Lymphatic Route in Cardiovascular Medicine: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Nolwenn Tessier.

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

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][5][6] (HIV [7]), but also for macromolecules [8], and the extensively hepatic-metabolized compounds [9,10][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 [29][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 [30,31[12][13][14][15][16],32,33,34], 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) [35][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 [36,37][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 [38][20]. The most commonly used non-viral vectors include lipid-based vectors using cationic lipids and polymer-based vectors using cationic polymers [39][21]. Cationic lipids complex with the genetic materials to form lipoplexes or lipid nanoparticles (LNP), while cationic polymers form polyplexes [40][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 [41,42][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 [48][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 [49,50,51][26][27][28].
Table 1. Oral delivery of various treatments for CVD.

Condition

Intervention and Identifier

Target

Intervention and Identifier

Target

Dose and Outcome

Dose and Outcome

Diabetes

Metformin

  

Diabetes

Proinsulin peptide vaccine C19-A3

CD4 T cells

From 500 to 850 mg, 2–3 times a day, during the meal [58]

[29]

Three equal doses—10–100 µg

Vaccine was well tolerated

[177

Diabetes

Sulfonylureas

Meglitinide

  

Dosage is very different from one class of medication to another [59]

[30]

Diabetes

Acarbose,

Miglitol

Voglibose

Carbohydrate digesting enzymes in the brush border

50 mg three times daily (up to 100 mg) [60]

[31]

Diabetes

Rosiglitazone

Pioglitazone

PPAR-α

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

Pioglitazone: 15–30 mg per day

[61]

[

32]
]. 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 [116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143][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

[

116]

[

76

]

]

[

111

]

Diabetes

Exenatide

Lixisenatide

Liraglutide

Exenatide LAR

Albiglutide

Dulaglutide

      

GLP-1 analogues [

Diabetes

C19-A3

(NCT02837094)

117

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

[178]

[

112]

[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

Diabetes

Vaccine formed of virus-like particles coupled to IAPP

  

PIpepTolDC vaccine (NCT04590872)

Tolerogenic DC Vaccine

Against the insoluble IAPP- derived amyloid aggregates

One dose and another after 28 days

No results yet, but, it is believed to be able to produce proinsulin-specific Treg

[179]

[

 

113

]

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

[118]

[

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

[119,120]

[

79][80]

Diabetes

Sitaglipin

Vildaglipin

Saxaglipin

Linaglipin

Aloglipin

Diabetes

hIL1bQb

vaccine

(NCT00924105)DPP4

2.5–100 mg once daily depending on the inhibitor used [62]

[33]
 

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

[

121]

[

81

]

Diabetes

Diabetes

Dapagliflozin

Canagliflozin

Empagliflozin

Neutralizing

antibodies against DPP4

SGLTP2

Dapagliflozin: 2.5–10 mg daily

Canagliflozin: 100–300 mg

Empagliflozin: 5–25 mg daily

[

  

63

]

[

34

]

The GLP-1 and GIP inhibitor, DPP4

  

Five doses—2–20 µg

Increased pancreatic and plasma insulin level and improved postprandial blood glucose level

[122]

[

82]

Diabetes
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 [180][114] (hepatitis, flu virus, tetanus) or with specific pathologies, such as rheumatoid arthritis and multiple sclerosis. It is frequently performed in the upper arm [181][115] but also in the hip or thigh [182][116]. It is possible to administer up to 5 mL via this route, based on the site of injection [183][117]. As lymphatic vessels are present in the skeletal muscle and the connective tissue [184][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 [185,186,187,188][119][120][121][122].
Table 4. CVD therapies using intramuscular administration.

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

[201]

[

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

[211]

[

128]

HF

SRD-001

(NCT04703842)

AAVI

SERCA2a

Phase I/II

(Active, not recruiting)

Single administration of 3 × 1013 vg

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)

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

HTN

HF

CVDhR32 vaccine

  

INXN-4001

(NCT03409627)

Non-viral, triple effector plasmid

Renin-derived peptide

  

SDF-1α,

S100A1,

VEGF-165

Phase I

(Completed)

Five doses—500 µg

Reduced systolic blood pressure by 15 mmHg

[123]

[

83]

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

[212]

[

129]

Diabetes

Insulin nanocarriers

  

Protection of insulin from enzymatic degradation

HTN

HF

ACRX-100

(NCT01082094)

Enhancement of stability, intestinal permeability, and bioavailability

[35]

Angiotensin I

vaccine (PMD3117)

