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Lymphatic Route in Cardiovascular Medicine
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This entry is adapted from 10.3390/pharmaceutics13081200

The lymphatic network is a unidirectional and low-pressure vascular system that is responsible for the absorption of interstitial fluids, molecules, and cells from the peripheral tissue, including the skin and the intestines. Targeting the lymphatic route for drug delivery employing traditional or new technologies and drug formulations is exponentially gaining attention in the quest to avoid the hepatic first-pass effect. 

lymphatics cardiovascular diseases drug delivery route nanotechnology
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Subjects: Pharmacology & Pharmacy
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Nolwenn Tessier
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Entry Collection: Hypertension and Cardiovascular Diseases
Revisions: 2 times (View History)
Update Date: 19 Aug 2021
Table of Contents

    1. Introduction

    Cardiovascular diseases (CVD) are one of the leading causes of death worldwide [1]. CVD include coronary heart disease, myocardial infarction (MI), heart failure (HF), stroke, and artery diseases [2]. Treatments for cardiovascular diseases are numerous, and the routes of administration are diverse. The chosen drug delivery route is a key determinant of the pharmacodynamics, pharmacokinetics, as well as toxicity of the delivered compounds. Yet, side effects or therapeutic failures are raising concerns, highlighting the need for new administration routes and improved formulation of molecules that reduce their degradation by hepatic metabolism. Drug delivery refers to the methods, approaches, or strategies employed for the transport of pharmaceutical compounds to an organism to achieve a desired therapeutic outcome. With this intent, various routes of administration are used to manage CVD and their risk factors, including parenteral (intravenous (IV), intradermal (ID), intramuscular (IM), subcutaneous (SC), and intraperitoneal (IP)), and transmucosal (oral, nasal, pulmonary, ocular, and genital) and transdermal route [3]. Drug absorption and transport through the lymphatic system makes it possible to avoid hepatic metabolism and is a privileged target in pathologies, such as particular types of cancer (chemotherapeutics [4]) or vaccines [5][6] (HIV [7]), but also for macromolecules [8], and the extensively hepatic-metabolized compounds [9][10].

    2. Conventional and Novel Therapies to Treat CVD

    Historically, small molecules have been used for the treatment of CVD. However, these molecules improve the symptoms and slow down the disease progression without having an actual regenerative effect on the affected tissues or organs [11]. Thus, the remaining unmet clinical needs necessitated the urgent seek for other potential therapeutic options.
    Gene therapy is one of the most promising treatment strategies for CVD [12][13][14][15][16], inherited or acquired, through targeting the causative genes engaged in the induction and progression of the disease. It works through replacing defective genes, silencing overexpressed ones or providing functional copies of specific therapeutic genes, thanks to DNA, RNA (siRNA, microRNA, mRNA), and antisense oligonucleotides (ASO) [17]. Back in the 1950s and 1960s, several attempts were made to directly transfect cells with DNA and RNA. Nevertheless, in vivo studies failed to show a noticeable success. Thus, selecting a suitable vector to deliver gene therapy is as important as selecting the agent itself [18][19]. Generally, vectors can be divided into viral and non-viral. The most commonly used viral vectors are retrovirus (RV), adenovirus (AV), adeno-associated virus (AAV), and lentivirus [20]. The most commonly used non-viral vectors include lipid-based vectors using cationic lipids and polymer-based vectors using cationic polymers [21]. Cationic lipids complex with the genetic materials to form lipoplexes or lipid nanoparticles (LNP), while cationic polymers form polyplexes [22]. In 2012, cardiovascular gene therapy was the third most common application for gene therapy (8.4% of the total gene therapy trials). However, clinically, it is still in the infancy stage, and a lot of effort is yet to be expended to correct the underlying basal molecular mechanisms behind different cardiovascular disorders [23][24].

    3. Treating CVD through Various Administration Routes

    3.1. Oral Administration

    Among the various routes of administration, the oral route is the most commonly employed. It exhibits many advantages, including pain avoidance, ease of administration, patient compliance, reduced care cost, and low incidence of cross-infection. Furthermore, it is amenable to various types and forms of pharmaceuticals [25] (Table 1). While some drugs are intended to target the gastrointestinal tract (GIT), the majority are employed to exert a systemic therapeutic effect. Nevertheless, the oral bioavailability of most pharmaceutical compounds depends mainly on their solubility, permeability, and stability in the GIT environment [26][27][28].
    Table 1. Oral delivery of various treatments for CVD.

    Condition

    Intervention and Identifier

    Target

    Dose and Outcome

    Diabetes

    Metformin

    		  

    From 500 to 850 mg, 2–3 times a day, during the meal [29]

    Diabetes

    Sulfonylureas

    Meglitinide

    		  

    Dosage is very different from one class of medication to another [30]

    Diabetes

    Acarbose,

    Miglitol

    Voglibose

    Carbohydrate digesting enzymes in the brush border

    50 mg three times daily (up to 100 mg) [31]

    Diabetes

    Rosiglitazone

    Pioglitazone

    PPAR-α

    Rosiglitazone: 4 mg per day (up to 8 mg)

    Pioglitazone: 15–30 mg per day [32]

    Diabetes

    Sitaglipin

    Vildaglipin

    Saxaglipin

    Linaglipin

    Aloglipin

    DPP4

    2.5–100 mg once daily depending on the inhibitor used [33]

    Diabetes

    Dapagliflozin

    Canagliflozin

    Empagliflozin

    SGLTP2

    Dapagliflozin: 2.5–10 mg daily

    Canagliflozin: 100–300 mg

    Empagliflozin: 5–25 mg daily [34]

    Diabetes

    AG019

    (NCT03751007) or in combination with the anti-CD3 monoclonal antibody teplizumab

    		  

    2 or 6 capsules per day for 8 weeks (repeated dose) or for one day (single dose)

    Diabetes

    Insulin nanocarriers

    		  

    Protection of insulin from enzymatic degradation

    Enhancement of stability, intestinal permeability, and bioavailability [17]

    Diabetes

    Electrostatically-complexed insulin with partially uncapped cationic liposomes

    		  

    Improved insulin pharmacokinetic profile [35]

    Diabetes

    Insulin-loaded PLGA

    		  

    Improved bioavailability and sustained hypoglycemic effect [36]

    Diabetes

    Exenatide combined to phase-changeable nanoemulsion with medium-chain fatty acid

    		  

    Enhancement of intestinal absorption and lymphatic transport [37]

    HTN

    Prazosine Terazosine Doxazosine

    Alpha-adrenergic receptor

    Prazosine: 3–7.5 mg per day in two doses

    Terazosine: 1–9 mg per day in the evening at bedtime

    Doxazosine: 4 mg per day [38]

    HTN

    Clonidine Methyldopa

    Alpha-adrenergic receptor (agonists)

    Clonidine: 0.1 mg twice daily [39]

    Methydopa: 250 mg two to three times daily [40]

    HTN

    Carvedilol into nanoemulsion

    Beta-adrenergic receptors

    Significant improvement in its absorption, permeability, and bioavailability [41][42]

    HTN

    Valsartan, Ramipril and Amlodipine into nanoemulsion

    		  

    Enhanced solubility, oral bioavailability, and pharmacological outcome [43]

    HTN

    Felodipine-loaded PLGA nanoparticles

    Calcium-channel

    Sustained drug release both in vitro and ex vivo [44]

    MI

    HF

    HTN

    Arrhythmia

    ß-blocker

    Beta-adrenergic receptors

    Acebutol: 200 mg twice daily [45]

    MI

    HF

    HTN

    Conversion enzyme

    inhibitors

    Conversion enzyme

    Captopril: 100 mg per day [46]

    MI

    HF

    HTN

    Valsartan

    Losartan

    Angiotensin II

    20 mg twice a day, up to 160 mg [47]

    HF

    HTN

    Hydrochlorothiazide

    Bumetanide

    Angiotensin/neprilysin receptor

    49 mg/51 mg twice daily and doubled after 2–4 weeks [48]

    HF

    HTN

    Sacubitril

    Valsartan

    Calcium channel

    5–10 mg daily [49]

    60 mg three times daily [50]

    HTN

    Arrhythmia

    Amlodipine

    Diltiazem

    Calcium channel

    5–10 mg daily [49]

    60 mg three times daily [50]

    HF

    Ivabradine

    		  

    Bradycardic

    5–7.5 mg twice a day [51]

    HF

    MI

    Eplerenone

    Spironolactone

    Aldosterone

    50 mg once a day [52] and 12.5–25 mg with each intake [53]

    HF

    Arrhythmia

    Digoxin

    		  

    0.25 mg once daily [54]

    HF

    MI

    HCL

    Statin

    HMG-CoA

    10 mg once daily [55]

    MI

    Aspirin

    Platelets

    325 mg, then 81 mg per day [56]

    MI

    Clopidogrel

    Prasugrel

    Ticagrelor

    Platelets

    300 mg, then 75 mg daily with aspirin

    60 mg, then 10 mg daily

    180 mg, then 90 mg twice a day [57][58]

    HCL

    Ezetimibe

    Intestinal cholesterol absorption

    10 mg once daily [59]

    HLD

    Tricor

    Triglide

    		  

    Fenofibrates 100–300 mg per day [60]

    HCL

    HLD

    Atorvastatin formulated into ethylcellulose nanoparticles

    		  

    Enhanced atorvastatin’s lymphatic absorption and oral bioavailability [61]

    HCL

    HLD

    Atorvastatin formulated into nanocrystals prepared with poloxamer 188

    		  

    Improved atorvastatin’s gastric solubility and bioavailability [62]

    Reduced circulating cholesterol, TG and LDL

    HCL

    HLD

    Atorvastatin formulated into polycaprolactone nanoparticles

    		  

    Enhanced atorvastatin’s bioavailability [63]

    HCL

    HLD

    Nanostructured lipid carriers

    		  

    Enhanced atorvastatin bioavailability by 2.1 fold compared to the commercial product: lipitor®

    Reduced the serum level of cholesterol, TG and LDL [64]

    HCL

    HLD

    Nanoemulsion

    		  

    Increased the bioavailability of atorvastatin compared to the commercial tablet ozovasTM [65]

    HCL

    HLD

    Simvastatin

    Rosuvastatin

    Fluvastatin

    Fibrates

    Ezetimibe

    lipid-based

    nanoparticles

    		  

    Improved bioavailability via lymphatic uptake [66][67][68][69][70][71][72][73][74]

    PPAR- α: peroxisome proliferator-activated receptor- α; DPP4: dipeptidyl peptidase-4; SGLTP2: Sodium glucose co-transporter-2; PLGA: Poly lactic-co-glycolic acid; HTN: Hypertension; MI: Myocardial infarction; HF: Heart failure; HCL: Hypercholesterolemia; HMG-CoA reductase: Hydroxymethyl glutaryl coenzyme A reductase; HLD: Hyperlipidemia; TG: Triglycerides; LDL: Low density lipoprotein.

