Placenta Barrier and Drug Delivery

 

Gowthamrajan Kuppusamy, Anindita De, Ayush Jaiswal, Ananya Chatterjee

JSS College of Pharmacy, Rocklands, Post Box 20, Ooty, Tamilnadu-643001

 

ABSTRACT:

The placenta is only a temporary, disc-shaped organ which connect mother with the fetus via the umbilical cord to the uterine wall to provide the nutrition and protection. At the current era pregnancy complications like including pre-eclampsia, fetal development restriction, premature birth, placental abruption, and late pregnancy loss makes the scientist to turn their focuses on placental barrier for the drug transport. The formation of the placenta immediately starts after the implementation of the blastocyst. The blastocyst trophoblast form multinucleated syncytiotrophoblast and proliferate to form cytotrophoblast cells. Trophoblastic composite and trophoblast intrusion contributes in the reconstructing of maternal spiral arteries within the uterine wall. The branch structure of trophoblast inside the lacunar spaces consequence in the constitution of villous trees responsiple for the exchange of nutrition and gas. Drug molecules basically pass through the placenta barrier using the passive diffusion, facilated transport and efflux, and transcytosis pathways. The passive diffusion of the drugs through the placenta depends on the nature of the drug where as Facillited transport is membrane proteins dependent. The hydrolyze adenosine triphosphate (ATP) is the key for the active transporation governed by ATP-binding cassette (ABC) protein. Endocytosis mechanism is responsible for both endogenous compound transport as well as xenobiotics such as drug-loaded nanoparticle present in placental syncytiotrophoblast. Nanotechnology approaches is the latest trend to deliver the drug to the fetus as well and to restrict the entry of the drugs to protect the fetus damage. Placenta on chip is few latest trend for the placental drug delivery. The review specifically forcus on the variors transport mechanism of the drugs through the placenta as well as the metabolism of the drugs.

 

 

 

INTRODUCTION:

The placenta is one of the most complex and important organ between the mother and fetus which act as an interface for transportation of all kind of materials for the protection as well as for the nutrition⁽¹⁾. Before the thalidomide-induced birth defects in the late 1950s and early 1960s drug transport through the placenta was not that much in the research interest⁽²⁾. But at the current era pregnancy complications⁽³⁾ like including pre-eclampsia⁽⁴⁾, fetal development restriction, premature birth⁽⁵⁾, placental abruption, and late pregnancy loss makes the scientist to turn their focuses on placental barrier for the drug transport⁽⁶⁾.

 

Though the reason for the pregnancy complexities till now not that much clear but it has been contended that placental plays a primary role. Currently scientist clarifies and understands the accurate nature and mechanisms of trans-placental drug delivery using various in vitro and in vivo models. Based on the research it also been enhancing concern in safe apply of drugs during pregnancy and designed formulation to cross the placenta to render therapeutic effects on the fetus. Medication during pregnancy is a common fact but the majority of drug trials till date have omitted the enrolment of pregnant women and not fully evaluate the risks of fetal exposure to these medications⁽⁷⁾. In the present scenario a thorough research is essential to understand the transfer of drugs through placental to ensure the safety and healthcare for mother and baby. The effect of the drugs on the fetal growth depends on the gestational age, dose, dosing frequency, route of administration, and drug clearance⁽⁸⁾. So the pharmacokintetic alteration of the drug due to the physiological changes during pregnancy is one of the important factors to be considered while delivering the drug. The increase in the maternal blood volume and decrease in the serum albumin concentrations affect the drug absorption distribution and bioactivity. Even in the increase maternal arterial blood pH, shift of the oxyhemoglobin dissociation curve affects the trans-placental transfer of active pharmaceutical ingredients (API)⁽⁹⁾. Progesterone- stimulated delays in gastric emptying nausea and vomiting, or an increase in gastric pH reduces the drug absorption during pregnancy. Increase in the glomerular filtration alter the clearance of the drug and its metabolites from the body⁽¹⁰⁾. The metabolizing enzyme significantly alters the drug fate inside the body is another important factor to considered. The review focused on the drug transfer mechanism through the placental for maternal-to-fetal also includes human placental anatomical structure and function and the drug metabolizing enzymes within the placenta with the latest development for the drug delivery.