Plasmid DNA

[17]
     

SDF-1

Phase I

(Completed)

Three or four doses—100 µg

The vaccine failed to reduce the blood pressure

[124]

[

84]

Single escalating doses, injected at multiple sites

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

[213]

[

130]

Diabetes

Electrostatically-complexed insulin with partially uncapped cationic liposomes

  

Improved insulin pharmacokinetic profile [64]

HTN

AngI-R vaccine

[35]
 

Modifiedendogenous angiotensin I peptide

HF

JVS-100

 

(NCT01643590)

Plasmid DNA

SDF-1

Four doses—50 µg

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

Phase II

(Completed)

[

125]

[

85]

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

[214]

[

131]

Diabetes

Insulin-loaded PLGA

  

Improved bioavailability and sustained hypoglycemic effect

HTN

HF

ATRQβ-001

JVS-100

(NCT01961726)

Plasmid DNA

[65]

[36]
 

Angiotensin II type I receptors

  

SDF-1

Phase I/II

(Unknown)

Two doses—100 µg

Protective role against target organ damage induced by hypertension

[126]

[

86]

Single injection of escalating doses (30 and 45 mg)

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

[215]

[

132]

Diabetes

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

  

HTN

Enhancement of intestinal absorption and lymphatic transport [

ATR12181 vaccine

HF

AZD8601

(NCT02935712)66]

(NCT03370887)

  

mRNA

[37]

Angiotensin II type I receptors

  

VEGF-A165

Phase IIa

(Active, not recruiting)

Nine doses—0.1 mg

Attenuated the development of hemodynamic alterations of hypertension

[127]

[

87]

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

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

[216]

[

133]

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

[

217]

[

134

HTN

Prazosine Terazosine Doxazosine

Alpha-adrenergic receptor

Prazosine: 3–7.5 mg per day in two doses

]

HTN

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

Doxazosine: 4 mg per day

[

71]

[

38

]

CYT006-AngQb vaccine

  

Against angiotensin II

  

HF

NAN-101

(NCT04179643)

100 or 300 µg

Reduction in blood pressure and reduced ambulatory daytime blood pressure

[128]

AAV

I-1c

Phase I

(Recruiting)

[88]

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

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

[218]

[

135]

HTN

Clonidine Methyldopa

Alpha-adrenergic receptor (agonists)

Clonidine: 0.1 mg twice daily

HF

HTN

Ang II-KLH

vaccine

AMI IHD

VM202RY

(NCT01422772)

(NCT03404024)

[

DNA plasmid

72]

[39]

Methydopa: 250 mg two to three times daily

[73]

[

HGF-X7

Phase II

(Recruiting)

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

Phase I: improved myocardial function and wall thickness

[219,220]

[

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

[220]

[

137]

MI

Ad-HGF

(NCT02844283)

AV

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 [185]

[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 [186]

[120]

MI

Influenza vaccine

  

Risk of cardiovascular-related death was significantly lower [187]

[121]

CVD

MI

Pneumococcal vaccines

  

Reduced incidence of cardiovascular events and mortality

Reduced risk of MI in the elderly

[188]

[

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 [207][123]. It is a preferential route to directly target lymphatic vessels due to their high density in the myocardium [159,208][104][124]. Various CVD and their treatments via intramyocardial injection are presented in Table 5 [201,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224][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

[209]

[

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

[210]

[

127]

HF

MYDICAR

(NCT01643330)
 

40

]

Angiotensin II

 

Three doses—5 µg

Suppressed post-MI cardiac remodeling and improved cardiac function

[129]

[

89]

HTN

Carvedilol into nanoemulsion

Beta-adrenergic receptors

MI

Celecoxib loaded in nanoparticles

  

Significant improvement in its absorption, permeability, and bioavailability [88,89]

[41][42]
   

Promoted vascularization in the ischemic myocardium and delayed HF progression

[

130]

[90]

HTN

Valsartan, Ramipril and Amlodipine into nanoemulsion

  

MI

Chitosan-hyaluronic acid based hydrogel containing deferoxamine-PLGA

nanoparticles

Enhanced solubility, oral bioavailability, and pharmacological outcome [90

  

]

[43]
   

HGF

Phase I/II (Unknown)

Persistent neovascularization in mice [131]

[91]

Single dose

Preclinical studies: Ad-HGF preserved cardiac function, reduced infarct size, and improved post-MI cardiac remodeling

[221][138]; fractional repeated dosing significantly improved cardiac function compared with single injection [222]

[

139]

