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    Topic review

    Lymphatic Route in Cardiovascular Medicine

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    Submitted by: Nolwenn Tessier
    (This entry belongs to Entry Collection "Hypertension and Cardiovascular Diseases ")

    Definition

    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. 

    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].

    The entry is from 10.3390/pharmaceutics13081200

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