    3.2. Subcutaneous Injection

    Subcutaneous injections consist of injecting a molecule under the dermis, in the SC cell layer (interstitial space), and slightly before the muscle, mostly in the abdomen or thigh. The injected molecules will, therefore, either be degraded or phagocytized at the site of injection and join the lymphatic system or the bloodstream [75]. To target the lymphatic system exclusively, this type of injection must be combined with the use of macromolecules. As described in Table 2, subcutaneous injections are used as treatment for various conditions [76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103].
    Table 2. Therapies targeting CVD using subcutaneous injection.

    Condition

    Intervention and Identifier

    Therapy

    Target

    Stage and Status

    Dose and Outcome

    Diabetes

    Insulin

    		      

    Different types of insulin

    At least 3 injections per day

    Dosage adapted to the patient [76]

    Diabetes

    Exenatide

    Lixisenatide

    Liraglutide

    Exenatide LAR

    Albiglutide

    Dulaglutide

    		      

    GLP-1 analogues [77]

    Exenatide: 5–10 µg twice a day

    Lixisenatide: 10–20 µg once daily

    Liraglutide: 0.6–1.8 mg once daily

    Exenatide LAR: 2 mg once a week

    Albiglutide: 30–50 mg once a week

    Dulaglutide: 0.75–1.5 mg once a week

    Diabetes

    Vaccine formed of virus-like particles coupled to IAPP

    		  

    Against the insoluble IAPP- derived amyloid aggregates

    		  

    Three doses—10 µg

    Strong immune response against these aggregates and restored insulin production Diminished the amyloid deposits in the pancreatic islets, reduced the level of the pro-inflammatory cytokine IL-1β, and reprieved the onset of amyloid-induced hyperglycemia [78]

    Diabetes

    IL-1β epitope peptide

    		  

    Against IL-1β

    		  

    Three doses—50 µg

    Enhancement glucose tolerance, improved insulin sensitivity, restored β-cell mass, reduced β-cell apoptosis, and enhanced β-cell proliferation, as well as downregulation of IL-1β expression and inhibition of the inflammatory activity [79][80]

    Diabetes

    hIL1bQb

    vaccine

    (NCT00924105)

    		  

    Against IL-1β

    		  

    Six doses—300 µg

    Mediated a dose-dependent IL-1β-specific antibody response

    More studies are required to precisely investigate the clinical efficiency of this vaccine [81]

    Diabetes

    Neutralizing

    antibodies against DPP4

    		  

    The GLP-1 and GIP inhibitor, DPP4

    		  

    Five doses—2–20 µg

    Increased pancreatic and plasma insulin level and improved postprandial blood glucose level [82]

    HTN

    hR32 vaccine

    		  

    Renin-derived peptide

    		  

    Five doses—500 µg

    Reduced systolic blood pressure by 15 mmHg [83]

    HTN

    Angiotensin I

    vaccine (PMD3117)

    		      

    Three or four doses—100 µg

    The vaccine failed to reduce the blood pressure [84]

    HTN

    AngI-R vaccine

    		  

    Modifiedendogenous angiotensin I peptide

    		  

    Four doses—50 µg

    15 mmHg reduction in systolic blood pressure and reduced angiotensin I/II level [85]

    HTN

    ATRQβ-001

    		  

    Angiotensin II type I receptors

    		  

    Two doses—100 µg

    Protective role against target organ damage induced by hypertension [86]

    HTN

    ATR12181 vaccine

    		  

    Angiotensin II type I receptors

    		  

    Nine doses—0.1 mg

    Attenuated the development of hemodynamic alterations of hypertension [87]

    HTN

    CYT006-AngQb vaccine

    		  

    Against angiotensin II

    		  

    100 or 300 µg

    Reduction in blood pressure and reduced ambulatory daytime blood pressure [88]

    HF

    HTN

    Ang II-KLH

    vaccine

    		  

    Angiotensin II

    		  

    Three doses—5 µg

    Suppressed post-MI cardiac remodeling and improved cardiac function [89]

    MI

    Celecoxib loaded in nanoparticles

    		      

    Promoted vascularization in the ischemic myocardium and delayed HF progression [90]

    MI

    Chitosan-hyaluronic acid based hydrogel containing deferoxamine-PLGA

    nanoparticles

    		      

    Persistent neovascularization in mice [91]

    HCL

    Alirocumab

    Evolocumab

    		  

    PCSK9

    		  

    One dose every two weeks [92][93]

    HCL

    Inclisiran

    		  

    PCSK9

    		  

    Two doses per year [94]

    HoFH

    HeFH

    severe HCL

    Mipomersen

    (NCT00607373)

    (NCT00706849)

    (NCT00770146)

    (NCT00794664)

    ASO

    ApoB

    Approved

    200 mg once/week.

    Phase III: reduction in LDL-C [95]

    ASCVD HCL HeFH

    Inclisiran

    (NCT03399370)

    (NCT03400800)

    (NCT03397121)

    siRNA

    PCSK9

    Approved

    284 mg inclisiran, injected on day 1, day 90 and then twice/year

    Phase III: reduction in LDL-C level [94][96]

    FCS

    Volanesorsen

    (NCT02211209)

    ASO

    ApoC3

    Approved

    300 mg once/week

    Phase III: reduction in mean plasma APOC3 and TG level [97]

    Elevated LP(a)

    ISIS-APO(a)Rx

    (NCT02160899)

    ASO

    APO(a)

    Phase II (Complete)

    Multiple escalating (100–300 mg) doses, injected on a weekly interval for 4 weeks each

    Phase I/II: reduction in plasma Lp(a) concentration [98]

    Elevated LP(a)

    CVD

    AKCEA-APO(a)-LRx

    (NCT03070782)

    (NCT02414594)

    (NCT04023552)

    GalNAc3

    conjugated-ASO

    APO(a)

    Phase III

    (Recruiting)

    80 mg administered monthly

    Phase I/II: reduction in plasma Lp(a) [98]

    HTG

    CVD

    FCS

    AKCEA-APOCIII-LRx

    (NCT02900027)

    (NCT03385239)

    (NCT04568434)

    GalNAc3

    conjugated-ASO

    APOC3

    Phase III

    (Recruiting)

    Multiple dosing injected as once/4 weeks for up to 49 weeks

    Phase II: reduction in ApoC3 and TG levels [99]

    HTG

    FH

    HLP

    Vupanorsen

    (NCT02709850)

    (NCT04459767)

    (NCT04516291)

    ASO

    ANGPTL3

    Phase IIb

    (Active, Not recruiting)

    Multiple escalating dosing (60–160 mg, once/2 or 4 weeks)

    Phase I: reduction in TG and LDL-C levels [100]

    HCL

    Neutralizing antibodies against PCSK9

    		  

    PCSK9

    		  

    Three doses—5–50 µg

    Long-lasting reduction in the level of total cholesterol, VLDL and

    chylomicron [101]

    HCL

    AT04A

    		  

    PCSK9

    		  

    Five doses

    Strong and persistent anti-PCSK9 antibody production, reduced plasma cholesterol level, attenuated progression of atherosclerosis and reduced vascular and systemic inflammation [102]

    HCL

    AT04A

    		  

    PCSK9

    		  

    Four doses—15 µg and 75 µg

    Reduced serum LDL-C level and elevated anti-PCSK9 antibody titer [103]

    HCL

    A peptide representing the mouse ANGPTL3

    		  

    Angiopoietin-like proteins 3 (ANGPTL3)

    		  

    Three doses—5 µg

    Reduced steady-state plasma TGs and promoted LPL activity

    GLP-1: glucagon-like peptide-1; IAPP: Islet amyloid polypeptide; DPP4: dipeptidyl peptidase-4; GIP: glucose-dependent insulinotropic polypeptide; HTN: Hypertension; HF: Heart failure; MI: Myocardial infarction; HCL: Hypercholesterolemia; HoFH: Homozygous familial hypercholesterolemia; HeFH: Heterozygous familial hypercholesterolemia; AngII-KLH: Angiotensin II—keyhole-limpet hemocyanin; PCSK9: Proprotein convertase subtilisin/kexin type 9; ASO: Antisense oligonucleotides; ApoB: Apolipoprotein B; LDL-C: low density lipoprotein cholesterol; ASCVD: Atherosclerotic cardiovascular disease; FCS: Familial chylomicronemia syndrome; TG: Triglycerides; LP(a): Lipoprotein(a); APO(a): Apolipoprotein (a); CVD: Cardiovascular diseases; GalNAc3: Triantennary N-acetyl galactosamine; HTG: Hypertriglyceridemia; FH: Familial hypercholesterolemia; HLP: Hyperlipoproteinemia; ANGPTL3: Angiopoietin-like proteins 3; VLDL: Very low density lipoprotein; LPL: Lipoprotein lipase.

    3.3. Intradermal Injection

    Lymphatic capillaries are present in the dermis and, thus, preferentially take up the injected molecules. Unlike the blood capillaries, initial lymphatics lack the basement membrane underlying the endothelial layer. The distal part of initial LV is exclusively composed of LECs with button-like junctions [104], leading to capillaries that have inter-endothelial gaps with size ranges from a few nanometers to several microns [4][105]. Small particles (<10 nm) [4] and medium-sized macromolecules (up to 16 kDa) [106] are mainly transported away from the interstitial spaces by blood capillaries, thanks to mass transport [107][108]. In contrast, lymphatic access of large particles with diameters exceeding 100 nm is hindered by their restricted movement through the interstitium, via diffusion and convection [4]. In between, particles with a size of 10–100 nm [4] and macromolecules with a size of 20–30 kDa [106] show preferential uptake into the highly permeable lymphatic capillaries either passively (paracellular) or actively (transcellular) through the lymphatic endothelial cells [109]. Indeed, it has been shown that the optimal diameter to target the lymphatic vessels in the dermis is 5 to 50 nm in mice [110].
    Table 3 presents several vaccines used for diabetes through intradermal injection [111][112][113].
    Table 3. Intradermal administration as treatment for diabetes.