 

Placenta anatomy:

The placenta is only a temporary, disc-shaped organ which connect mother with the fetus via the umbilical cord to the uterine wall to provide the nutrition, growth hormones thermo –regulation, waste and gas exchange and to fight against internal infection⁽¹¹⁾. The formation of the placenta immediately starts after the implementation of the blastocyst. The blastocyst trophoblast form multinucleated syncytiotrophoblast and proliferate to form cytotrophoblast cells. Trophoblastic composite and trophoblast intrusion contributes in the reconstructing of maternal spiral arteries within the uterine wall. The branch structure of trophoblast inside the lacunar spaces consequence in the constitution of villous trees⁽¹²⁾. The intervillous place provided oxygen carrying blood from villi to the umbilical vein, and nonoxygenated blood is returned to the placental villi via the umbilical arteries. Over the maturation of the villi cytotrophoblast component reduced markly and left with only a single layer of syncytiotrophoblast which separates maternal blood and fetal capillary endothelium. Over the period of the pregnancy placenta undergone several changes⁽¹³⁾. The ratio of cytotrophoblast to syncytiotrophoblast reduced in due time. Even the cuboidal cytotrophoblast cells lose their thickness and the layer became non-contiguous. Overall, the placental turns thinner over time with the changes of construction and cellular distribution of transporter proteins^(14).

 

Figure (1): Functional unit of human placenta: chorionic villus

 

Uterine flow a significance role in the transportation of the drug during pregnancy. The blood flow in maternal uterine in ∼600 ml min⁻¹ and 80% of the flow passes to the placenta^(15). The flow affected by mean uterine insertion pressure and reciprocally related to uterine vascular resistor. The maternal hypotension cuts down the uteroplacental circulation and enhanced uterine pressure during uterine contractions. α-adrenergic receptors of uteroplacental arteries sympathetic stimulate and lead to uterine artery vasoconstriction^(16).

 

Classification of the drugs for placenta transport

Waddell and Marlowe shows 3 types of transfer pharmacokinetics across the placenta. Based on that The drugs are categorised in main 3 category^(17). The effects of drugs on the fetus may be either direct or may be mediated via the alteration of uteroplacental blood flow and the nature of the transport mechanism of the drug. Three types of drug transfer across the placenta are recognized and drugs are classified based on the nature of the drug transport.

 

Table 1: Type of drug transport based on the nature of transport

Type of Drugs	Mechanism	Example
Type 1 drugs	Complete and rapidly transfer through placenta based on the concentrations gradient balancing in maternal and fetal blood.	Thiopental
Type 2 drugs	Exceeding transfer of drugs which pass placenta and to achieve greater concentrations in fetal compared to maternal blood.	Ketamine
Type 3 drugs	Uncompleted transfer of drugs which do not cross the placenta completely and achieve greater concentrations maternal compared with fetal blood	Succinylcholine

 

Again as per the classification of FDA the drugs are classified in five different pregnancy-risk⁽¹⁸⁾ categories and supported by the in vivo animal and human trials^(19). The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy.

 

Table 2: Classification of Drugs based on pregnancy-risk (USFDA)

Category	Definition	Example
A	No risk found in the in the first trimester, and the possibleness of fetal damage appears outback.	Vitamins and levothyroxine.
B	Neither the animal model nor controlled studies in pregnant women shows any fetal damage, or animal models indicated fetal risk, but not the controlled studies in pregnant women	Acetaminophen (20)and amoxicillin(21).
C	No available studies in women or animals or animal study shows the featal risk	Diltiazem and spironolactone
D	There is evidence of fetal danger but certain emergency positions where the benefit overbalance damage	Phenytoin and valproic acid
X	Confirm fetal risk based on both animal and human study distinctly overbalance any benefit in pregnant women	Thalidomide (22) and warfarin

 

Drug transfer through placenta: factors:

Drugs transport from mother to fetus carried out in the intervillious space. Then pass through the syncytiotrophoblast, fetal connective tissue and then the endothelium of fetal capillaries. Various factors affect the transportation among them physical nature of the drug, pharmacological condition of mother and fetus and pharmacological condition of the drug in the body plays the most significant role. Factors affecting drug transport across the placenta are listed in figure 2.

