Advance in placenta drug delivery: concern for placenta-originated disease therapy

Figures & data

Figure 1. Application strategies for nanoparticle-mediated drug delivery in pregnancy. Three therapeutic scenarios are depicted: (A) treatment of maternal conditions without fetoplacental exposure; (B) treatment of placental conditions without maternal or fetal exposure; (C) treatment of fetal conditions without maternal or placental exposure.

Table 1. Representative studies exploring the application of nanotechnology for placenta-originated disease therapy.

Disease	Nanocarriers	Administration methods	Therapeutic action	Model	Outcome	Ref.
Fetal growth restriction	Liposome	Not applicable	Increase EGR expression	Human placental explants	Increased nutrient transport capacity of placental explants	(Renshall et al., 2021)
	Liposome	Tail vein injection	Increase IGF2 expression	The P0 mouse model of fetal growth restriction	Increased placental weight and improved fetal weight	(King et al., 2016)
	Polyplex	Intra-placental injection	Increase IGF1 expression	Placental insufficiency mouse model	Increased the labyrinth thickness and pup weight	(Abd Ellah et al., 2015)
	Polymer	Tail vein injection	Antioxidation	Prenatal hypoxia rat model	Prevent oxidative stress in placentas	(Aljunaidy et al., 2018)
	Polymer	Not applicable	Increase hIGF1 expression	In vitro syncytiotrophoblast models	Functional changes to cellular activity and protection for oxidative stress	(Wilson et al., 2020)
Preeclampsia	Dendrimer siRNA complex	Tail vein injection	Inhibit sFlt-1 expression	Pre-eclamptic rat model	Increased embryonic weight while reducing hypertension, proteinuria, and sFlt-1 level	(Yu et al., 2017)
	Lipid-polymer nanoparticle	Intravenous injection	Down-regulating Nrf2 and sFlt1	Adult pregnancy-associated hypertension mice	Alleviated symptoms of preeclampsia	(Li et al., 2020a)
	Lipid-polymer nanoparticle	Intravenous injection	Decrease sFlt-1 expression	Pregnant CD1 mice	Decreased the protein and mRNA expression of sFlt-1 in serum	(Li et al., 2020b)
	Cholesterol siRNA complex	Tail vein or subcutaneous injection	Inhibit sFlt-1 expression	Pregnant CD1 mice and a baboon preeclampsia model	Decreased the mRNA expression of sFlt-1 in mouse placenta and no change in pup weight	(Turanov et al., 2018)

Figure 2. Diagram of the physiological structure of the placenta. (A) Modified spiral arteries enable sufficient perfusion of the placenta with maternal blood that bathes the intervillous space and makes direct contact with the SCT. (B) SCT is a master regulator of placental translocation. (C) Fetal blood enters the placenta via the umbilical artery (blue) and flows into the capillaries in the placental villi before returning to the fetus via the umbilical vein (red). (SCT: syncytiotrophoblasts, VCT: villous cytotrophoblast, TGC: trophoblast giant cells, HB: Hofbauer cells, FB: fibroblasts, CCC: cytotrophoblast cell column, DC: decidual cells, iEVT: interstitial extravillous trophoblast, enEVT: endovascular extravillous trophoblast, egEVT: endoglandular extravillous trophoblast, ULE: uterine luminal epithelium, FEC: fetal endothelial cell). Image from reference (Arumugasaamy et al., 2020) cited with permission. Copyright © 2020 Elsevier B.V.

Figure 3. Transport of nanodrugs in the placenta. Trophoblast uptake through the paracellular pathway (A), endocytosis (B), and transporter-mediated pathway (C). Trophoblast exocytosis of nanoplatforms (D).

Figure 4. Pregnant mice injected intravenously with Cy 5 solution or Cy 5-loaded liposomes of different sizes were processed and analyzed after 2 and 8 h. (A) Fluorescent sections containing Cy 5 in the placenta and fetus of pregnant mice. (B) Cy 5 fluorescence intensity in placenta and fetus of pregnant mice. (C) Quantitative analysis of Cy 5 content in the placenta and fetal tissues of pregnant mice by liquid chromatography-mass spectrometry. Image from reference (Tang et al., 2022) cited with permission. Copyright © 2022 Elsevier B.V.

