smad7, and Smurf2 play a role in coordinating the formation of the recalled-blastema-like during zebrafish organ regeneration.
Smad3 and Jun have been reported to participate in the regulation of G1 to S phase cell cycle transitions by maintaining sufficient cyclin D1 kinase activity [ 44 , 45 ]. Additionally, Smad3 has been reported to co-mediate and control the differentiation of stem cells into T-cells, myofibroblasts, oligodendrocyte progenitors, and others [ 46 ]. It was proposed that the regulation of the G1 phase of the cell cycle might affect cell type during the differentiation of human embryonic stem cells [ 47 ]. Similarly, the regulation of the G1 phase by Jun indicated that Jun might regulate differentiation ability in zebrafish.
Consequently, we anticipate that Smad3 and Jun may participate in mediating the differentiation of the recalled-blastema-like into the proper cell types during zebrafish regeneration Fig. Skib and Spaw were also identified as core proteins based on our comparisons. We speculate that the biological function of these two proteins might be involved in pattern formation as part of the underlying mechanism for zebrafish organ regeneration processes.
In previous experiments, overexpression of Skib resulted in a dorsalized phenotype while inhibition of Skib led to the loss of head structures during the development of zebrafish embryos, demonstrating that Skib can regulate pattern formation [ 48 , 49 ]. Furthermore, an experiment on the asymmetric development of cardiac morphogenesis in zebrafish showed that Spaw is required for a correct left-and-right asymmetry pattern for the migration of cardiac progenitor cells [ 50 ].
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Increased expression of Spaw also results in looping defects in the zebrafish heart [ 51 ]. Despite the limitation of the time course microarray data to within three days, these studies provide evidence of the potential roles played by Spaw and Skip in pattern formation by progenitor cells Fig. However, we also believe that other important mechanisms exist, which are specific to particular organs during the zebrafish regeneration process. This topic will be discussed in the following sections. Since there is very little information regarding the gonadotropin releasing hormone receptor pathway which was one of the primary pathway in heart regeneration studies, we will focus our discussion on the second primary pathway.
One of prominent functions of integrins is to regulate the binding affinity of fibrin and fibrinogen for blood platelets. At the same time, the fibroblast growth factor FGF signaling pathway and platelet-derived growth factor PDGF signaling pathway were also observed among the organ-specific proteins for the heart regeneration process in our PPI network. FGF and its receptors participate in the regulation of cell differentiation, proliferation, angiogenesis, and survival [ 53 ], while the PDGF signaling pathway controls the binding of platelets to fibrin to form clots and stop bleeding [ 54 ].
It has been proposed that FGF signaling interacts directly with integrin signaling [ 55 ], such that PDGF and FGF may co-regulate binding affinity for fibrin and fibrinogen to allow for rapid hemostasis through the mediation of integrins during heart injury. This might serve as the primary regenerative strategy for heart regeneration during the injury response step Fig.
Regeneration strategy of proteins specific to the heart, cerebellum, fin, and retina in the recalled-blastema-like regenerative model. In heart-specific proteins, Integrin, PDGF, and FGF co-regulate binding affinity of fibrin and fibrinogen for platelets to speed hemostasis in the injury response step. In cerebellum-specific pathways, Wnt signaling promotes formation of the recalled-blastema-like formation via Wnt3 and participates in the regulation of neuronal differentiation and cerebellum structure via Wnt3a and Ppp2ca. For fin-specific proteins, it was observed that angiogenesis provides nutrition to promote the recalled-blastema-like formation and pattern formation through Wnt signaling.
In retina-specific proteins, Bdnf enhances optic cell survivability and stabilizes the regeneration process. These proteins may trigger differentiation and de-differentiation processes for the zebrafish regeneration process. Wnt3 expression is positively correlated with the proliferation of neural stem cells, promoting neuron proliferation [ 56 ].
The promotion of neural stem cell proliferation by Wnt3 indicates the formation of the recalled-blastema-like, and can be classified in the recalled-blastema-like formation step of the regenerative model, as shown in Fig. Siah1 has been reported to be involved in the CNS injury response [ 57 ]. Wnt3a is required for the formation of cerebellum structures and participates in the regulation of cerebellum structure, indicating that it has a role in pattern formation in the proliferating blastema, while Ppp2ca participates in the differentiation of neural stem cells [ 56 , 58 ].