 

 

Figure 2: Factors for the drugs transportation through placenta

 

Even the transport of the drug also influence by the epigenetic changes, genetic deviations, protein expression difference as well as mother and fetus health ^(23-25).

 

Drug transportation through placenta

For the endogenous compounds reaching to the fetus have to pass through the syncytiotrophoblast, basement membrane, and the fetal capillary endothelium^(23). The crossing of those ingredients is totally based on their physical and chemical attributes, energy gradient, epigenetic alters, genetic differences, differences in protein expression, and maternal and fetal health conditions⁽²⁶⁾. Drug molecules basically pass through the placenta barrier using the passive diffusion, facilated transport and efflux, and transcytosis pathways.

 

 

The transport mechanisms are also responsible for the rate and extent of trans-placental transmit of drugs taken by the pregnant women. Essentially all most all the drugs cross barrier and some of them cumulate in the placenta that can even exceed into the maternal plasma⁽²⁷⁾. It’s also reported that the drug which are not efficiently transferred across the placenta affects the development of the fetus by altering the placental function.

 

Figure 3: Mechanisms of placental drug transfer

 

Passive diffusion:

The passive diffusion of the drugs through the placenta depends on the nature of the drug⁽²⁸⁾. The lipophilic compounds facilities to transport through the phospholipids bilayer more readily. The molecular weight of the drug also affects the drug transport. The small molecules with the molecular weight less than 500 Da crossing the more easily than the macro molecules. The passive diffusion not energy gradient nor the membrane protein facilitator dependent but the drug transpiration is highly concentration gradient dependent ^(29). Examples of the drug that fallows the passive diffusion in the placenta barriers are lidocaine, azidothymidine, warfarin, and others⁽³⁰⁾. The transportation of this kind of molecules is basically depends on the inonization of the API. The ionization of the compound have the pH-dependent accumulation in the fetus compartment^(31). The more the ionization is less the lipophilicity and for that has the lesser tendency to cross the placental barrier. Usually, the lower pH of the fetal circulation than the maternal circulation changes the proportion of ionized to non-ionized species and, effectively trapping or excluding the transportation ^(32). Generally the endogenous compounds enter through the passive diffusion mechanism and the placental perfusion model gangliosides GM3. GM3 are quickly taken up by placenta⁽³³⁾.

 

The protein binding of the drugs also effects the dispersion through placenta. Drugs must dissociate from plasma proteins so that it can move into apical syncytiotrophoblast membrane exceptional is the albumin protein.

 

Facilitated diffusion:

Facillited transport of the drug is membrane proteins dependent. The hydrolyze adenosine triphosphate (ATP) based on energy based concentration or ionic gradients and enzymatic transportation of the drugs^(34). The membrane protein like Solute Carrier Family including organic anion transporters (OATs), organic anion transporting polypeptides (OATPs), organic cation trans porters (OCTs and OCTNs), multidrug and toxin extruding protein 1 (MATE1), and nucleoside transporters (NTs) are the well known for the facilitated diffusion^(35,36). Among all the OATs, OAT4 is explicit on the basolateral membrane of the syncytiotrophoblast and capable for the bidirectional transportation. The research shows that OAT4 specifically transport of endogenous and exogenous compounds. The specific endogenous compound that readily pass through the placenta are 16-α hydroxydehydroepiandrosterone sulfate, a metabolite of dehydro epiandrosterone sulfate, into the syncytiotrophoblast for estriol synthesis, as well as the transport of estrone-3-sulfate⁽³³⁾. The transporter is also responsible for transport of exogenous compounds including olmesartan, perfluoroalkyl acids, and many others. The function of the OAT4 transporter enhance in the presence of ionic gradients inside aimed chloride gradient enhancing substrate transport out of the syncytiotrophoblast, but the mechanism generally being reduced in the absence of sodium. But the exact pathway is yet to be clarified. In the case of the OATP family, OATP2B1 and OATP4A1 is the most studied placental trophoblast based transporter. OATP2B1 is basically responsible for the uptake of anions from the fetal circulation into the trophoblast cells and facilited the transportation of estrone sulfate and dehydroepiandrosterone sulphate^(37). Hypothesis also suggested that glutamate transport also OATP2B1 and OAT4 dependent. The process is sodium dependent. OATP4A1 mostly expressed on the apical membrane of syncytiotrophoblast is very less studied transporter. The researcher till now reported the transportation of hormone through OATP4A1 only.

