Drug Delivery of Angiogenic Factors

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Overview of Angiogenesis

Angiogenesis, or the development of new blood vessels, is a critical process in human biology. This development can occur as the extension of new blood vessels from existing vessels in the body, or as de novo formation (Patel & Mikos, 2004). Primarily, vasculogenesis, or the de novo formation, will occur during the developmental stages of an embryo. Although, vasculogenesis has been shown to occur in adulthood as well.  Angiogenesis from existing blood vessels occurs more frequently in adulthood as it as an important mechanism in multiple pathologies as well as wound healing (Bhise, Shmueli, Sunshine, Tzeng, & Green, 2011).

Stages of Angiogenesis

Angiogenesis occurs in multiple stages of blood vessel formation. First, upon the secretion and sensing of various growth factors, such as VEGF, EGF, FGF, TGF-beta, endothelial cells that line vessel walls will be stimulated to undergo angiogenesis. Of these growth factors, VEGF is of the most importance. The second stage of angiogenesis involves pericyte detachment from the vascular wall. Normally, pericytes will stabilize the vasculature so their detachment, and then recruitment of other proteases, will stimulate basement membrane degradation. After basement membrane degradation, endothelial cells that line the vessel wall will begin to form sprouts as the tip cell migrates along an angiogenic factor gradient. Tube formation follows tip cell migration and the endothelial cells begin to differentiate and proliferate to extend the sprouting. Different signaling pathways become present at later stages of angiogenesis. Particularly, Notch1 and DLL4 become increasingly more important in vessel formation during these later stages where they regulate vessel size. Finally, pericytes will be recruited to the new blood vessels that have formed to stabilize the new structures. PDGF, in particular, becomes increasingly more important at this later stage as it will stimulate pericyte reattachment and then reduce the proliferation of new endothelial cells. Overall, growth factors and receptors that regulate the process of angiogenesis undergo excessive crosstalk and modulate the development at various stages and in varying degrees, making the overall formation of new blood vessels a highly complex process.

Figure 1: Stages of Angiogenesis

Types of Angiogenesis

In addition to de novo vasculogenesis and the capillary growth that occurs during angiogenesis, blood vessels can also form as a result of collateral vessel growth. During this type of angiogenic response, occlusions in one vessel can stimulate the formation of a branch to another vessel due to mechanical induced strains (Carmeliet, 2003). This remodeling of the blood vessels is seen during myocardial and peripheral ischemia, but in response to these disease states, collateral blood vessels may not be capable of fully re-establishing blood supply and vascular function to the tissue (Patel & Mikos, 2004).

Angiogenic Related Diseases

As mentioned previously, angiogenesis is a critical mechanism during multiple disease states. Depending on the disease state, angiogenesis will be upregulated or downregulated. Disease states that involve a downregulation or inhibition of angiogenesis leads to pathology including chronic wounds, myocardial ischemia, peripheral arterial disease, neuropathies, and more (Patel & Mikos, 2004). Also, pro-angiogenesis is an essential step in organ transplant or integrating scaffolds into surrounding tissue.  Vascular structure tends to be the limiting factor in engineered tissue replacements (Patel & Mikos, 2004).  On the other hand, diseases such as cancer, psoriasis, arthritis, asthma, Alzheimer’s disease, and macular degeneration involve an upregulation in angiogenesis that contributes to furthered pathogenesis. In treating these various disease states, it is critical to utilize the correct growth factors or drugs that would elicit either a pro or anti-angiogenic response depending on the specific pathology.

Growth Factors and Drugs Associated with Angiogenesis

As mentioned previously, there are a variety of growth factors and drugs associated with angiogenesis whether in a promoting or inhibiting way.  As laid out in Table 1 there are some interesting overlaps and correlations that continue to need to be explored.