These cerebellum-specific proteins can be classified into the differentiation and pattern formation steps of the recalled-blastema-like regenerative model Fig.
These neuron-related studies support the possibility that the Wnt signaling pathway plays an essential role in cerebellum regeneration. Overall, the focus of the regeneration strategy of the cerebellum may be on the proliferation of neural stem cells and the following differentiation and pattern formation of injured tissue through Wnt signaling. In the case of zebrafish fin regeneration, the primary pathway enriched in organ-specific proteins was angiogenesis, and this included Mapk14a, Axin2, Pdgfaa, and Hspb1 See Table 2. One of the angiogenesis proteins, Mapk14a, known as p38a, has been reported to regulate the differentiation of myoblasts, prevent fibrosis, and to improve and repair muscles [ 59 ].
Skeletal muscle differentiation was shown to be mediated by both the muscle-specific transcription factor myogenin and Mapk14a [ 60 ]. Without Mapk14a signaling, myogenin may lead to the down-regulation of genes involved in cell cycle progression [ 60 ]. Another identified organ-specific protein, Axin2, is involved in cell differentiation and the regulation of osteoblast differentiation.
Additionally, Pdgfaa was shown to participate in the positive regulation of cell proliferation and migration [ 61 ]. It has been reported that the release of Pdgfaa greatly promotes the effective recruitment of human mesenchymal stem cells [ 62 ]. Overall, Mapk14a and Axin2 co-regulate the regeneration of bone and muscle, while Pdgfaa accelerates these processes through the recruitment of stem cells.
These proteins can be classified in the recalled-blastema-like formation and pattern formation steps of our recalled-blastema-like regeneration model Fig. An experiment into the axonal regeneration of retinal ganglion cells indicated that Bdnf promotes short-term cell survival after optic nerve injury [ 65 ], indicating the essential role played by Bdnf in retinal regeneration.
Given that the upregulation of these neurodegenerative pathways might have a negative effect on the neuron regeneration process and cause secondary damage to neural systems, the activation of Bdnf in retina-specific proteins may indicate the importance of preventing such secondary damage in neurons during zebrafish retina regeneration. It has been reported that Bdnf promotes and stabilizes the morphological maturation of retinal axonal arbors by influencing both the synapses and axon branches, indicating that Bdnf also helps stabilize the retina regeneration process [ 66 ].
Consequently, the primary regenerative strategy of retina-specific proteins may be to prevent secondary damage to the retinal neurons and to augment the survival of optic cells during the injury response step Fig. For organ-specific proteins, we also observed rapid hemostasis through the co-regulation of integrins, PDGF, and FGF in heart-specific proteins during the injury response step. For cerebellum-specific proteins, Wnt signaling participates in neural stem cell proliferation through mediation by Wnt3 and differentiation by Ppp2ca. For fin-specific proteins, both Mapk14a and Axin2 regulate the differentiation of myoblasts and osteoblasts.
By conducting the analysis using our recalled-blastema-like formation model, we provided a model to explain the proteins, interaction and their roles in regeneration process of zebrafish. Moreover, these proteins could be used as targets for further study into the underlying mechanism of zebrafish organ regeneration.
Zebrafish were maintained based on the guidelines described in the Zebrafish Book. Test subjects were first anesthetized using a mixture of MS Sigma-Aldrich and isoflurane Baxter , to allow for faster recovery and achieve a higher success rate after surgery. Different phenotypes of injured zebrafish heart. The stages of heart regeneration after amputation arranged by day, including a uncut, b 1 dpa, c 4 dpa, d 10 dpa, e 18 dpa, and f 30 dpa. The disadvantage of the system is high cost, which makes productivity more difficult and the reduced ability to adjust the dosages.
Targeted drug delivery systems have been developed to optimize regenerative techniques. The system is based on a method that delivers a certain amount of a therapeutic agent for a prolonged period of time to a targeted diseased area within the body. This helps maintain the required plasma and tissue drug levels in the body, thereby preventing any damage to the healthy tissue via the drug.