    Condition

    Intervention and Identifier

    Target

    Dose and Outcome

    Diabetes

    Proinsulin peptide vaccine C19-A3

    CD4 T cells

    Three equal doses—10–100 µg

    Vaccine was well tolerated [111]

    Diabetes

    C19-A3

    (NCT02837094)

    CD4 T cells

    Three doses—10 ug

    In vitro and ex vivo studies of in human skin reported rapid diffusion of the injected particles through the skin layers and preferential uptake by Langerhans cells in the epidermis, which have a primary role in the tolerance mechanism [112]

    Diabetes

    PIpepTolDC vaccine (NCT04590872)

    Tolerogenic DC Vaccine

    One dose and another after 28 days

    No results yet, but, it is believed to be able to produce proinsulin-specific Treg [113]
    DC: Dendritic cells; Treg: immunoregulatory T cells.

    3.4. Intramuscular Injection

    Intramuscular injections are used to target the deeper muscle tissue that is highly irrigated. This route of injection allows a rapid absorption and prolonged action. The medication would enter the bloodstream directly and, thus, allow the “bypass” of the hepatic metabolism. It is mainly used for the administration of vaccines [114] (hepatitis, flu virus, tetanus) or with specific pathologies, such as rheumatoid arthritis and multiple sclerosis. It is frequently performed in the upper arm [115] but also in the hip or thigh [116]. It is possible to administer up to 5 mL via this route, based on the site of injection [117]. As lymphatic vessels are present in the skeletal muscle and the connective tissue [118], this leads to the assumption the lymphatic system might be involved in the drug absorption following intramuscular administration. As presented in Table 4, several conditions are treated with this type of injection [119][120][121][122].
    Table 4. CVD therapies using intramuscular administration.

    Condition

    Intervention and Identifier

    Target

    Dose and Outcome

    Diabetes

    Preproinsulin-encoding plasmid DNA

    Pancreatic islets

    40% higher survival rate as compared to the control group [119]

    HTN

    CoVaccine HT

    (NCT00702221)

    Against angiotensin II

    Three doses

    Terminated in 2016 due to dose-limiting adverse effects

    HTN

    AGMG0201

    vaccine

    Against angiotensin II

    High or low dose (0.2 mg plasmid DNA and 0.5 or 0.25 mg Ang II-KLH conjugate) Ongoing

    ACS

    HF

    CVD

    Inactivated influenza vaccine

    		  

    Less frequent hospitalization from ACS, hospitalization from HF and stroke [120]

    MI

    Influenza vaccine

    		  

    Risk of cardiovascular-related death was significantly lower [121]

    CVD

    MI

    Pneumococcal vaccines

    		  

    Reduced incidence of cardiovascular events and mortality

    Reduced risk of MI in the elderly [122]

    MI

    HF

    Stroke

    Influenza vaccine

    (NCT02831608)

    		  

    The primary endpoints: death, new MI and stent thrombosis

    Secondary endpoints: patients with hospitalization for HF

    HTN: Hypertension; AngII-KLH: Angiotensin II—keyhole-limpet hemocyanin; ACS: Acute coronary syndrome; CVD: cardiovascular disease; HF: Heart failure; MI: Myocardial infarction.

    3.5. Intramyocardial Injection

    Direct intramyocardial injection is the most effective and commonly used way for gene delivery to the heart owing to its ability to achieve a high concentration of the injected compound at the injection site [123]. It is a preferential route to directly target lymphatic vessels due to their high density in the myocardium [104][124]. Various CVD and their treatments via intramyocardial injection are presented in Table 5 [125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141].
    Table 5. Use of intramyocardial injections in several therapies targeting CVD.

    Condition

    Intervention and Identifier

    Therapy

    Target

    Stage and Status

    Dose and Outcome

    HF

    Ad5.hAC6

    (NCT007)

    Ad5

    AC6

    Phase I/II

    (Completed)

    Single administration of escalating doses (3.2 × 109 vp to 1012 vp)

    Phase II: Reduced HF admission rate. Enhanced left ventricular function beyond the optimal HF therapy following a single administration [126]

    HF

    Ad5.hAC6

    (NCT03360448)

    Ad5

    AC6

    Phase III

    (withdrawn)

    Phase III: withdrawn for re-evaluation

    HF

    MYDICAR

    (NCT00454818)

    AAV1

    SERCA2a

    Phase I/II (Completed)

    Single administration of escalating doses (1.4 × 1011–1 × 1013 DRP of AAV1/SERCA2a)

    Phase I/II (CUPID): high-dose treatment resulted in increased time and reduced frequency of cardiovascular events within a year and reduced cardiovascular hospitalizations [127]

    HF

    MYDICAR

    (NCT01643330)

    AAV1

    SERCA2a

    Phase IIb

    (completed)

    Single infusion of 1 × 1013 DRP of AAV1/SERCA2a

    Phase IIb (CUPID-2b): no improvement was observed at the tested dose in patients with HF during the follow-up period [125]

    HF

    MYDICAR

    (NCT01966887)

    AAVI

    SERCA2a

    Phase II

    (Terminated)

    1 × 1013 DRP of AAV1/SERCA2a as a single intracoronary infusion

    Phase II: no improvement observed in the ventricular remodeling.The study terminated driven by the CUPID-2 trial neutral outcome [128]

    HF

    SRD-001

    (NCT04703842)

    AAVI

    SERCA2a

    Phase I/II

    (Active, not recruiting)

    Single administration of 3 × 1013 vg

    CUPID-3: aims to investigate the safety and efficacy of SRD-001 in anti-AAV1 neutralizing antibody-negative subjects with HFrEF

    HF

    CVD

    INXN-4001

    (NCT03409627)

    Non-viral, triple effector plasmid

    SDF-1α,

    S100A1,

    VEGF-165

    Phase I

    (Completed)

    Single 80 mg dose, given in 40 mL or 80 mL at a rate of 20 mL/min

    Phase I: an improvement in the quality of life in 50% of patients was reported [129]

    HF

    ACRX-100

    (NCT01082094)

    Plasmid DNA

    SDF-1

    Phase I

    (Completed)

    Single escalating doses, injected at multiple sites

    Preclinical studies: enhanced vasculogenesis and improved cardiac function reported with all doses [130]

    HF

    JVS-100

    (NCT01643590)

    Plasmid DNA

    SDF-1

    Phase II

    (Completed)

    Single injection of escalating doses (15 and 30 mg)

    Phase II (STOP-HF): JVS-100 showed potential to improve cardiac function through reducing left ventricular remodeling and improving ejection fraction [131]

    HF

    JVS-100

    (NCT01961726)

    Plasmid DNA

    SDF-1

    Phase I/II

    (Unknown)

    Single injection of escalating doses (30 and 45 mg)

    Phase I (RETRO-HF): JVS-100 showed promising signs of clinical efficacy [132]

    HF

    AZD8601

    (NCT02935712)

    (NCT03370887)

    mRNA

    VEGF-A165

    Phase IIa

    (Active, not recruiting)

    Single injection of escalating doses (3 mg and 30 mg)

    Preclinical studies: promoted angiogenesis, improved cardiac function and enhanced survival were reported [133]

    Phase I: ID injection of AZD8601 was well tolerated and enhanced the basal skin blood flow [134]

    HF

    NAN-101

    (NCT04179643)

    AAV

    I-1c

    Phase I

    (Recruiting)

    Single escalating doses (3 × 1013 vg–3 × 1014 vg) of NAN-101

    Preclinical studies: enhancement in left ventricular ejection fraction and improved cardiac performance [135]

    AMI IHD

    VM202RY

    (NCT01422772)

    (NCT03404024)

    DNA plasmid

    HGF-X7

    Phase II

    (Recruiting)

    Single escalating (0.5–3 mg) doses, administered into multiple sites

    Phase I: improved myocardial function and wall thickness

    [136][137]

    MI

    Angina pectoris

    AdVEGF-D (NCT01002430)

    AV

    VEGF-D

    Phase I/IIa

    (Completed)

    Single escalating (1 × 109–1 × 1011 Vpu) doses, injected into multiple sites in the endocardium

    Phase 1/IIa: AdVEGF-D improved myocardial perfusion reserve in the injected region [137]

    MI

    Ad-HGF

    (NCT02844283)

    AV

    HGF

    Phase I/II (Unknown)

    Single dose

    Preclinical studies: Ad-HGF preserved cardiac function, reduced infarct size, and improved post-MI cardiac remodeling [138]; fractional repeated dosing significantly improved cardiac function compared with single injection [139]

    MI

    L-type Ca2+ channels’ AID peptide and antioxidant molecule (curcumin) in poly nanoparticles

    		      

    Reduced the elevated level of ROS and the intracellular Ca2+ [140]

    LPLD

    Alipogene tiparvovec

    (NCT00891306)

    AAV

    LPL

    Approved

    1 × 1012 GC/kg

    Phase II/III: reduction in mean total plasma and chylomicron TG level [141]

    HF: Heart failure; hAC6: Human adenylyl cyclase type 6; vp: Virus particles; AAV: Adeno-associated virus; SERCA2a: Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase; DRP: DNase-resistant particles; HFrEF: HF with reduced ejection fraction; CVD: Cardiovascular diseases; SDF-1a: stromal cell-derived factor 1; VEGF: Vascular endothelial growth factor; I-1c: Constitutively active inhibitor-1; vg: Viral genomes; AMI: Acute myocardial infarction; IDH: Ischemic heart disease; HGF-X7: Hepatocyte growth factor-X7; AV: Adenovirus; Vpu: Viral protein U; HGF: Hepatocyte growth factor; AID: alpha-interacting domain; ROS: reactive oxygen species; LPL: Lipoprotein lipase; TG: Triglycerides; GC: Genome copies.

    3.6. Intravenous Injection

    Intravenous injections are often used for rehydration, nutrition, and therapeutic treatments (for example, blood transfusion or chemotherapy), as well as to avoid hepatic metabolism [142]. The interest of this route of administration is the continuous treatment, or regular frequencies, by the installation of a catheter [143]. However, the lymphatic system is only scarcely involved following IV injections [144][145][146]. Table 6 presents several conditions treated with this type of injection [45][54][56][147][148][149][150][151][152][153][154][155][156][157][158][159][160].
    Table 6. Intravenous administration of medication as treatment for CVD.