Early Stages

Growth factors that are involved in the angiogenic process become critical at various stages during the process. These early stage growth factors that are extremely critical in angiogenesis include VEGF, EGF, FGF, and TGF-beta. VEGF is the most important growth factor in this process, but others have been studied as well including IGF-1 plasmid in promoting angiogenesis in vivo (Rabinovsky & Draghia-Akli, 2004) for example. However, there are certain limitations involved with the delivery of growth factors as a therapeutic use. Limitations of using and delivering growth factors as a therapeutic strategy include short half-lives, fast clearance rates, and off-target side-effects. Additionally, if administering drugs systemically in small doses, there is an increased risk of drug resistance.  Table 1 displays a variety of known growth factors and the associated effects.

Table 1: Known Growth Factors and Their Roles (Carmeliet, 2003; Gale et al., 2000; Somiraa S. Said J. Geoffrey Pickering Kibret Mequanint, 2012)

Limitations

Limitations do exist in the delivery of angiogenic factors as they are not specific to a desired tissue and will have an increased uptake when delivered systemically.  Many types of cells share receptors pertaining to certain growth factors that includes VEGF.  Delivering of these growth factors without any guidance or specific targeting these growth factors can accumulate in off-target sites and could cause certain negative effects.  As with other drugs, depending on the drug delivery method absorption and excretion can be varying, and thus it is important to control these parameters as well as others to optimize the effectiveness of said drug or growth factor.

Negative Side Effects

Most negative side effects extend from increased wall permeability due to the delivery of these initial growth factors such as VEGF.  The immature vasculature stimulated has leaky walls as the strength and stability has yet to be accomplished.  This occurring in off-site tissue can induce effects that are not desirable.  As we will mention in anti-angiogenic therapies, tumors benefit from induced angiogenesis during growth that allows sustained oxygen and nutrient supply to the core of the tumor.  Releasing pro-angiogenic growth factors could stimulate dormant tumor growth in the body and help establish its vascular network.  Besides potential tumor sites benefiting from angiogenic activity, increased permeability could cause edemas and abnormal blood vessels.  Thus, it is important to reduce the exposure that off-site tissue has to growth factors delivered as a drug therapy.

Growth factors associated with later stages of angiogenic activity share less effects as do the growth factors expressed at early stages, but these mature stage growth factors tend to have little to no desired effect without the initial trigger of the initial process but they still could be associated with abnormal vessel growth and other adverse effects (Stephen E. Epstein, MD; Ran Kornowski, MD; Shmuel Fuchs, & MD; Harold F. Dvorak, 2001).  Most limitations exist with the timing of release of such growth factors.  As mentioned previously the delivery of pro-maturing factors could find its way to tumor or other desirable areas and continue to progress the malignant tissue.  Tumors tend to express unorganized and leaky vasculature and the addition of pro-maturation could help stabilize and sustain the tumor nutrient supply.  Besides a targeted delivery, it is important to deliver a delayed release or dosage to present the right trigger for continued maturation of the tissue.  If the growth factors are delivered too early or before initial stages have been started, one may see little effect or even inhibition of the other growth factors needed for initialization.

Anti-Angiogenic Effects

Many anti-angiogenic factors that can be used as therapeutics to stop the progression of vessel formation work to inhibit the “activated” endothelial cell from sprouting. To inhibit the cellular responses of the sprouting endothelial cells, anti-angiogenic agents may work to hinder migration, proliferation, and the ability of these endothelial cells to form vascularization out of existing capillaries. Natural agents that work to inhibit angiogenesis include angiostatin and endostatin (Patel & Mikos, 2004). However, other agents have been synthetically made to inhibit angiogenesis. These agents include TNP-470 and thalidomide(Patel & Mikos, 2004).