The drug delivery system is highly integrated and requires various disciplines, such as chemists, biologists, and engineers, to join forces to optimize this system. In traditional drug delivery systems such as oral ingestion or intravascular injection, the medication is distributed throughout the body through the systemic blood circulation. For example, by avoiding the host's defense mechanisms and inhibiting non-specific distribution in the liver and spleen,  a system can reach the intended site of action in higher concentrations.
Targeted delivery is believed to improve efficacy while reducing side-effects. When implementing a targeted release system, the following design criteria for the system must be taken into account: the drug properties, side-effects of the drugs, the route taken for the delivery of the drug, the targeted site, and the disease.
Increasing developments to novel treatments requires a controlled microenvironment that is accomplished only through the implementation of therapeutic agents whose side-effects can be avoided with targeted drug delivery. Advances in the field of targeted drug delivery to cardiac tissue will be an integral component to regenerate cardiac tissue. There are two kinds of targeted drug delivery: active targeted drug delivery, such as some antibody medications, and passive targeted drug delivery, such as the enhanced permeability and retention effect EPR-effect.
This ability for nanoparticles to concentrate in areas of solely diseased tissue is accomplished through either one or both means of targeting: passive or active. Several substances can achieve this, with one of them being polyethylene glycol PEG. By adding PEG to the surface of the nanoparticle, it is rendered hydrophilic, thus allowing water molecules to bind to the oxygen molecules on PEG via hydrogen bonding. The result of this bond is a film of hydration around the nanoparticle which makes the substance antiphagocytic. The particles obtain this property due to the hydrophobic interactions that are natural to the reticuloendothelial system RES , thus the drug-loaded nanoparticle is able to stay in circulation for a longer period of time.
Active targeting of drug-loaded nanoparticles enhances the effects of passive targeting to make the nanoparticle more specific to a target site. There are several ways that active targeting can be accomplished. One way to actively target solely diseased tissue in the body is to know the nature of a receptor on the cell for which the drug will be targeted to.
This form of active targeting was found to be successful when utilizing transferrin as the cell-specific ligand. This means of targeting was found to increase uptake, as opposed to non-conjugated nanoparticles. Active targeting can also be achieved by utilizing magnetoliposomes, which usually serves as a contrast agent in magnetic resonance imaging. Furthermore, a nanoparticle could possess the capability to be activated by a trigger that is specific to the target site, such as utilizing materials that are pH responsive.
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However, some areas of the body are naturally more acidic than others, and, thus, nanoparticles can take advantage of this ability by releasing the drug when it encounters a specific pH. One of the side effects of tumors is hypoxia , which alters the redox potential in the vicinity of the tumor. By modifying the redox potential that triggers the payload release the vesicles can be selective to different types of tumors. By utilizing both passive and active targeting, a drug-loaded nanoparticle has a heightened advantage over a conventional drug.
It is able to circulate throughout the body for an extended period of time until it is successfully attracted to its target through the use of cell-specific ligands, magnetic positioning, or pH responsive materials. Because of these advantages, side effects from conventional drugs will be largely reduced as a result of the drug-loaded nanoparticles affecting only diseased tissue. There are different types of drug delivery vehicles, such as polymeric micelles, liposomes, lipoprotein-based drug carriers, nano-particle drug carriers, dendrimers, etc.
An ideal drug delivery vehicle must be non-toxic, biocompatible, non-immunogenic, biodegradable,  and must avoid recognition by the host's defense mechanisms . The most common vehicle currently used for targeted drug delivery is the liposome. The low infusion rates require one to make up drugs and compounds at concentrations that may be outside of the solubility range. In addition, the flow rate of an osmotic mini pump is fixed and once implanted it cannot be stopped and restarted. Therefore, in order to infuse several different solutions over time or generate a dose response, implanting new osmotic mini pumps or using mini pumps with cannulas filled with different solutions separated by bubbles or mineral oil to prevent mixing 12 are required.
The purpose of this study was to develop an improved method to chronically deliver drugs to specific organs for targeted drug delivery. In these proof of concept experiments, we targeted the medullary region of the kidney because chronic tethered catheter use has been instrumental in our understanding of kidney physiolgy 5 , 6 , 7. C The pump fits in a subcutaneous pocket on the dorsal side of the rat. Rats were fed a normal salt diet 0. For all animal surgeries, proper aseptic technique was used, and all drapes, supplies, surgery tools and gloves were sterilized.