 

Another category of the transporter for the placenta drug delivery are Organic cation transporters 1, 2, and 3 (OCT1, OCT2, and OCT3)^(38). These transporters are basically expressed on the basolateral membrane of the syncytiotrophoblast. Their expression may be variable at different gestational ages. Theses transporters are basically involved in the endogenous substance transport. In the case of the xenobiotics OCT3 plays the important role. MATE1 usually work along with the OCT3 for placenta and in renal tissues and highly depends on pH^(39). MATE1 also fallow the smiliar mechanism like organic cation transport with on the apical membrane of the syncytiotrophoblast and OCT3 on basolateral membrane, both pumping organic captions into the mother’s blood circulation.

 

Again organic cation transporters (OCTN1, OCTN2, and OCTN3) also showed on the apical membrane of the syncytiotrophoblast responsible for the transport of carnitine^(40). Transplacental carnitine channelize is important for the fetus. Fetus unable to synthesize ample amounts of carnitine which is helping in the oxidation of fatty acids in the mitochondria. In the lack of the Carnitine the newborn may can affected by cardiomyopathy, muscle weakness, hypoglycaemia. Even some time it may be able to case sudden infant death.

 

Active transport:

The active transportation⁽⁴¹⁾ of the drugs is totally energy-dependent and governed by ATP-binding cassette (ABC) protein^(42). Active transporters and subfamilies are explicit in the placenta, on both the apical and basolateral membranes. They works based on the principle of energy discharged by ATP hydrolysis to pump drugs and xenobiotics. The process is against concentration gradient. These transporters include P-glycoprotein (P-gp)⁽⁴³⁾, breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins (MRPs⁾⁽⁴⁴⁾

 

(P-gp commonly known as MDR1 (ABCB1) is most well studied due to its diverse substrate portfolio. P-gp is necessitated in the outflow of both endogenous and exogenous⁽⁴⁵⁾. P-gp is well known to forbid placental transition of dexamethasone, a synthetic glucocorticoid, as well as a number of other drugs such as verapamil, paclitaxel, bupropion, zidovudine, tenofovir disoproxil fumarate, cyclosporine, and others.

 

Breast cancer resistance protein (ABCG2) is equality creditworthy for the efflux of endogenous and exogenous materials. Endogenous substrates like steroid sulfates (and porphyrins, including heme are mostly efflux by this transporter⁽⁴⁶⁾. Drugs that outflow by these transporter include zidovudine, tenofovir disoproxil fumarate, bupropion, nitrofurantoin, and glyburide etc.

 

Multidrug resistance-associated protein 1 or MRP1 (ABCC1) is expressed on the basolateral membrane of the syncytiotrophoblast and on the abluminal side of the fetal capillary endothelium responsible for transport of both endogenous and exogenous material^(33). MRP1 is partly creditworthy for the channelize of methyl mercury to the fetus blood flow for that a higher levels of methyl mercury in umbilical cord blood in comparison to maternal always present. Unlike MRP1, MRP2 (ABCC2) is placed on the apical membrane of syncytiotrophoblast⁽⁴⁷⁾. Basically MRP2 is responsible for the protection of fetus against destructive xenobiotics as well as in transporting endogenous compounds. MRP2 transport mostly leukotrienes and bilirubin as well as its also capable of transport a number of sulfate, glucuronide, and glutathione conjugates. Xenobiotics that are carried over by MRP2 include tenofovir disoproxil fumarate and talinolol etc^(48).