Gene Delivery

One way that pro-angiogenic or anti-angiogenic factors are delivered is through the presentation of DNA to cells in the tissue and the vascularization.  This allows for certain growth factor protein production, blocking certain pathways or inhibiting of receptors to prevent overexpressed factors from triggering a response due to the presence of growth factors to instigate the desired effects.  There are many different methods of presenting these DNA strands which include DNA plasmids, adenoviruses, retroviruses and even lentiviruses (Somiraa S. Said J. Geoffrey Pickering Kibret Mequanint, 2012).  There are many different ways in which DNA can be presented but there still exists some risk with introducing foreign DNA and viruses into a patient for treatment.  These could trigger an immune response or immunization from further effectiveness if the delivery mechanism does not consider these responses.  One example is the delivery of a VEGF plasmid DNA by a viral vector known as CMV or cytomegalovirus (Chang et al., 2016). Other strategies for anti-angiogenic therapeutics, which are currently in phase II clinical trials, involve delivering a pro-apoptotic transgene after targeting tumor endothelial cells (Gruslova et al., 2015).

Cell Delivery

Cell delivery is another attractive strategy to stimulate or inhibit the angiogenic process. Because whole cell delivery has its own limitations, the use of exosomes as a natural source of cellular products has been studied, especially for wound healing applications (Rani & Ritter, 2016). In particular, mesenchymal stem cell extracellular vesicles have shown to enhance tubule formation in human umbilical vein endothelial cells (J. Zhang et al., 2015). Additionally, extracellular vesicles from CD34+ cells, which are cell that have been shown to increase angiogenesis in ischemic tissue, have been examined and have shown to also enhance angiogenesis and the length of vessel formation in human umbilical vein endothelial cells (Sahoo et al., 2011). Some studies have elucidated the mechanism behind certain extracellular vesicles in activating angiogenesis. For example, extracellular vesicles from mesenchymal stem cells are involved in the upregulation of signaling pathways such as AKT, ERK, and STAT3 and induce expression of specific growth factors (HGF, IGF1, and NGF) (Shabbir, Cox, Rodriguez-Menocal, Salgado, & Van Badiavas, 2015). Although it is unclear of the exact mechanisms behind how extracellular vesicles can promote angiogenesis, the use of these cellular components is an attractive strategy for therapeutic wound healing because it could reduce the limitation with direct whole cell implantation such as rejection and retention.  Autologous cells are another way to bypass this immune response where analogous cells have failed, but this system could be slow and time consuming to produce enough cells ex vivo. Current clinical trials do exist that are able to harvest autologous cells from the body and either reprogram or redeliver to certain areas in the body.  Ixymyelocel-T is a treatment option that utilizes this by harvesting certain key mononuclear cells from a patient’s bone marrow and use as treatment for patients with ischemic heart failure.

Drug Delivery

As we have gained understanding, we see the importance of specific drug delivery for many types of drug therapies and treatments.  This has essentially been utilized in many different disease states to allow for maximum effect while reducing off-target effects.  There are a variety of ways to deliver drugs which include through digestion and absorption in the intestines to systemically through the blood.  Also, there are potentials in some situations to allow local delivery as well as release from a drug depot that can be implanted.  Thus, there are a variety of methods for drug delivery and determine the best system for each scenario is difficult and a challenge on its own.

Systemic delivery as mentioned before as it pertained to growth factors has limitations as the blood can potentially expose the entire body to a drug or effect.  Also, physiological systems are in play to filter and breakdown material as it flows through the blood.  Thus, the key considerations for systemic delivery include reducing exposure to off target tissue, increasing circulation time to allow more drug effect, and retention at the desired location.  Chemotherapy as it pertained to cancer treatment initially was done by utilizing the fact that tumors tend to exhibit leaky vasculature and increased EPR effect.  This hoped that drugs would leak out into the tumor environment from the blood and increase retention. As this was shown to be the case, it still did little to stop the effect of the majority percentage of drug that accumulated at other tissues including the kidney and liver.  Thus, it is important to expand on current treatments and increase retention needed at desired locations.

Local and sustained delivery is another method for drug delivery.  Either by injecting drugs into tissues or implanting scaffolds/depots into the tissues, one has a first-stop location for drug delivery.  This is not always the easiest case depending on the location of the region.  Obviously, this is utilized in superficial wounds or sites, but this does require the integration of the implantation to fuse with surrounding tissue and also allow for regeneration in the cavity.  Sustained delivery also exists limitations in release rates.  Drug-eluting devices or depots have finite number of therapy that can be released and specific release rate associated with the biomaterial selected.  There are ways of extending, shortening or changing the release pattern but this tends to require extensive modifications for even the smallest of changes and force the material to stretch its chemical mixture to the extreme to even squeeze out the smallest extra amount.