Table 2. Characteristics of nanoplatforms that would be beneficial in treating pregnancy complications.

Placenta-targeting molecules	Receptor	DDS	Targeting effect/retention effect	Outcomes	Ref.
CGKRK	Membrane-associated calreticulin	Liposomes	The enrichment of CGKRK in the placenta was increased by about 8 times compared with other organs.	Tumor-homing peptides facilitate targeted delivery of peptide-decorated liposomes to the mouse placenta	(King et al., 2016)
iRGD (CRGDKGPDC)	αν Integrin	Liposomes	The enrichment of iRGD in the placenta was increased by about 7 times compared with other organs	Tumor-homing peptides facilitate targeted delivery of peptide-decorated liposomes to the mouse placenta	(King et al., 2016)
Synthetic placental CSA binding peptide	Placental chondroitin sulfate A	Nanoparticles	The accumulation of T-NPCy5-siRNA in the placenta was about 3 times as much as that in the unmodified group	T-NPsisFLT1 selectively accumulate in placenta and downregulate sFlt-1 expression in mice	(Li et al., 2020b)
Synthetic peptide CNKGLRNK	Endothelium of the uterine spiral arteries and placental labyrinth	Liposomes	Targeted preparations could still be observed in the placental labyrinth and decidual spiral artery 48 hours after administration	CNKGLRNK-decorated liposomes selectively bound to the endothelium of the uterine spiral arteries and placental labyrinth in vivo	(Cureton et al., 2017)
OTR-antibody	OTR	Immunoliposomes	The fluorescence intensity of immunoliposomes in the uterus was 7 times that of untargeted liposomes.	Immunoliposomes efficiently delivered indomethacin to the uterus and reduced the rates of preterm birth compared with untargeted liposomes	(Paul et al., 2017)
EGFR antibody	EGFR	Nanocells	Only the targeted preparation group showed strong doxorubicin fluorescence in syncytiotrophoblast cells at 7 hours after administration	EGFR-targeted EnGeneIC Delivery Vehicles loaded with doxorubicin significantly inhibited trophoblastic tumor cell growth	(Kaitu’u-Lino et al., 2013)
CSA-binding peptide	Placental chondroitin sulfate A	Lipid-polymer nanoparticle	Only the targeted treatment group detected the drug in the placenta 48 hours after administration	plCSA-BP facilitate targeted delivery of nanoparticles decorated with plCSA-BP to the placental trophoblasts	(Zhang et al., 2018b)
CSA-binding peptide	Placental chondroitin sulfate A	Lipid-polymer nanoparticle	Targeted nanoparticles could be absorbed by JEG3 cells within 30 minutes	plCSA-BP facilitate targeted delivery of nanoparticles decorated with plCSA-BP to the placental trophoblasts	(Zhang et al., 2018d)
CSA-binding peptide	Placental chondroitin sulfate A	Lipid-polymer nanoparticle	The amount of CSA targeted preparation absorbed by JEG3 cells was 3 times that of the nontargeted group	Targeted delivery of DOX to choriocarcinoma	(Zhang et al., 2018a)
CSA-binding peptide	Placental chondroitin sulfate A	Lipid-polymer nanoparticle	Only the targeted treatment group detected the drug in the placenta 48 hours after administration	Targeted delivery of methotrexate to the placental trophoblasts	(Zhang et al., 2018c)

Figure 5. (A) Analysis of sections of different tissue blocks incubated with anti-C4S (2B6) and plCSA-BP revealed that plCSA-BP specifically binds to placental tissue. (B) plCSA-BP specifically binds to trophoblast at different gestational stages in mice. Trophoblast cells (CK8, red), biotin-plCSA-BP (green), and nuclei (DAPI, blue). Dec: decidua; Em: embryo; Jz: junctional zone; Lab: labyrinth. (C) Quantitative analysis of MTX concentrations in placenta and fetuses by HPLC. nd: not detected. MNPs: Lipid-polymer nanoparticles loaded with MTX; SCR-MNPs: The scrambled peptide-conjugated nanoparticles loaded with MTX; plCSA-MNPs: plCSA-BP-conjugated nanoparticles loaded with MTX. Image from reference (Zhang et al., 2018b) cited with permission. Copyright © Ivyspring International Publisher.

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