 

Endocytosis:

Endocytosis mechanism is responsible for both endogenous compound transport as well as xenobiotics such as drug-loaded nanoparticle present in placental syncytiotrophoblast. Receptor specific endocytosis responsible for the uptake of essential nutrients from the maternal blood⁽³³⁾. Endocytosis of nanoparticles by the placenta is important in that it can alter the transplacental passage of drugs.

 

Placental drug metabolizing enzymes:

The placental enzyme⁽⁴⁹⁾ catalyzed both Phase I (drug oxidation, reduction and hydrolysis) and Phase II (conjugation) materials^(23).

 

Basically the isoforms of the Placental cytochrome P450 (CYP) includes 1A1, 2E1, 3A4, 3A5, 3A7, 4B1 and 19 and among them the placental aromatase (CYP19) and CYP11A are the major one for the mentabolism of the endogenous and exogenous compounds⁽⁵⁰⁾

 

Among the Phase I enzyme placentas include alcohol dehydrogenases, epoxide hydrolases and N-acetyltransferases and for the Placental phase II enzymes uridine diphosphate glucoronosyltransferases (UGTs), glutathione S-transferase, epoxide hydrolase, N-acetyltransferase, and sulphotransferases are responsible for the metabolism of the drug^(51). Human placentas also express UGT2B4, 2B7, 2B10, 2B11 and 2B15 mRNA. UGT2B1 and 2B7 were also found at the protein level and were focalized to the syncytiotrophoblast.

 

Even the deconjugation reactions also found in the placenta example by glucuronidases, as was demonstrated for the xenoestrogen bisphenol A in a sheep model⁽⁵²⁾. During the pregnancy the placental drug metabolizing enzymes changes for instance CYP3A7 in the human placenta is induced during pregnancy, whereas UGTs are present at the placenta throughout pregnancy. Drugs which have been shown to undergo significant placental metabolism include structural analogues of endogenous compounds, such as zidovudine and dideoxyinosine, but also other compounds such as oxcarbazepine⁽⁵³⁾. The enzyme of the placenta CYP19 metabolised glyburide, buprenorphine, and methadone. The drug Olanzapine and zidovudine was found to cnjugated to N-glucuronide in the ex vivo model of perfused cotyledon.

 

Though the extent of placental metabolic barrier limits fetal exposure to the drugs is to be minor compared to that of the maternal liver but contribute to the formation of fetotoxic reactive metabolites.

 

Outlook:

During pregnancy the exposure of the drug are basically to treat the mother but its also effect the pathological conditions of the fetus. Better understanding of the meternal-fetal pharmacokinetics of the substance transportation and enzyme metabolism can minimize the unnecessary drug abuse and side effects. It also helpful for the optimize drug delivery to the fetus through placenta.

 

Nano-technological outlook for placenta Drug delivery:

Drug carrier or the inhibitors highly modulate the placental pharmacokinetics of drugs. Although the effect of the modulator on carriers at drug-eliminating organs offset on the placenta is found. Reduction of the exposure of the drug to the fetus or target specific drug delivery to the placenta or fetus is achieved by the nanosized drug carriers. Researcher already shows that without the target specific ligands ⁽⁵⁴⁾ also the drug can accumulate in the placenta but effectiveness and the reduction of the drug relate side effects and only possible via the target specific drug carrier mechanism specifically for the treatment of trophoblast tumors or infections. Recently the scientist formulated antibody conjugated doxorubicin-loaded nanocells to target trophoblastic tumors which specifically binds the epidermal growth factor receptor (EGFR, highly expressed on the placental surface) ^(55).

 

Though the research is also shows that the risk of fetal exposure and toxicity following maternal use of nano-formulations is negligible. Ongoing studies evaluate nanoparticles as potential means for drug delivery in pregnant women (NCT02199756 and NCT02720887; clinicaltrials.gov). the recent trend of the nanoparticles for the placenta targets are basically the conjugated polymeric or lipid nanoparticles. Table 3 contain the latest nanotechnoilogical approaches for the placenta drug delivery.