    Condition

    Intervention and Identifier

    Therapy

    Target

    Stage and Status

    Dose and Outcome

    HTN

    NO-releasing nanoparticles

    		      

    Reduction in the mean arterial blood pressure [147]

    HF

    Arrhythmia

    Digoxin

    		      

    Dose: 0.25 mg once daily [54]

    MI

    HF

    HTN

    Arrhythmia

    ß-blocker

    		  

    Beta-adrenergic receptors

    		  

    Acebutol: 200 mg twice daily [45]

    HF

    Mesoporous silicon vector (Nanoconstruct)

    		      

    Able to internalize, accumulate, and traffic within the cardiomyocytes [148]

    HF

    Combination of biocompatible magnetic nanoparticles and low-frequency magnetic stimulation

    		  

    Cardio-myocytes

    		  

    Managed the drug release by controlling the applied frequencies [149]

    HF

    S100A1-loaded nanoparticles, decorated with N-acetylglucosamine

    		      

    Regulated Ca2+ release and restored contractile function in the isolated failing cardiomyocytes [150]

    HF

    Biodegradable nanoparticles conjugated with myocyte-targeting peptide and PDT-enabling photosensitizer

    PDT

    Cardio-myocytes

    		  

    Induced cell-specific death upon application of laser light, leaving adjacent and surrounding cells completely intact [151]

    MI

    Unfractionated

    heparin

    		      

    Anticoagulant

    60 IU/kg for initial bolus

    12 IU/kg/h for maintenance [152]

    MI

    Aspirin

    		  

    Platelets

    		  

    325 mg, then 81 mg per day [56]

    MI

    Human recombinant VEGF-165

    		      

    Significant improvement in the infarcted zone perfusion and cardiac function for up to six weeks post-MI [153].

    MI

    Nanoparticles containing siRNA

    		      

    Anti-inflammatory effect in the infarcted heart and reduction of the post-MI heart failure [154]

    MI

    Magnetic nanoparticles-loaded cells

    		      

    Robust improvement in the left ventricular and cardiac function [155]

    MI

    Insulin-like growth factor electrostatically-complexed with PLGA nanoparticles

    		      

    Higher incidence in preventing cardiomyocytes’ apoptosis, reducing infarct size, and enhancing left ventricular function [156]

    MI

    Pitavastatin in PLGA nanoparticles

    		      

    Cardioprotective effect against ischemia-reperfusion injury [157]

    HoFH

    AAV8.TBG.HldlR

    (NCT02651675)

    AAV

    hLDLR

    Phase I/II (Completed)

    Single dose

    Preclinical studies: reduction in total cholesterol [158][159]

    Elevated LDL-C

    ALN-PCS02

    (NCT01437059)

    siRNA

    PCSK9

    Phase I

    (Completed)

    Single escalating (15 and 400 μg/kg) doses

    Phase I: reduction in the level of circulating PCSK9 protein and LDL-C [160]

    HTN: Hypertension; NO: nitric oxide; HF: Heart failure; MI: Myocardial infarction; PDT: Photodynamic therapy; VEGF: Vascular endothelial growth factor; PLGA: Poly lactic-co-glycolic acid; AAV: Adeno-associated virus; HoFH: Homozygous familial hypercholesterolemia; hLDLR: Human low density lipoprotein receptor; TBG: Thyroxine-binding globulin; LDL-C: low density lipoprotein cholesterol.

    3.7. Intraperitoneal Injection

    Intraperitoneal administration, in which therapeutic compounds are injected directly into the peritoneal cavity, is another attractive approach of the parenteral extravascular strategies. It is used specifically for the local treatment of peritoneal cavity disorders, e.g., peritoneal malignancies and dialysis. The peritoneal cavity contains the abdominal organs and the peritoneal fluid, normally composed of water, proteins, electrolytes, immune cells, and other interstitial fluid substances [161]. The high absorption rate associated to IP administration is promoted by the vast blood supply to the peritoneal cavity, along with its large surface area, which is further increased by the microvilli covering the mesothelial layer [162]. Injected compounds can enter the circulatory system after IP injection via both blood and lymphatic capillaries draining the peritoneal submesothelial layer [162][163][164]. Besides, the peritoneal absorption of molecules is greatly affected by their physicochemical characteristics. This route of administration also allows for the injection of large volumes (up to 10 mL) [162]. Extensive experimental studies carried out on animals have revealed that the peritoneal cavity has favorable absorption of lipophilic and unionized compounds [165]. This type of injection is most exploited for preclinical studies, since it is the simplest to perform, especially in small animals and with little impact on the animals’ stress [162][166]. IP use in humans is limited, despite showing many benefits in previous studies and even being recommended, for certain types of chemotherapy, by the National Cancer Institute [167][168][169].