Strategies to Control Angiogenesis

In this section, we review the strategies that have been or are currently being utilized in the delivery of pro- and anti-angiogenic therapies.  We explored the literary search to determine certain trends and novel methods for drug delivery that are being explored with certain angiogenic-related therapies.

 

 

Table 2: Various delivery of VEGF and other singular growth factors

Pro-Angiogenic Therapy

There are a variety of examples of VEGF delivery for pro-angiogenic delivery as well as other growth factors(Golub et al., 2010) that continues to exist and be explored, but there does seem to be a more recently on the delivering of more than one growth factor for the effective angiogenic response desired.  Understanding that there is a complexity to angiogenesis and the wide variety of cross-talk and communication among cells is difficult to mimic has allowed researchers to realize that multiple growth factors play a role in stabilized growth of angiogenesis.  Also, there has been an increase into the investigation of timed control release of growth factors at certain stages of this process and the utilization of sequences of therapies to further increase vascularization in a damaged tissue (Cao & Mooney, 2007; Ennett, Kaigler, & Mooney, 2006).  There have been variety of combinations and sequences and as previously mentioned cell therapy for the delivery of multiple growth factors. Table 3 looks at a variety of studies done into multiple growth factors, type of drug delivery, combination or sequential, in various models that look for increase in angiogenic activity.

Table 3: Looking at the field of different combinations and sequences of multiple growth factor delivery.  Looking at the drug delivery methods as well as in sequence or in combinations.

Localized Site

Localized delivery in certain models is an easy way to deliver the desired drug and dosage to a localized region.  This allows for increased exploration in vitro and in vivo to understand the combined effects of many different growth factors and combinations.  These tend to correlate with certain release rates of the delivery or multiple injections.  Investigation has been done to control these release rates by difference methods that include ph-response (Garbern, Minami, Stayton, & Murry, 2011), external stimuli such as ultrasound or light (Brudno et al., 2015), viral vector (H. Zhang et al., 2013), controlling the porosity of the hydrogel depot (Jay & Saltzman, 2009), or by simple degrading of the delivery mechanism.

 

Figure 2: Different methods of drug release from local depots (Brudno et al., 2015)

 

This localized delivery correlates significantly with some sort of integrated scaffold or hydrogel for the release of these growth factors.  Angiogenesis is a process that takes times to migrate, differentiate, and progress the vascularization and this tends to require a consistent delivery of growth factors to continue the process.  There have been explorations into a variety of hydrogel drug depot models where some can be seen from Table 3 above. For the delivery of multiple growth factors presents an even bigger problem.  This usual entails separate drug release mechanisms especially those pertaining to specific time point release.  One way that two growth factors were integrated into a scaffold is done by Richardson, et al. by mixing VEGF into polymer particles before processing and pre-encapsulating a secondary growth factor into PLG microspheres and then integrating the spheres into another scaffold (Richardson, Peters, Ennett, & Mooney, 2001).  Since 2001, there have been plenty of other examples of integrating multiple drugs into scaffolds for separate release but essentially to get this effect, it tends to require drugs to be held in two different ways.

Systemic Delivery

Other than local delivery, systemic delivery better mimics the drug kinetics as seen in clinical trials.  As it may be easy to deliver drugs to specific location in a mouse or other animal model, this may not be an option for performance in clinical trials with humans.  As mentioned previously, it is important to increase circulation time, increase retention at desired location, and minimize effects to other parts of the body.  With angiogenic therapies this could be utilized given specific growth factors can be delivered at specific time points without the reliance on a drug depot to release at the correct time.  In this way, systemic delivery has been utilized to explore multiple growth factors and temporal control of the release.  Certain research has looked into inactivating drugs.