A small incision is made through the skin and muscle, and the kidney exposed. The adrenal gland of the left kidney was carefully freed from the upper pole of the renal capsule before the renal pedicle is ligated with silk suture Ethicon, Summerville, NJ and the kidney removed. The muscle was sutured closed with prolene suture Ethicon and the skin was closed with surgical staples. The animal was placed in a clean cage and allowed to recover for 7 days before the pump surgery.
These pumps are In the MS study see below the pumps were new but in the dDAVP study see below the pumps were sterilized and reused. The sterilization protocol in listed in Supplementary Note 1. The joint between catheters was sealed and secured by a small drop of superglue Fig.
The pump was then placed subcutaneously on the back, and sutured into the muscle Fig. The muscles were then sutured together and the skin closed with staples. The rats were allowed to recover for 2 days prior to delivery of drugs or saline. Detailed explanation of the surgery is located in Supplementary Note 1 and can be found in the Nature Protocol Exchange. The pump was then filled with either vehicle, 1. Emptying and refilling of the pumps was all done via a syringe and needle percutaneously without the need to re-open the wound and externalize the pump.
The rats were also challenged with high salt diet 4. Flow rate accuracy was determined ex vivo and in vivo with new and previous used pumps. For in vivo determination, pumps were programmed listed in Table 1 and implanted as described above. From either the weight ex vivo or volume in vivo the volume pumped was plotted against time and linear regression analysis performed.
The slopes calculated from these data were compared to the slope of the expected volumes. Mean s. The supernatant herein referred to as lysate from this spin was used to determine expression of AQP2 and phosphorylated AQP2. Histones were then extracted from the nuclear pellet by acid extraction with 5 volumes of 0.
Flow rate accuracy of the pumps in both an in vivo and ex vivo setting was determined using a variety of programs in the pumps.
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The manufacturer did not provide any accuracy measurements in an in vivo setting. Reused pumps were also evaluated in ex vivo and in vivo settings. Finally, with a subset of the in vivo pumps, there were 2 varied flow rate protocols: 1. Food intake, sodium, potassium and chloride excretion and creatinine clearance were similar between the groups Fig. Rats were switched from a normal salt NS to high salt diet plus intramedullary infusion. C Urine osmolality was significantly increased with dDAVP interstitial infusion, compared to saline infused rats dotted line. To confirm catheter position, each kidney was dissected at the insertion site Fig.
S2A , and catheter placement was determined by tracing the track left by the catheter Fig. Proper placement was seen in all 8 animals, with the catheter track ending at the junction between the outer OM and inner medulla IM Fig. MS resulted in a significantly higher H3 acetylation compared to vehicle infused rats in the OM, but there were no significant differences in acetylation status in the cortical samples. As shown in Fig.
Chronic catheterization is used in both basic science research with animal models, and in the clinic to deliver drugs and other agents. An unfortunate side effect of chronic catheter use is biofilm accumulation and infection 8 , because they must be externalized to a pump. Thus, there is a need to improve on current methodologies. In the current study, small programmable, implantable peristaltic pumps were used to deliver drugs to the renal medulla. The medulla of the kidney plays a critical role in the regulation of whole body water homeostasis. This is predominantly regulated through the actions of the hormone vasopressin acting on the renal collecting duct to promote water channel aquaporin-2 expression, phosphorylation and apical surface expression resulting in water retention anti-diuresis In the current study, we present the use of implantable pumps to deliver the vasopressin receptor-2 agonist, dDAVP to the interstitial region of the renal medulla.
As predicted, delivery of dDAVP to the renal medulla led to an increase in all of the hallmark signs of water retention. There were no incidences of infection in either the kidney, or around the pump. This experiment confirms that implantable pumps are ideal for delivery of drugs to specific organs than the classical used of externalized catheters. Histone deacetylase inhibitors have emerged as novel therapeutic interventions for the treatment of not only cancer, but also cardiovascular and neurological diseases Specific organ or tumor delivery of HDAC inhibitors may also help prevent undesirable side effects, such as hyponatremia that have been reported with systemic HDAC inhibitor interventions 22 , In the current study, the Class I HDAC inhibitor, MS was used to demonstrate the specificity of delivery that can be achieved with implantable pumps.