    References

    1. Kaptoge, S.; Pennells, L.; De Bacquer, D.; Cooney, M.T.; Kavousi, M.; Stevens, G.; Riley, L.M.; Savin, S.; Khan, T.; Altay, S.; et al. World Health Organization cardiovascular disease risk charts: Revised models to estimate risk in 21 global regions. Lancet Glob. Health 2019, 7, e1332–e1345.
    2. Virani, S.S.; Alonso, A.; Aparicio, H.J.; Benjamin, E.J.; Bittencourt, M.S.; Callaway, C.W.; Carson, A.P.; Chamberlain, A.M.; Cheng, S.; Delling, F.N. Heart disease and stroke statistics—2021 update: A report from the American Heart Association. Circulation 2021, 143, e254–e743.
    3. Tiwari, G.; Tiwari, R.; Sriwastawa, B.; Bhati, L.; Pandey, S.; Pandey, P.; Bannerjee, S.K. Drug delivery systems: An updated review. Int. J. Pharm. Investig. 2012, 2, 2.
    4. Ryan, G.M.; Kaminskas, L.M.; Porter, C.J. Nano-chemotherapeutics: Maximising lymphatic drug exposure to improve the treatment of lymph-metastatic cancers. J. Control. Release 2014, 193, 241–256.
    5. Maisel, K.; Sasso, M.S.; Potin, L.; Swartz, M.A. Exploiting lymphatic vessels for immunomodulation: Rationale, opportunities, and challenges. Adv. Drug Deliv. Rev. 2017, 114, 43–59.
    6. Pal, I.; Ramsey, J.D. The role of the lymphatic system in vaccine trafficking and immune response. Adv. Drug Deliv. Rev. 2011, 63, 909–922.
    7. Sleeman, J.P. The relationship between tumors and the lymphatics: What more is there to know? Lymphology 2006, 39, 62–68.
    8. Porter, C.J.; Charman, S.A. Lymphatic transport of proteins after subcutaneous administration. J. Pharm. Sci. 2000, 89, 297–310.
    9. Zhang, X.-Y.; Lu, W.-Y. Recent advances in lymphatic targeted drug delivery system for tumor metastasis. Cancer Biol. Med. 2014, 11, 247–254.
    10. Yáñez, J.A.; Wang, S.W.; Knemeyer, I.W.; Wirth, M.A.; Alton, K.B. Intestinal lymphatic transport for drug delivery. Adv. Drug Deliv. Rev. 2011, 63, 923–942.
    11. Li, T.; Liang, W.; Xiao, X.; Qian, Y.J. Nanotechnology, an alternative with promising prospects and advantages for the treatment of cardiovascular diseases. Int. J. Nanomed. 2018, 13, 7349.
    12. Wong, M.S.; Hawthorne, W.J.; Manolios, N. Gene therapy in diabetes. Self Nonself 2010, 1, 165–175.
    13. Phillips, M.I. Gene therapy for hypertension: Sense and antisense strategies. Expert Opin. Biol. Ther. 2001, 1, 655–662.
    14. Tromp, T.R.; Stroes, E.S.; Hovingh, G.K. Gene-based therapy in lipid management: The winding road from promise to practice. Expert Opin. Investig. Drugs 2020, 29, 483–493.
    15. Kieserman, J.M.; Myers, V.D.; Dubey, P.; Cheung, J.Y.; Feldman, A.M. Current landscape of heart failure gene therapy. J. Am. Heart Assoc. 2019, 8, e012239.
    16. Shimamura, M.; Nakagami, H.; Taniyama, Y.; Morishita, R. Gene therapy for peripheral arterial disease. Expert Opin. Biol. Ther. 2014, 14, 1175–1184.
    17. Zhao, R.; Lu, Z.; Yang, J.; Zhang, L.; Li, Y.; Zhang, X. Drug Delivery System in the Treatment of Diabetes Mellitus. Front. Bioeng. Biotechnol. 2020, 8, 880.
    18. Avery, O.T.; MacLeod, C.M.; McCarty, M. Studies on the chemical nature of the substance inducing transformation of pneumococcal types: Induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. J. Exp. Med. 1944, 79, 137–158.
    19. Meyerson, S.L.; Skelly, C.L.; Curi, M.A.; Schwartz, L.B. Gene therapy for cardiovascular disease. Semin. Cardiothorac. Vasc. Anesth. 2000, 4, 289–300.
    20. Bulcha, J.T.; Wang, Y.; Ma, H.; Tai, P.W.; Gao, G. Viral vector platforms within the gene therapy landscape. Signal Transduct. Target. Ther. 2021, 6, 1–24.
    21. Su, C.-H.; Wu, Y.-J.; Wang, H.-H.; Yeh, H.-I. Nonviral gene therapy targeting cardiovascular system. Am. J. Physiol. Heart Circ. Physiol. 2012, 303, H629–H638.
    22. Hall, A.; Lächelt, U.; Bartek, J.; Wagner, E.; Moghimi, S.M. Polyplex Evolution: Understanding Biology, Optimizing Performance. Mol. Ther. 2017, 25, 1476–1490.
    23. Scimia, M.C.; Gumpert, A.M.; Koch, W.J. Cardiovascular gene therapy for myocardial infarction. Expert Opin. Biol. Ther. 2014, 14, 183–195.
    24. Cannatà, A.; Ali, H.; Sinagra, G.; Giacca, M. Gene therapy for the heart lessons learned and future perspectives. Circ. Res. 2020, 126, 1394–1414.
    25. Zhang, J.; Xie, Z.; Zhang, N.; Zhong, J. Nanosuspension drug delivery system: Preparation, characterization, postproduction processing, dosage form, and application. In Nanostructures for Drug Delivery; Elsevier: Amsterdam, The Netherlands, 2017; pp. 413–443.
    26. Fox, C.B.; Kim, J.; Le, L.V.; Nemeth, C.L.; Chirra, H.D.; Desai, T.A. Micro/nanofabricated platforms for oral drug delivery. J. Control. Release 2015, 219, 431–444.
    27. Trevaskis, N.L.; McEvoy, C.L.; McIntosh, M.P.; Edwards, G.A.; Shanker, R.M.; Charman, W.N.; Porter, C.J. The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (CP524,515 and CP532,623). Pharm. Res. 2010, 27, 878–893.
    28. Vinarov, Z.; Abdallah, M.; Agundez, J.A.G.; Allegaert, K.; Basit, A.W.; Braeckmans, M.; Ceulemans, J.; Corsetti, M.; Griffin, B.T.; Grimm, M.; et al. Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review. Eur. J. Pharm. Sci. 2021, 162, 105812.
    29. Sanchez-Rangel, E.; Inzucchi, S.E. Metformin: Clinical use in type 2 diabetes. Diabetologia 2017, 60, 1586–1593.
    30. Sola, D.; Rossi, L.; Schianca, G.P.C.; Maffioli, P.; Bigliocca, M.; Mella, R.; Corlianò, F.; Fra, G.P.; Bartoli, E.; Derosa, G. Sulfonylureas and their use in clinical practice. Arch. Med. Sci. 2015, 11, 840–848.
    31. van de Laar, F.A. Alpha-glucosidase inhibitors in the early treatment of type 2 diabetes. Vasc. Health Risk Manag. 2008, 4, 1189–1195.
    32. Lebovitz, H.E. Thiazolidinediones: The Forgotten Diabetes Medications. Curr. Diabetes Rep. 2019, 19, 151.
    33. Gallwitz, B. Clinical Use of DPP-4 Inhibitors. Front. Endocrinol. 2019, 10, 389.
    34. Neuen, B.L.; Cherney, D.Z.; Jardine, M.J.; Perkovic, V. Sodium-glucose cotransporter inhibitors in type 2 diabetes: Thinking beyond glucose lowering. CMAJ 2019, 191, E1128–E1135.
    35. Kim, K.S.; Kwag, D.S.; Hwang, H.S.; Lee, E.S.; Bae, Y.H. Immense insulin intestinal uptake and lymphatic transport using bile acid conjugated partially uncapped liposome. Mol. Pharm. 2018, 15, 4756–4763.
    36. Jain, S.; Rathi, V.V.; Jain, A.K.; Das, M.; Godugu, C. Folate-decorated PLGA nanoparticles as a rationally designed vehicle for the oral delivery of insulin. Nanomedicine 2012, 7, 1311–1337.
    37. Lin, P.Y.; Chen, K.H.; Miao, Y.B.; Chen, H.L.; Lin, K.J.; Chen, C.T.; Yeh, C.N.; Chang, Y.; Sung, H.W. Phase-Changeable Nanoemulsions for Oral Delivery of a Therapeutic Peptide: Toward Targeting the Pancreas for Antidiabetic Treatments Using Lymphatic Transport. Adv. Funct. Mater. 2019, 29, 1809015.
    38. Cohn, J.N.; Archibald, D.G.; Ziesche, S.; Franciosa, J.A.; Harston, W.E.; Tristani, F.E.; Dunkman, W.B.; Jacobs, W.; Francis, G.S.; Flohr, K.H. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N. Engl. J. Med. 1986, 314, 1547–1552.
    39. MacDougall, A.I.; Addis, G.J.; MacKay, N.; Dymock, I.W.; Turpie, A.G.; Ballingall, D.L.; MacLennan, W.J.; Whiting, B.; MacArthur, J.G. Treatment of hypertension with clonidine. Br. Med. J. 1970, 3, 440–442.
    40. Mah, G.T.; Tejani, A.M.; Musini, V.M. Methyldopa for primary hypertension. Cochrane Database Syst. Rev. 2009, 4, CD003893.
    41. Date, A.A.; Desai, N.; Dixit, R.; Nagarsenker, M. Self-nanoemulsifying drug delivery systems: Formulation insights, applications and advances. Nanomedicine 2010, 5, 1595–1616.
    42. Sun, M.; Zhai, X.; Xue, K.; Hu, L.; Yang, X.; Li, G.; Si, L. Intestinal absorption and intestinal lymphatic transport of sirolimus from self-microemulsifying drug delivery systems assessed using the single-pass intestinal perfusion (SPIP) technique and a chylomicron flow blocking approach: Linear correlation with oral bioavailabilities in rats. Eur. J. Pharm. Sci. 2011, 43, 132–140.
    43. Nekkanti, V.; Wang, Z.; Betageri, G.V. Pharmacokinetic evaluation of improved oral bioavailability of valsartan: Proliposomes versus self-nanoemulsifying drug delivery system. AAPS PharmSciTech 2016, 17, 851–862.
    44. Shah, U.; Joshi, G.; Sawant, K.J. Improvement in antihypertensive and antianginal effects of felodipine by enhanced absorption from PLGA nanoparticles optimized by factorial design. Mater. Sci. Eng. C 2014, 35, 153–163.
    45. Bangalore, S.; Steg, G.; Deedwania, P.; Crowley, K.; Eagle, K.A.; Goto, S.; Ohman, E.M.; Cannon, C.P.; Smith, S.C.; Zeymer, U.; et al. β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 2012, 308, 1340–1349.
    46. Lazar, H.L. Role of angiotensin-converting enzyme inhibitors in the coronary artery bypass patient. Ann. Thorac. Surg. 2005, 79, 1081–1089.
    47. Güleç, S. Valsartan after myocardial infarction. Anadolu Kardiyol. Derg. 2014, 14, S9–S13.
    48. Hubers, S.A.; Brown, N.J. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. Circulation 2016, 133, 1115–1124.
    49. Fares, H.; DiNicolantonio, J.J.; O’Keefe, J.H.; Lavie, C.J. Amlodipine in hypertension: A first-line agent with efficacy for improving blood pressure and patient outcomes. Open Heart 2016, 3, e000473.
    50. Rodríguez Padial, L.; Barón-Esquivias, G.; Hernández Madrid, A.; Marzal Martín, D.; Pallarés-Carratalá, V.; de la Sierra, A. Clinical Experience with Diltiazem in the Treatment of Cardiovascular Diseases. Cardiol. Ther. 2016, 5, 75–82.