Targeting Mechanisms

Other than promoting angiogenesis, pro-angiogenic factors could be a targeting method for recruiting cells.  This is done naturally but also certain growth factor delivery has shown synergy with attracting progenitor cells that are circulating the blood; for instance, VEGF and SDF were used to attract CACs to local site in this way (Anderson et al., 2015).  Also, the opposite is possible.  Targeting endothelial cells that are upregulated in expression for cell adhesion in a myocardial infarction can be used to deliver VEGF.  This was done using liposomes to home to the endothelial cells expressing adhesion receptors and then delivering VEGF at that location (Scott et al., 2009).

Anti-Angiogenic Therapy

Especially for cancer treatment applications, studies have found that inhibiting angiogenesis through various strategies can help to suppress tumor growth make conventional chemotherapy therapy more effective. Combination therapies that block signaling of more than just one growth factor have also been more effective (Bhise et al., 2011). Additionally, utilizing anti-angiogenic antibodies and angiogenic binding strategies can help to enhance the efficacy of chemotherapy drugs by delivery to specific sites.

Localized Site

To help with local delivery of anti-angiogenic agents, studies have examined utilizing nanoparticles to delivery agents intratumorally in a more sustained manner. These agents may not have that capability if delivered on their own. For example, using anti-angiogenic peptides is limited due to their short-half lives. Therefore, incorporating these peptides in a delivery mechanism that offers prolonged release is critical. Self-assembled glycol chitosan nanoparticles that have been hydrophilically modified with 5β-cholanic acid have been studied for the delivery of RGD peptides as an anti-angiogenic model drug in cancer therapy (Kim et al., 2008). Overall, the peptide could be efficiently encapsulated and demonstrate prolonged delivery, whereas this would not be achieved if peptides alone were delivered. Functionally, the peptide release also showed to inhibit bFGF-induced angiogenesis, decrease tumor growth, and decreased microvessel density in vivo.

Figure 3: Chemical structures of the RGD peptide (A) and labelled RGD peptide (B). HGC nanoparticles with hydrophobic modification (C). RGD-HGC nanoparticles directly administered intratumorally (D). Reproduced from (Kim et al., 2008).

Strategies to limit angiogenesis through trapped VEGF have also been examined. Lai et al. have found that blocking VEGF function via bovine serum albumin-capped graphene oxide (BSA-GO) nanosheets was capable of inhibiting proliferation, migration and tube formation of HUVECs in vitro. BSA-GO exhibited high stability and extremely strong binding affinities towards VEGF-A165. In vivo studies that injected the BSA-GO into a rabbit corneal neovascularization model locally into the corneal stroma was also capable of blocking new blood vessel formation (Lai et al., 2016).

Other local delivery strategies have examined applications for wet age-related macular degeneration ad diabetic macular edema. In particular, small molecule inhibitors of angiogenesis (SRPK1) have been developed to demonstrate enhanced permeability for the application of trans-scleral delivery through eye drops (Batson et al., 2016). With these novel small molecule inhibitors, drugs can reach therapeutic levels even in the posterior regions of the eye.

Polymeric Delivery

Polymer conjugates as anti-angiogenic delivery mechanisms have been examined and reviewed by Segal and Satchi-Fainaro. These polymer drug delivery systems can either be synthesized for passive or active targeting to deliver at specific sites. Of these polymers discussed, N-(2-Hydroxypropyl)methacrylamide (HPMA) has been conjugated to anti-angiogenic agents such as TNP-470, a low molecular weight analog of fumagillin, and can be delivered by protease degradation of the cleavable linkages (Satchi-Fainaro et al., 2004). Other HPMA conjugates have incorporated different drugs such as paclitaxel to act as an anti-angiogenic agent. In these studies, a linker can be degraded by the lysosomal enzyme cathepsin B, which is overexpressed in tumor epithelial cells (Miller, Erez, Segal, Shabat, & Satchi-Fainaro, 2009). To facilitate targeting strategies, HPMA copolymers have also been conjugated with quinic acid to target E- and P-selectin expressing cells, which are overexpressed in blood vessels during the inflammatory response (Shamay, Paulin, Ashkenasy, & David, 2009). PGA has also been studied and conjugated to agents such as Paclitaxel and have been conjugated to cyclic RGD peptidomimetic as well to actively target proliferating tumor endothelial cells over-expressing αvβ3 integrin (Eldar-Boock et al., 2011). β-poly(L-malic acid)-PMLA is another polymer that has been used to deliver anti-angiogenic agents. PMLA is biodegraded in the body and releases drugs in that mechanism (Fujita et al., 2006).  PVA, PLA, PEG derivatives, and PLGA have also been examined as carriers of anti-angiogenic agents, but have mostly been incorporated as injectable or orally administered microspheres or micelles (Benny et al., 2008; Murata, Takashima, Toyoshima, Yamamoto, & Okada, 2008; Yasukawa et al., 1999).