 

Table 3: Latest nano-technological approach for the placenta drug delivery

Nanoformulation	Drugs	Targets	Outcome	Ref
Lipid-polymer nanoparticles	methotrexate (MTX)-loaded placental chondroitin sulfate A peptide	Placental trophoblast	Target specific drug delivry of the drug payloads to the placenta trophoblast	(56)
Poly lactic-co-glycolic acid (PLGA) nanoparticles	Placental growth factor (PGF)	acute myocardial infarction	PLGA-based nanoparticles appear to be a better approach to delivery PGF for cardiac drug delivery	(57)
Cyclodextrin-PEI-based polymer nanoparticle	TAT peptide conjugated plasmid DNA delivery	Placenta mesenchymal stem cells	Enhance the target specificity of the plasmid DNA to PMSCs	(58)
Polymeric nanoparticles	Dexamethasone	BeWo b30 cell line of placenta	Direct drug delivery to the fetus fetus, for congenital adrenal hyperplasia.	(59)
Liposome	tumor-homing peptide sequences CGKRK and iRGD conjuagated Carboxyfluorescein and insulin-like growth factor 2 delivery	Placental surface	placenta-specific therapeutics and overcome the drug related toxicity	(60)
Modified PEGylated cationic liposome (RGD-Lip)	arginine-glycine-aspartic acid peptide (RGD) noncoding conjugated RNA	Preeclampsia	Targeting noncoding RNA delivery to placenta enriched/specific genes.	(61)
Liposome	miR-148a and miR-152 microRNAs	HLA-G expression	Local deposition of the miRNA for new contraceptive therapy.	(62)
Cationic small unilamellar (SUV) liposomes	Warfarin	Placenta	The formulation reduced the trans placental transfer of warfarin and reduce  fetus damage	(63)
Poly-amidoamine (PAMAM) nanoparticles	siRNA-sFlt	Preeclampsia	Target specifically reduce the sFlt1 secretion and improve pregnancy outcomes in a preeclamptic	(64)
PAMAM dendrimer	Fluorescently (Alexa 488)	Transplacental transfers	Mother specific drug delivery carrier.	(65)
Micelle-like nanoparticles (MNP)	Clonazepam	BeWo cells of placenta	Reduce the fetus drug exposure and reduce the drug related toxicity. .	(66)
EnGeneIC Delivery Vehicles (EDVs) nanocells	EGFR conjucated Doxorubicin	Ctopic pregnancy, choriocarcinoma, and placenta accreta	Specifically target the carcinoma cells without transporting through placenta	(67)

 

Placenta-on-a-chip to screen for drug safety during pregnancy:

Placenta on chip’⁽⁶⁸⁾ technologies are one of the latest trends for the in vitro transfer of drugs and drug formulations across the human placental barrier. The model mimics the multilayered microfluidic system coculture of human trophoblast cells and human fetal endothelial cells to reproduce the formation of microvilli and the syncytialization of trophoblasts. The chip was tested using the human trophoblast cells on one side and endothelial cells on the other, to mimic the placental barrier. The research shows that the technology can mimic the fate of the drug in placenta. Future validation still needed to us the chip used routinely for drug screens.

 

CONCLUSIONS:

The placental drug delivery is not only related during the period of pregnancy is affect throughout the life time. To give birth to a healthy fetus the placenta fulfils the function of the appropriate transporter of the essential compounds between the mother and the fetus assist with carriers, enzymes and transcytotic pathways. Endogenous, exogenous and xenobiotics highly affect the fetus and fetal development. Understanding drug pharmacokinetics and pharmacodynamics is a first step towards improving therapeutic regimes for the drug and health for the mother. Latest technologies may protect the fetus and the placenta from adverse drug effects but still needed more research. Alternatively, drugs and drug delivery forms can be designed to specifically target the placenta and fetus also open up the new direction.

 

ACKNOWLEDGEMENT:

The authors would like to thank Department of Science and Technology – Fund for Improvement of Science and Technology Infrastructure in Universities and Higher Educational Institutions (DST-FIST), New Delhi for their infrastructure support to our department.

 

CONFLICT OF INTEREST:

No conflict of interest

 

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Received on 04.12.2018          Modified on 14.01.2019

Accepted on 21.02.2019        © RJPT All right reserved