    51. Badu-Boateng, C.; Jennings, R.; Hammersley, D. The therapeutic role of ivabradine in heart failure. Ther. Adv. Chronic Dis. 2018, 9, 199–207.
    52. Pitt, B.; Remme, W.; Zannad, F.; Neaton, J.; Martinez, F.; Roniker, B.; Bittman, R.; Hurley, S.; Kleiman, J.; Gatlin, M.; et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 2003, 348, 1309–1321.
    53. Pitt, B.; Zannad, F.; Remme, W.J.; Cody, R.; Castaigne, A.; Perez, A.; Palensky, J.; Wittes, J. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. N. Engl. J. Med. 1999, 341, 709–717.
    54. Campbell, T.J.; MacDonald, P.S. Digoxin in heart failure and cardiac arrhythmias. Med. J. Aust. 2003, 179, 98–102.
    55. Ramkumar, S.; Raghunath, A.; Raghunath, S. Statin Therapy: Review of Safety and Potential Side Effects. Acta Cardiol. Sin. 2016, 32, 631–639.
    56. Jneid, H.; Bhatt, D.L.; Corti, R.; Badimon, J.J.; Fuster, V.; Francis, G.S. Aspirin and clopidogrel in acute coronary syndromes: Therapeutic insights from the CURE study. Arch. Intern. Med. 2003, 163, 1145–1153.
    57. Tran, H.; Mehta, S.R.; Eikelboom, J.W. Clinical update on the therapeutic use of clopidogrel: Treatment of acute ST-segment elevation myocardial infarction (STEMI). Vasc. Health Risk Manag. 2006, 2, 379–387.
    58. Welsh, R.C.; Sidhu, R.S.; Cairns, J.A.; Lavi, S.; Kedev, S.; Moreno, R.; Cantor, W.J.; Stankovic, G.; Meeks, B.; Yuan, F.; et al. Outcomes Among Clopidogrel, Prasugrel, and Ticagrelor in ST-Elevation Myocardial Infarction Patients Who Underwent Primary Percutaneous Coronary Intervention From the TOTAL Trial. Can. J. Cardiol. 2019, 35, 1377–1385.
    59. Vavlukis, M.; Vavlukis, A. Adding ezetimibe to statin therapy: Latest evidence and clinical implications. Drugs Context 2018, 7, 212534.
    60. Tziomalos, K.; Athyros, V.G. Fenofibrate: A novel formulation (Triglide) in the treatment of lipid disorders: A review. Int. J. Nanomed. 2006, 1, 129–147.
    61. Shaker, M.A.; Elbadawy, H.M.; Al Thagfan, S.S.; Shaker, M.A. Enhancement of atorvastatin oral bioavailability via encapsulation in polymeric nanoparticles. Int. J. Pharm. 2021, 592, 120077.
    62. Sharma, M.; Mehta, I. Surface stabilized atorvastatin nanocrystals with improved bioavailability, safety and antihyperlipidemic potential. Sci. Rep. 2019, 9, 16105.
    63. Kumar, N.; Chaurasia, S.; Patel, R.R.; Khan, G.; Kumar, V.; Mishra, B. Atorvastatin calcium loaded PCL nanoparticles: Development, optimization, in vitro and in vivo assessments. RSC Adv. 2016, 6, 16520–16532.
    64. Elmowafy, M.; Ibrahim, H.M.; Ahmed, M.A.; Shalaby, K.; Salama, A.; Hefesha, H. Atorvastatin-loaded nanostructured lipid carriers (NLCs): Strategy to overcome oral delivery drawbacks. Drug Deliv. 2017, 24, 932–941.
    65. Jain, K.; Kumar, R.S.; Sood, S.; Gowthamarajan, K. Enhanced oral bioavailability of atorvastatin via oil-in-water nanoemulsion using aqueous titration method. J. Pharm. Sci. Res. 2013, 5, 18.
    66. Tiwari, R.; Pathak, K. Nanostructured lipid carrier versus solid lipid nanoparticles of simvastatin: Comparative analysis of characteristics, pharmacokinetics and tissue uptake. Int. J. Pharm. 2011, 415, 232–243.
    67. Dudhipala, N.; Veerabrahma, K. Improved anti-hyperlipidemic activity of Rosuvastatin Calcium via lipid nanoparticles: Pharmacokinetic and pharmacodynamic evaluation. Eur. J. Pharm. Biopharm. 2017, 110, 47–57.
    68. El-Helw, A.-R.M.; Fahmy, U.A. Improvement of fluvastatin bioavailability by loading on nanostructured lipid carriers. Int. J. Nanomed. 2015, 10, 5797.
    69. Chen, Y.; Lu, Y.; Chen, J.; Lai, J.; Sun, J.; Hu, F.; Wu, W. Enhanced bioavailability of the poorly water-soluble drug fenofibrate by using liposomes containing a bile salt. Int. J. Pharm. 2009, 376, 153–160.
    70. Mohsin, K.; Alamri, R.; Ahmad, A.; Raish, M.; Alanazi, F.K.; Hussain, M.D. Development of self-nanoemulsifying drug delivery systems for the enhancement of solubility and oral bioavailability of fenofibrate, a poorly water-soluble drug. Int. J. Nanomed. 2016, 11, 2829.
    71. Tran, T.H.; Ramasamy, T.; Truong, D.H.; Choi, H.-G.; Yong, C.S.; Kim, J.O. Preparation and characterization of fenofibrate-loaded nanostructured lipid carriers for oral bioavailability enhancement. AAPS Pharmscitech 2014, 15, 1509–1515.
    72. Agrawal, Y.O.; Mahajan, U.B.; Agnihotri, V.V.; Nilange, M.S.; Mahajan, H.S.; Sharma, C.; Ojha, S.; Patil, C.R.; Goyal, S.N. Ezetimibe-Loaded Nanostructured Lipid Carrier Based Formulation Ameliorates Hyperlipidaemia in an Experimental Model of High Fat Diet. Molecules 2021, 26, 1485.
    73. Bandyopadhyay, S.; Katare, O.; Singh, B. Optimized self nano-emulsifying systems of ezetimibe with enhanced bioavailability potential using long chain and medium chain triglycerides. Colloids Surf. B Biointerfaces 2012, 100, 50–61.
    74. Shevalkar, G.; Vavia, P. Solidified nanostructured lipid carrier (S-NLC) for enhancing the oral bioavailability of ezetimibe. J. Drug Deliv. Sci. Technol. 2019, 53, 101211.
    75. McLennan, D.N.; Porter, C.J.; Charman, S.A. Subcutaneous drug delivery and the role of the lymphatics. Drug Discov. Today Technol. 2005, 2, 89–96.
    76. American Diabetes, A. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020, 43, S14–S31.
    77. Hinnen, D. Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes. Diabetes Spectr. 2017, 30, 202–210.
    78. Roesti, E.S.; Boyle, C.N.; Zeman, D.T.; Sande-Melon, M.; Storni, F.; Cabral-Miranda, G.; Knuth, A.; Lutz, T.A.; Vogel, M.; Bachmann, M.F. Vaccination against amyloidogenic aggregates in pancreatic islets prevents development of type 2 diabetes mellitus. Vaccines 2020, 8, 116.
    79. Zhang, Y.; Yu, X.-L.; Zha, J.; Mao, L.-Z.; Chai, J.-Q.; Liu, R.-T. Therapeutic vaccine against IL-1β improved glucose control in a mouse model of type 2 diabetes. Life Sci. 2018, 192, 68–74.
    80. Zha, J.; Chi, X.-W.; Yu, X.-L.; Liu, X.-M.; Liu, D.-Q.; Zhu, J.; Ji, H.; Liu, R.-T. Interleukin-1β-targeted vaccine improves glucose control and β-cell function in a diabetic KK-Ay mouse model. PLoS ONE 2016, 11, e0154298.
    81. Cavelti-Weder, C.; Timper, K.; Seelig, E.; Keller, C.; Osranek, M.; Lässing, U.; Spohn, G.; Maurer, P.; Müller, P.; Jennings, G.T. Development of an interleukin-1β vaccine in patients with type 2 diabetes. Mol. Ther. 2016, 24, 1003–1012.
    82. Pang, Z.; Nakagami, H.; Osako, M.K.; Koriyama, H.; Nakagami, F.; Tomioka, H.; Shimamura, M.; Kurinami, H.; Takami, Y.; Morishita, R. Therapeutic vaccine against DPP4 improves glucose metabolism in mice. Proc. Natl. Acad. Sci. USA 2014, 111, E1256–E1263.
    83. Qiu, Z.; Chen, X.; Zhou, Y.; Lin, J.; Ding, D.; Yang, S.; Chen, F.; Wang, M.; Zhu, F.; Yu, X. Therapeutic vaccines against human and rat renin in spontaneously hypertensive rats. PLoS ONE 2013, 8, e66420.
    84. Brown, M.J.; Coltart, J.; Gunewardena, K.; Ritter, J.M.; Auton, T.R.; Glover, J.F. Randomized double-blind placebo-controlled study of an angiotensin immunotherapeutic vaccine (PMD3117) in hypertensive subjects. Clin. Sci. 2004, 107, 167–173.
    85. Hong, F.; Quan, W.Y.; Pandey, R.; Yi, S.; Chi, L.; Xia, L.Z.; Yuan, M.; Ming, L.J. A vaccine for hypertension based on peptide AngI-R: A pilot study. Int. J. Cardiol. 2011, 148, 76–84.
    86. Chen, X.; Qiu, Z.; Yang, S.; Ding, D.; Chen, F.; Zhou, Y.; Wang, M.; Lin, J.; Yu, X.; Zhou, Z. Effectiveness and safety of a therapeutic vaccine against angiotensin II receptor type 1 in hypertensive animals. Hypertension 2013, 61, 408–416.
    87. Zhu, F.; Liao, Y.H.; Li, L.D.; Cheng, M.; Wei, F.; Wei, Y.M.; Wang, M. Target organ protection from a novel angiotensin II receptor (AT1) vaccine ATR12181 in spontaneously hypertensive rats. Cell. Mol. Immunol. 2006, 3, 107–114.
    88. Tissot, A.C.; Maurer, P.; Nussberger, J.; Sabat, R.; Pfister, T.; Ignatenko, S.; Volk, H.-D.; Stocker, H.; Müller, P.; Jennings, G.T. Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: A double-blind, randomised, placebo-controlled phase IIa study. Lancet 2008, 371, 821–827.
    89. Watanabe, R.; Suzuki, J.-I.; Wakayama, K.; Maejima, Y.; Shimamura, M.; Koriyama, H.; Nakagami, H.; Kumagai, H.; Ikeda, Y.; Akazawa, H. A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction. Sci. Rep. 2017, 7, 43920.
    90. Margulis, K.; Neofytou, E.A.; Beygui, R.E.; Zare, R.N. Celecoxib nanoparticles for therapeutic angiogenesis. ACS Nano 2015, 9, 9416–9426.
    91. Vignesh, S.; Sivashanmugam, A.; Annapoorna, M.; Janarthanan, R.; Subramania, I.; Jayakumar, R. Injectable deferoxamine nanoparticles loaded chitosan-hyaluronic acid coacervate hydrogel for therapeutic angiogenesis. Colloids Surf. B Biointerfaces 2018, 161, 129–138.
    92. Tomlinson, B.; Hu, M.; Zhang, Y.; Chan, P.; Liu, Z.-M. Alirocumab for the treatment of hypercholesterolemia. Expert Opin. Biol. Ther. 2017, 17, 633–643.
    93. Kasichayanula, S.; Grover, A.; Emery, M.G.; Gibbs, M.A.; Somaratne, R.; Wasserman, S.M.; Gibbs, J.P. Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor. Clin. Pharmacokinet. 2018, 57, 769–779.
    94. Ray, K.K.; Wright, R.S.; Kallend, D.; Koenig, W.; Leiter, L.A.; Raal, F.J.; Bisch, J.A.; Richardson, T.; Jaros, M.; Wijngaard, P.L.J.; et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N. Engl. J. Med. 2020, 382, 1507–1519.