 

Table 4: Polymeric drug-delivery strategies for anti-angiogenic therapeutics (Segal & Satchi-Fainaro, 2009).

 

 

Figure 4: HPMA polymeric delivery strategy for anti-angiogenic therapy (Segal & Satchi-Fainaro, 2009).

Systemic Delivery

Beyond polymeric strategies to delivery anti-angiogenic agents systemically, lipophilic amino-acid dendrimers have also been examined. One study has studied using these dendrimers as anti-VEGF oligonucleotide carriers to deliver therapeutics oligonucleotides that would inhibit choroidal neovascularization (Marano, Toth, Wimmer, Brankov, & Rakoczy, 2005). Dendrimers are attractive carriers because of their small size and because they can protect the active agent from the limitations of systemic delivery, while not affecting the drug’s ability to interact with the target site. While studying drug-delivery strategies that can be administered systemically, it is also critical to examine the release strategies of these carriers to determine the effectiveness as a therapeutic.

Release Mechanisms

Nanocarriers have been modified to release anti-angiogenic agents in response to different stimuli. For example, colorectal cancer, like other solid tumors, exhibit distinct architectures and microenvironments such as the extensive secretion of matrix metalloproteinases. In utilizing this high prevalence of MMPs to their advantage, Shi et al developed a novel MMP-2 responsive nanocarrier made of amphiphilic polyethylene glycol (PEG)-peptide diblock copolymer (PPDC) for simultaneous loading and release of two hydrophobic agents to prevent tumor growth and angiogenesis at the tumor site (Shi et al., 2016).

Figure 5: Nanoparticles for MMP-2-responsive delivery of anti-angiogenic and pro-apoptotic drugs (Shi et al., 2016).

Other release mechanisms for delivering anti-angiogenic agents, in particular for unwanted neovascularization of the cornea, involve an RGD peptide-hyaluronic acid (HA) conjugated complex coating on a gelatin nanoparticle (Chang et al., 2016). The nanoparticles were loaded with epigalloccatechin-3-gallate (EGCG), an anti-angiogenic factor and were also synthesized for αvβ3 integrin targeting, which is an integrin overexpressed in proliferating endothelial cells during angiogenesis. Overall, these particles exhibited a loading efficiency up to 95% and a slow release profile that released 30% of EGCG after 30 hours (Chang et al., 2016). When administered as eye drops, the nanoparticles also were successful in inhibiting corneal neovascularization in a mouse model.

Targeting Mechanisms

Targeting drug delivery is a critical strategy to limit off target effects. This is especially important for potent anti-angiogenic factors that would have severe consequences if administered to sites of healthy tissue. For asthmatic applications where excessive angiogenesis is a hallmark, potent anti-angiogenic agents have been examined. Studies have utilized specific micelles that target αvβ3-integrins, which are overexpressed in proliferating endothelial cells during angiogenesis. By targeting potent anti-angiogenic agents directly to these sites, prodrugs can be more effectively administered. In particular, lipase-labile prodrugs delivered via this mechanism suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges (Lanza et al., 2017).