HTN

Felodipine-loaded PLGA nanoparticles

Calcium-channel

Sustained drug release both in vitro and ex vivo [93]

[44]

HCL

MI

Alirocumab

Evolocumab

  

PCSK9

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

        

One dose every two weeks [132,133]

[92][93]

Reduced the elevated level of ROS and the intracellular Ca2+ [223]

[140]

MI

HF

HTN

Arrhythmia

ß-blocker

Beta-adrenergic receptors

Acebutol: 200 mg twice daily

HCL

LPLD

Inclisiran

Alipogene tiparvovec

(NCT00891306)

[74]

  

AAV

[45]

PCSK9

  

LPL

Approved

Two doses per year [134]

[94]

1 × 1012 GC/kg

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

[224]

[

141]

MI

HF

HTN

HoFH

HeFH

severe HCL

Conversion enzyme

inhibitors

Mipomersen

(NCT00607373)

(NCT00706849)

(NCT00770146)

(NCT00794664)

Conversion enzyme

ASO

Captopril: 100 mg per day [75]

[46]

ApoB

Approved

200 mg once/week.

Phase III: reduction in LDL-C

[135]

[

95]

MI

HF

HTN

Valsartan

Losartan

Angiotensin II

ASCVD HCL HeFH

Inclisiran

(NCT03399370)

(NCT03400800)

(NCT03397121)

20 mg twice a day, up to 160 mg [76]

[47]

siRNA

PCSK9

Approved

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

Phase III: reduction in LDL-C level

[134,136]

[

94][96]

HF

HTN

Hydrochlorothiazide

Bumetanide

Angiotensin/neprilysin receptor

FCS

Volanesorsen

(NCT02211209)

49 mg/51 mg twice daily and doubled after 2–4 weeks [77]

[48]

ASO

ApoC3

Approved

300 mg once/week

Phase III: reduction in mean plasma APOC3 and TG level

[137]

[

97]

HF

HTN

Sacubitril

Valsartan

Calcium channel

Elevated LP(a)

ISIS-APO(a)Rx

(NCT02160899)

5–10 mg daily

ASO

[78]

[49]

60 mg three times daily

[79]

[

50]

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

[138]

[

98]

HTN

Arrhythmia

Amlodipine

Diltiazem

Calcium channel

5–10 mg daily [

Elevated LP(a)

CVD

AKCEA-APO(a)-LRx

(NCT03070782)

(NCT02414594)

(NCT04023552)

78]

GalNAc3

conjugated-ASO[49]

60 mg three times daily

[79]

[

50]

APO(a)

Phase III

(Recruiting)

80 mg administered monthly

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

[138]

[

98]

HF

HTG

CVD

FCS

Ivabradine

  

AKCEA-APOCIII-LRx

(NCT02900027)

(NCT03385239)

(NCT04568434)

Bradycardic

5–7.5 mg twice a day

[

GalNAc3

conjugated-ASO

80

]

[

51]

APOC3

Phase III

(Recruiting)

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

Phase II: reduction in ApoC3 and TG levels

[139]

[

99]

HF

MI

HTG

FH

HLP

Eplerenone

Spironolactone

Vupanorsen

(NCT02709850)

(NCT04459767)

(NCT04516291)

Aldosterone

ASO

50 mg once a day [81][52] and 12.5–25 mg with each intake [82]

[53]

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

[140]

[

100]

HF

Arrhythmia

Digoxin

  

0.25 mg once daily [83]

HCL

Neutralizing antibodies against PCSK9

[54

  

]

PCSK9

  

Three doses—5–50 µg

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

chylomicron

[

141]

[

101

]

HF

MI

HCL

Statin

HMG-CoA

HCL

10 mg once daily [

AT04A

84]

[55]
 

PCSK9

  

Five doses

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

[142]

[

102]

MI

Aspirin

Platelets

325 mg, then 81 mg per day [85]

[

HCL

AT04A

56]
 

PCSK9

  

Four doses—15 µg and 75 µg

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

[143]

[

103]

MI

HCL

Clopidogrel

Prasugrel

Ticagrelor

A peptide representing the mouse ANGPTL3

Platelets

300 mg, then 75 mg daily with aspirin

60 mg, then 10 mg daily

180 mg, then 90 mg twice a day

[

86,87]

[

  

Angiopoietin-like proteins 3 (ANGPTL3)

57

]

[58]
 

Three doses—5 µg

HCL

Ezetimibe

Intestinal cholesterol absorption

10 mg once daily [99]

[59]