    95. Santos, R.D.; Raal, F.J.; Catapano, A.L.; Witztum, J.L.; Steinhagen-Thiessen, E.; Tsimikas, S. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein (a) in various populations with hypercholesterolemia: Results of 4 phase III trials. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 689–699.
    96. Raal, F.J.; Kallend, D.; Ray, K.K.; Turner, T.; Koenig, W.; Wright, R.S.; Wijngaard, P.L.; Curcio, D.; Jaros, M.J.; Leiter, L.A. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N. Engl. J. Med. 2020, 382, 1520–1530.
    97. Witztum, J.L.; Gaudet, D.; Freedman, S.D.; Alexander, V.J.; Digenio, A.; Williams, K.R.; Yang, Q.; Hughes, S.G.; Geary, R.S.; Arca, M. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N. Engl. J. Med. 2019, 381, 531–542.
    98. Viney, N.J.; van Capelleveen, J.C.; Geary, R.S.; Xia, S.; Tami, J.A.; Rosie, Z.Y.; Marcovina, S.M.; Hughes, S.G.; Graham, M.J.; Crooke, R.M. Antisense oligonucleotides targeting apolipoprotein (a) in people with raised lipoprotein (a): Two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016, 388, 2239–2253.
    99. Pharma, I. Positive Phase 2 Clinical Data of AKCEA-APOCIII-L(Rx) at ESC Congress 2020; Ionis Pharma: Boston, MA, USA; Carlsbad, CA, USA, 2020.
    100. Graham, M.J.; Lee, R.G.; Brandt, T.A.; Tai, L.-J.; Fu, W.; Peralta, R.; Yu, R.; Hurh, E.; Paz, E.; McEvoy, B.W. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N. Engl. J. Med. 2017, 377, 222–232.
    101. Kawakami, R.; Nozato, Y.; Nakagami, H.; Ikeda, Y.; Shimamura, M.; Yoshida, S.; Sun, J.; Kawano, T.; Takami, Y.; Noma, T. Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9) epitope in mice. PLoS ONE 2018, 13, e0191895.
    102. Landlinger, C.; Pouwer, M.G.; Juno, C.; van der Hoorn, J.W.; Pieterman, E.J.; Jukema, J.W.; Staffler, G.; Princen, H.M.; Galabova, G. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE* 3Leiden. CETP mice. Eur. Heart J. 2017, 38, 2499–2507.
    103. Crossey, E.; Amar, M.J.; Sampson, M.; Peabody, J.; Schiller, J.T.; Chackerian, B.; Remaley, A.T. A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine 2015, 33, 5747–5755.
    104. Brakenhielm, E.; Alitalo, K. Cardiac lymphatics in health and disease. Nat. Rev. Cardiol. 2019, 16, 56–68.
    105. Ananthakrishnan, P.; Mariani, G.; Moresco, L.; Giuliano, A.E. The anatomy and physiology of lymphatic circulation. In Radioguided Surgery; Springer: New York, NY, USA, 2008; pp. 57–71.
    106. Supersaxo, A.; Hein, W.R.; Steffen, H. Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm. Res. 1990, 7, 167–169.
    107. Hirano, K.; Hunt, C.A. Lymphatic transport of liposome-encapsulated agents: Effects of liposome size following intraperitoneal administration. J. Pharm. Sci. 1985, 74, 915–921.
    108. Flessner, M.; Dedrick, R.; Schultz, J.S. Exchange of macromolecules between peritoneal cavity and plasma. Am. J. Physiol. Heart Circ. Physiol. 1985, 248, H15–H25.
    109. Lim, H.Y.; Thiam, C.H.; Yeo, K.P.; Bisoendial, R.; Hii, C.S.; McGrath, K.C.; Tan, K.W.; Heather, A.; Alexander, J.S.J.; Angeli, V. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab. 2013, 17, 671–684.
    110. Reddy, S.T.; Rehor, A.; Schmoekel, H.G.; Hubbell, J.A.; Swartz, M.A. In vivo targeting of dendritic cells in lymph nodes with poly (propylene sulfide) nanoparticles. J. Control. Release 2006, 112, 26–34.
    111. Thrower, S.L.; James, L.; Hall, W.; Green, K.M.; Arif, S.; Allen, J.S.; Van-Krinks, C.; Lozanoska-Ochser, B.; Marquesini, L.; Brown, S.; et al. Proinsulin peptide immunotherapy in type 1 diabetes: Report of a first-in-man Phase I safety study. Clin. Exp. Immunol. 2009, 155, 156–165.
    112. Dul, M.; Nikolic, T.; Stefanidou, M.; McAteer, M.; Williams, P.; Mous, J.; Roep, B.; Kochba, E.; Levin, Y.; Peakman, M. Conjugation of a peptide autoantigen to gold nanoparticles for intradermally administered antigen specific immunotherapy. Int. J. Pharm. 2019, 562, 303–312.
    113. Nikolic, T.; Zwaginga, J.J.; Uitbeijerse, B.S.; Woittiez, N.J.; de Koning, E.J.; Aanstoot, H.-J.; Roep, B.O. Safety and feasibility of intradermal injection with tolerogenic dendritic cells pulsed with proinsulin peptide—For type 1 diabetes. Lancet Diabetes Endocrinol. 2020, 8, 470–472.
    114. Nicoll, L.H.; Hesby, A. Intramuscular injection: An integrative research review and guideline for evidence-based practice. Appl. Nurs. Res. 2002, 15, 149–162.
    115. Nakajima, Y.; Mukai, K.; Takaoka, K.; Hirose, T.; Morishita, K.; Yamamoto, T.; Yoshida, Y.; Urai, T.; Nakatani, T. Establishing a new appropriate intramuscular injection site in the deltoid muscle. Hum. Vaccin. Immunother. 2017, 13, 2123–2129.
    116. Ogston-Tuck, S. Intramuscular injection technique: An evidence-based approach. Nurs. Stand. 2014, 29, 52–59.
    117. Rodger, M.A.; King, L. Drawing up and administering intramuscular injections: A review of the literature. J. Adv. Nurs. 2000, 31, 574–582.
    118. Kivelä, R.; Havas, E.; Vihko, V. Localisation of lymphatic vessels and vascular endothelial growth factors-C and -D in human and mouse skeletal muscle with immunohistochemistry. Histochem. Cell Biol. 2007, 127, 31–40.
    119. Abai, A.M.; Hobart, P.M.; Barnhart, K.M. Insulin delivery with plasmid DNA. Hum. Gene Ther. 1999, 10, 2637–2649.
    120. Phrommintikul, A.; Kuanprasert, S.; Wongcharoen, W.; Kanjanavanit, R.; Chaiwarith, R.; Sukonthasarn, A. Influenza vaccination reduces cardiovascular events in patients with acute coronary syndrome. Eur. Heart J. 2011, 32, 1730–1735.
    121. Gurfinkel, E.P.; Mendiz, O.; Mautner, B. Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) study. Eur. Heart J. 2004, 25, 25–31.
    122. Vlachopoulos, C.V.; Terentes-Printzios, D.G.; Aznaouridis, K.A.; Pietri, P.G.; Stefanadis, C.I. Association between pneumococcal vaccination and cardiovascular outcomes: A systematic review and meta-analysis of cohort studies. Eur. J. Prev. Cardiol. 2015, 22, 1185–1199.
    123. Tilemann, L.; Ishikawa, K.; Weber, T.; Hajjar, R.J. Gene therapy for heart failure. Circ. Res. 2012, 110, 777–793.
    124. Huang, L.-H.; Lavine, K.J.; Randolph, G.J. Cardiac Lymphatic Vessels, Transport, and Healing of the Infarcted Heart. JACC Basic Transl. Sci. 2017, 2, 477–483.
    125. Greenberg, B.; Butler, J.; Felker, G.M.; Ponikowski, P.; Voors, A.A.; Desai, A.S.; Barnard, D.; Bouchard, A.; Jaski, B.; Lyon, A.R. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): A randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet 2016, 387, 1178–1186.
    126. Hammond, H.K.; Penny, W.F.; Traverse, J.H.; Henry, T.D.; Watkins, M.W.; Yancy, C.W.; Sweis, R.N.; Adler, E.D.; Patel, A.N.; Murray, D.R. Intracoronary gene transfer of adenylyl cyclase 6 in patients with heart failure: A randomized clinical trial. JAMA Cardiol. 2016, 1, 163–171.
    127. Jessup, M.; Greenberg, B.; Mancini, D.; Cappola, T.; Pauly, D.F.; Jaski, B.; Yaroshinsky, A.; Zsebo, K.M.; Dittrich, H.; Hajjar, R.J. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID) a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation 2011, 124, 304–313.
    128. Hulot, J.S.; Salem, J.E.; Redheuil, A.; Collet, J.P.; Varnous, S.; Jourdain, P.; Logeart, D.; Gandjbakhch, E.; Bernard, C.; Hatem, S.N. Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: Results from the AGENT-HF randomized phase 2 trial. Eur. J. Heart Fail. 2017, 19, 1534–1541.
    129. Precigen Triple-Gene. Precigen Triple-Gene Provides Six-Month Follow-Up Data from Phase I Study of INXN-4001, a Multigenic Investigational Therapeutic Candidate for Heart Failure. 2020. Available online: https://www.prnewswire.com/news-releases/precigen-triple-gene-provides-six-month-follow-up-data-from-phase-i-study-of-inxn-4001-a-multigenic-investigational-therapeutic-candidate-for-heart-failure-301107258.html (accessed on 1 April 2021).
    130. Model, M.I. 425. Arginine and Tetrahydrobiopterin Synergistically Potentiate the Antirestenotic Effect of Vascular Gene Therapy with Inducible Nitric Oxide Synthase. Mol. Ther. 2010, 18, 1.
    131. Chung, E.S.; Miller, L.; Patel, A.N.; Anderson, R.D.; Mendelsohn, F.O.; Traverse, J.; Silver, K.H.; Shin, J.; Ewald, G.; Farr, M.J. Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: The STOP-HF randomized Phase II trial. Eur. Heart J. 2015, 36, 2228–2238.
    132. Juventas Therapeutics. Juventas Therapeutics Completes Enrollment of Phase I/II RETRO-HF Trial and Demonstrates Safety for Retrograde Infusion of JVS-100 in Patients with Heart Failure. 2014. Available online: https://www.prnewswire.com/news-releases/juventas-therapeutics-completes-enrollment-of-phase-iii-retro-hf-trial-and-demonstrates-safety-for-retrograde-infusion-of-jvs-100-in-patients-with-heart-failure-270890361.html (accessed on 1 May 2021).
    133. Anttila, V.; Saraste, A.; Knuuti, J.; Jaakkola, P.; Hedman, M.; Svedlund, S.; Lagerström-Fermér, M.; Kjaer, M.; Jeppsson, A.; Gan, L.-M.; et al. Synthetic mRNA encoding VEGF-A in patients undergoing coronary artery bypass grafting: Design of a phase 2a clinical trial. Mol. Ther. Methods Clin. Dev. 2020, 18, 464–472.
    134. Gan, L.-M.; Lagerström-Fermér, M.; Carlsson, L.G.; Arfvidsson, C.; Egnell, A.-C.; Rudvik, A.; Kjaer, M.; Collén, A.; Thompson, J.D.; Joyal, J.; et al. Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes. Nat. Commun. 2019, 10, 871.