Another effective strategy for targeted delivery mechanism for anti-angiogenic therapeutics is utilizing a PEG modified nanodrug of low molecular weight heparin and ursolic acid, both of which can be used as anti-angiogenic therapeutics (Li et al., 2016). This therapy is designed to target the tumor environment by targeting sigma receptors that are highly upregulated in tumor cells and have shown success in vitro and in vivo to inhibit tumor growth

Figure 6: Sigma receptor delivery of heparin and ursolic acid in tumor environment (Li et al., 2016).

Different strategies, such as VB-111 which is currently in phase II clinical trials, target tumor environments for glioblastoma multiforme therapy by using a modified murine promoter (PPE-1-3x) to specifically target endothelial cells in the tumor vasculature (Gruslova et al., 2015). After targeting this angiogenic environment, VB-111 acts as a gene therapy to trigger apoptosis by delivering Adenovirus 5 with a pro-apoptotic transgene. After intravenous delivery, this strategy has demonstrated inhibition of tumor growth and significant decreases in microvessel density.

Conclusions

For pro-angiogenic therapies it is important to mimic the complex system that is angiogenesis.  This requires multiple growth factors and the timing of the delivery of such.  Given certain limitation and negative-effects to other tissue, it is also important to allow for maximum dosing and limited healthy tissue exposure by targeting delivery and release at the desired site.  We looked at different ways that this can be accomplished either by targeting mechanisms for delivery of growth factors delivered systemically, loading of a hydrogel or scaffold drug depot or even locally injecting at the site.  Continued research will continue to expand the understanding of angiogenesis with angiogenic promoting cells.  This can be further enhanced for long-term delivery by finding ways to deliver drugs systemically that be targeted repeatedly.  This has been explored by other researchers such as Brudno, et. al. and Wu, et al.  Brudno’s group looked at using nucleotides and click chemistry methods to capture drugs circulating in the blood.  This enhanced retention of the drugs and inactivated the drugs while circulating the body.  In particular, this research looked to be used to deliver chemotherapies to tumor sites that had a local hydrogel injected at the site that could be continuously reloaded but this could also be potentially expanded to angiogenic factors (Brudno 2015). Wu’s group went ahead and did this reloadable delivery system and applied it to promoting angiogenesis in hind-limb ischemia models.  It utilized a hyaluronic acid hydrogel at the local ischemic site that was conjugated with anti-PEG antibodies that could captured PEGylated growth factors as it circulated the body (Wu 2016).  This method did rely on some EPR effects for the delivery at the site that may not transition into clinical studies, but is a positive step in the further development of angiogenic therapies. All of this research can dive into the continuous understanding of time point sensitive growth factor delivery and full vascularization in wound healing and damaged tissue.

For anti-angiogenic therapies, it is critical to target delivery systems directly to sites of injury or disease sites to prevent off-target side effects that can come from potent anti-angiogenic agents or pro-apoptotic drugs. Examples in this review article range from directing anti-angiogenic therapies to tumor environments via MMP-2-responsive nanocarrier, or other tumor environment triggers, to incorporating binding motifs to recognize receptors that localize drug-release only to areas of excessive neovascularization. Direct injections for anti-angiogenic therapies will have more flexibility in carrier design, but have also shown promise in inhibiting angiogenesis in some disease applications such as corneal neovascularization. In the future, the wide range of polymeric delivery systems that have been developed for anti-angiogenic therapies could be further modified and developed for more stringent release profiles that will limit any anti-angiogenic therapy directly to the necessary location. As with pro-angiogenic therapies, future directions will rely on multiple factors for the most optimal therapeutic effectiveness. This has already been established for some preclinical trials, one being Navicixizumab, the bispecific antibody inhibition of both DLL4 and VEGF (Jimeno et al. 2016). Future work for anti-angiogenic therapies, especially for cancer, should work to incorporate temporal inhibition of more growth factors beyond VEGF. Overall, the future for pro- and anti-angiogenic therapies is promising for the treatment of diseases that currently suffer from reduced drug efficacy.

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