Reduced steady-state plasma TGs and promoted LPL activity

HLD

Tricor

Triglide

  

Fenofibrates 100–300 mg per day [100]

[60]

HCL

HLD

Atorvastatin formulated into ethylcellulose nanoparticles

  

Enhanced atorvastatin’s lymphatic absorption and oral bioavailability [101]

[61]

HCL

HLD

Atorvastatin formulated into nanocrystals prepared with poloxamer 188

  

Improved atorvastatin’s gastric solubility and bioavailability [102]

[62]

Reduced circulating cholesterol, TG and LDL

HCL

HLD

Atorvastatin formulated into polycaprolactone nanoparticles

  

Enhanced atorvastatin’s bioavailability [103]

[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

[104]

[

64]

HCL

HLD

Nanoemulsion

  

Increased the bioavailability of atorvastatin compared to the commercial tablet ozovasTM [105]

[65]

HCL

HLD

Simvastatin

Rosuvastatin

Fluvastatin

Fibrates

Ezetimibe

lipid-based

nanoparticles

  

Improved bioavailability via lymphatic uptake [106,107,108,109,]110,111,[67]112,[68]113,114]

[66[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 [115][75

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 [159][104], leading to capillaries that have inter-endothelial gaps with size ranges from a few nanometers to several microns [4,160][4][105]. Small particles (<10 nm) [4] and medium-sized macromolecules (up to 16 kDa) [161][106] are mainly transported away from the interstitial spaces by blood capillaries, thanks to mass transport [162,163][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 [161][106] show preferential uptake into the highly permeable lymphatic capillaries either passively (paracellular) or actively (transcellular) through the lymphatic endothelial cells [164][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 [165][110].
Table 3 presents several vaccines used for diabetes through intradermal injection [177,178,179][111][112][113].
Table 3. Intradermal administration as treatment for diabetes.

Condition

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 [230][142]. The interest of this route of administration is the continuous treatment, or regular frequencies, by the installation of a catheter [231][143]. However, the lymphatic system is only scarcely involved following IV injections [232,233,234][144][145][146]. Table 6 presents several conditions treated with this type of injection [74,83,85,235,236,237,238,239,240,241,242,243,244,245,246,247,248][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 [235]

[147]

HF

Arrhythmia

Digoxin

      

Dose: 0.25 mg once daily [83]

[54]

MI

HF

HTN

Arrhythmia

ß-blocker

  

Beta-adrenergic receptors

  

Acebutol: 200 mg twice daily [74]

[45]

HF

Mesoporous silicon vector (Nanoconstruct)

      

Able to internalize, accumulate, and traffic within the cardiomyocytes [236]

[148]

HF

Combination of biocompatible magnetic nanoparticles and low-frequency magnetic stimulation

  

Cardio-myocytes

  

Managed the drug release by controlling the applied frequencies [237]

[149]

HF

S100A1-loaded nanoparticles, decorated with N-acetylglucosamine

      

Regulated Ca2+ release and restored contractile function in the isolated failing cardiomyocytes [238]

[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 [239]

[151]

MI

Unfractionated

heparin

      

Anticoagulant

60 IU/kg for initial bolus

12 IU/kg/h for maintenance

[

240]

[

152

]

MI

Aspirin

  

Platelets

  

325 mg, then 81 mg per day [85]

[56]

MI

Human recombinant VEGF-165

      

Significant improvement in the infarcted zone perfusion and cardiac function for up to six weeks post-MI [241][153].

MI

Nanoparticles containing siRNA

      

Anti-inflammatory effect in the infarcted heart and reduction of the post-MI heart failure [242]

[154]

MI

Magnetic nanoparticles-loaded cells

      

Robust improvement in the left ventricular and cardiac function [243]

[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 [244]

[156]

MI

Pitavastatin in PLGA nanoparticles

      

Cardioprotective effect against ischemia-reperfusion injury [245]

[157]

HoFH

AAV8.TBG.HldlR

(NCT02651675)

AAV

hLDLR

Phase I/II (Completed)

Single dose

Preclinical studies: reduction in total cholesterol

[246,247]

[

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

[248]

[

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 [272][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 [273][162]. Injected compounds can enter the circulatory system after IP injection via both blood and lymphatic capillaries draining the peritoneal submesothelial layer [273,274,275][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) [273][162]. Extensive experimental studies carried out on animals have revealed that the peritoneal cavity has favorable absorption of lipophilic and unionized compounds [276][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 [273,277][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 [278,279,280][167][168][169].

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