    135. Ishikawa, K.; Fish, K.M.; Tilemann, L.; Rapti, K.; Aguero, J.; Santos-Gallego, C.G.; Lee, A.; Karakikes, I.; Xie, C.; Akar, F.G. Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure. Mol. Ther. 2014, 22, 2038–2045.
    136. Kim, J.S.; Hwang, H.; Cho, K.; Park, E.; Lee, W.; Paeng, J.; Lee, D.; Kim, H.; Sohn, D.; Kim, K. Intramyocardial transfer of hepatocyte growth factor as an adjunct to CABG: Phase I clinical study. Gene Ther. 2013, 20, 717–722.
    137. Hartikainen, J.; Hassinen, I.; Hedman, A.; Kivelä, A.; Saraste, A.; Knuuti, J.; Husso, M.; Mussalo, H.; Hedman, M.; Rissanen, T.T.; et al. Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: A phase I/IIa study with 1-year follow-up. Eur. Heart J. 2017, 38, 2547–2555.
    138. Liu, J.; Wu, P.; Wang, Y.; Du, Y. Ad-HGF improves the cardiac remodeling of rat following myocardial infarction by upregulating autophagy and necroptosis and inhibiting apoptosis. Am. J. Transl. Res. 2016, 8, 4605.
    139. Wang, W.; Wang, M.-Q.; Wang, H.; Gao, W.; Zhang, Z.; Zhao, S.; Xu, H.-Z.; Chen, B.; Zhu, M.-X.; Wu, Z.-Z. Effects of adenovirus-mediated hepatocyte growth factor gene therapy on postinfarct heart function: Comparison of single and repeated injections. Hum. Gene Ther. 2016, 27, 643–651.
    140. Hardy, N.; Viola, H.M.; Johnstone, V.P.; Clemons, T.D.; Cserne Szappanos, H.; Singh, R.; Smith, N.M.; Iyer, K.S.; Hool, L.C. Nanoparticle-mediated dual delivery of an antioxidant and a peptide against the L-Type Ca2+ channel enables simultaneous reduction of cardiac ischemia-reperfusion injury. ACS Nano 2015, 9, 279–289.
    141. Carpentier, A.C.; Frisch, F.; Labbe, S.M.; Gagnon, R.; de Wal, J.; Greentree, S.; Petry, H.; Twisk, J.; Brisson, D.; Gaudet, D. Effect of alipogene tiparvovec (AAV1-LPLS447X) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J. Clin. Endocrinol. 2012, 97, 1635–1644.
    142. Jin, J.-F.; Zhu, L.-L.; Chen, M.; Xu, H.-M.; Wang, H.-F.; Feng, X.-Q.; Zhu, X.-P.; Zhou, Q. The optimal choice of medication administration route regarding intravenous, intramuscular, and subcutaneous injection. Patient Prefer. Adherence 2015, 9, 923–942.
    143. 2—Intravenous Drug Administration. In Techniques in the Behavioral and Neural Sciences; Claassen, V. (Ed.) Elsevier: Amsterdam, The Netherlands, 1994; Volume 12, pp. 5–22.
    144. Xie, Y.; Bagby, T.R.; Cohen, M.S.; Forrest, M.L. Drug delivery to the lymphatic system: Importance in future cancer diagnosis and therapies. Expert Opin. Drug Deliv. 2009, 6, 785–792.
    145. Caliph, S.M.; Trevaskis, N.L.; Charman, W.N.; Porter, C.J. Intravenous dosing conditions may affect systemic clearance for highly lipophilic drugs: Implications for lymphatic transport and absolute bioavailability studies. J. Pharm. Sci. 2012, 101, 3540–3546.
    146. Yadav, P.; McLeod, V.M.; Nowell, C.J.; Selby, L.I.; Johnston, A.P.R.; Kaminskas, L.M.; Trevaskis, N.L. Distribution of therapeutic proteins into thoracic lymph after intravenous administration is protein size-dependent and primarily occurs within the liver and mesentery. J. Control. Release 2018, 272, 17–28.
    147. Cabrales, P.; Han, G.; Roche, C.; Nacharaju, P.; Friedman, A.J.; Friedman, J.M. Sustained release nitric oxide from long-lived circulating nanoparticles. Free Radic. Biol. Med. 2010, 49, 530–538.
    148. Ruiz-Esparza, G.U.; Segura-Ibarra, V.; Cordero-Reyes, A.M.; Youker, K.A.; Serda, R.E.; Cruz-Solbes, A.S.; Amione-Guerra, J.; Yokoi, K.; Kirui, D.K.; Cara, F.E. A specifically designed nanoconstruct associates, internalizes, traffics in cardiovascular cells, and accumulates in failing myocardium: A new strategy for heart failure diagnostics and therapeutics. Eur. J. Heart Fail. 2016, 18, 169–178.
    149. Marrella, A.; Iafisco, M.; Adamiano, A.; Rossi, S.; Aiello, M.; Barandalla-Sobrados, M.; Carullo, P.; Miragoli, M.; Tampieri, A.; Scaglione, S. A combined low-frequency electromagnetic and fluidic stimulation for a controlled drug release from superparamagnetic calcium phosphate nanoparticles: Potential application for cardiovascular diseases. J. R. Soc. Interface 2018, 15, 20180236.
    150. Maxwell, J.T.; Somasuntharam, I.; Gray, W.D.; Shen, M.; Singer, J.M.; Wang, B.; Saafir, T.; Crawford, B.H.; Jiang, R.; Murthy, N. Bioactive nanoparticles improve calcium handling in failing cardiac myocytes. Nanomedicine 2015, 10, 3343–3357.
    151. Avula, U.M.R.; Kim, G.; Lee, Y.-E.K.; Morady, F.; Kopelman, R.; Kalifa, J. Cell-specific nanoplatform-enabled photodynamic therapy for cardiac cells. Heart Rhythm. 2012, 9, 1504–1509.
    152. Onwordi, E.N.; Gamal, A.; Zaman, A. Anticoagulant Therapy for Acute Coronary Syndromes. Interv. Cardiol. 2018, 13, 87–92.
    153. Liu, G.; Li, L.; Huo, D.; Li, Y.; Wu, Y.; Zeng, L.; Cheng, P.; Xing, M.; Zeng, W.; Zhu, C. A VEGF delivery system targeting MI improves angiogenesis and cardiac function based on the tropism of MSCs and layer-by-layer self-assembly. Biomaterials 2017, 127, 117–131.
    154. Majmudar, M.D.; Keliher, E.J.; Heidt, T.; Leuschner, F.; Truelove, J.; Sena, B.F.; Gorbatov, R.; Iwamoto, Y.; Dutta, P.; Wojtkiewicz, G. Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice. Circulation 2013, 127, 2038–2046.
    155. Ottersbach, A.; Mykhaylyk, O.; Heidsieck, A.; Eberbeck, D.; Rieck, S.; Zimmermann, K.; Breitbach, M.; Engelbrecht, B.; Brügmann, T.; Hesse, M. Improved heart repair upon myocardial infarction: Combination of magnetic nanoparticles and tailored magnets strongly increases engraftment of myocytes. Biomaterials 2018, 155, 176–190.
    156. Chang, M.-Y.; Yang, Y.-J.; Chang, C.-H.; Tang, A.C.; Liao, W.-Y.; Cheng, F.-Y.; Yeh, C.-S.; Lai, J.J.; Stayton, P.S.; Hsieh, P.C. Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction. J. Control. Release 2013, 170, 287–294.
    157. Nagaoka, K.; Matoba, T.; Mao, Y.; Nakano, Y.; Ikeda, G.; Egusa, S.; Tokutome, M.; Nagahama, R.; Nakano, K.; Sunagawa, K. A new therapeutic modality for acute myocardial infarction: Nanoparticle-mediated delivery of pitavastatin induces cardioprotection from ischemia-reperfusion injury via activation of PI3K/Akt pathway and anti-inflammation in a rat model. PLoS ONE 2015, 10, e0132451.
    158. Kassim, S.H.; Li, H.; Bell, P.; Somanathan, S.; Lagor, W.; Jacobs, F.; Billheimer, J.; Wilson, J.M.; Rader, D.J. Adeno-associated virus serotype 8 gene therapy leads to significant lowering of plasma cholesterol levels in humanized mouse models of homozygous and heterozygous familial hypercholesterolemia. Hum. Gene Ther. 2013, 24, 19–26.
    159. Greig, J.A.; Limberis, M.P.; Bell, P.; Chen, S.-J.; Calcedo, R.; Rader, D.J.; Wilson, J.M. Nonclinical pharmacology/toxicology study of AAV8. TBG. mLDLR and AAV8. TBG. hLDLR in a mouse model of homozygous familial hypercholesterolemia. Hum. Gene Ther. Clin. Dev. 2017, 28, 28–38.
    160. Fitzgerald, K.; Frank-Kamenetsky, M.; Shulga-Morskaya, S.; Liebow, A.; Bettencourt, B.R.; Sutherland, J.E.; Hutabarat, R.M.; Clausen, V.A.; Karsten, V.; Cehelsky, J. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: A randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 2014, 383, 60–68.
    161. Pannu, H.K.; Oliphant, M. The subperitoneal space and peritoneal cavity: Basic concepts. Abdom. Imaging 2015, 40, 2710–2722.
    162. Al Shoyaib, A.; Archie, S.R.; Karamyan, V.T. Intraperitoneal Route of Drug Administration: Should it Be Used in Experimental Animal Studies? Pharm. Res. 2020, 37, 12.
    163. Michailova, K.N.; Usunoff, K.G. Serosal Membranes (Pleura, Pericardium, Peritoneum): Normal Structure, Development and Experimental Pathology; Springer Science & Business Media: Berlin/Heidelberg, Germany, 2006; Volume 183.
    164. Lee, G.; Han, S.; Inocencio, I.; Cao, E.; Hong, J.; Phillips, A.R.J.; Windsor, J.A.; Porter, C.J.H.; Trevaskis, N.L. Lymphatic Uptake of Liposomes after Intraperitoneal Administration Primarily Occurs via the Diaphragmatic Lymphatics and is Dependent on Liposome Surface Properties. Mol. Pharm. 2019, 16, 4987–4999.
    165. Torres, I.; Litterst, C.; Guarino, A. Transport of model compounds across the peritoneal membrane in the rat. Pharmacology 1978, 17, 330–340.
    166. Turner, P.V.; Brabb, T.; Pekow, C.; Vasbinder, M.A. Administration of substances to laboratory animals: Routes of administration and factors to consider. J. Am. Assoc. Lab. Anim. Sci. 2011, 50, 600–613.
    167. Alberts, D.S.; Liu, P.; Hannigan, E.V.; O’Toole, R.; Williams, S.D.; Young, J.A.; Franklin, E.W.; Clarke-Pearson, D.L.; Malviya, V.K.; DuBeshter, B. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N. Engl. J. Med. 1996, 335, 1950–1955.
    168. Armstrong, D.K.; Bundy, B.; Wenzel, L.; Huang, H.Q.; Baergen, R.; Lele, S.; Copeland, L.J.; Walker, J.L.; Burger, R.A. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N. Engl. J. Med. 2006, 354, 34–43.
    169. National Cancer Institute. NCI Clinical Announcement on Intraperitoneal Chemotherapy for Ovarian Cancer. 2006. Available online: https://ctep.cancer.gov/highlights/docs/clin_annc_010506.pdf (accessed on 1 May 2021).
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      Tessier, N. Lymphatic Route in Cardiovascular Medicine. Encyclopedia. Available online: https://encyclopedia.pub/entry/13317 (accessed on 01 June 2023).
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