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Advances in Drug Delivery to the Reproductive System 379
their bioavailability [20]. A range of NPs has been effectively utilized as delivery systems in therapeutic approaches aimed at addressing numerous disorders related to reproductive health.
One study demonstrated the successful encapsulation of the
estrogen metabolite 2-methoxyoestradiol within nanoparticles
composed of poly(sebacic acid)-co-poly(ethylene glycol) (PEG)
21]. This metabolite is known to induce apoptosis in tumor
[
cells. In vitro studies on human leiomyoma (fibroid) cells revealed
that these nanoparticles (NPs) led to cellular degradation and
subsequent cell death. The controlled and sustained release of the
drug from the NPs mitigated the risk of abrupt release spikes,
resulting in prolonged therapeutic effects. These results indicate
the potential application of NPs in the management of fibroids.
The administration of pharmacological agents during pregnancy presents considerable risks to both the mother and fetus,
thereby constraining treatment options for gestational conditions.
Nanoparticles have emerged as a promising solution to these challenges, enabling targeted delivery of therapeutics across the placenta in complex pregnancy scenarios. Additionally, NPs have been
employed in the treatment of ectopic pregnancies. Bacteria-derived
nanoparticles were engineered, referred to as “EnGeneIC delivery
vehicles,” which were modified with antibodies that specifically
target the epidermal growth factor receptor (EGFR) prevalent in
placental cells [
22]. These NPs were loaded with the chemothera-
peutic agent doxorubicin (DOX) to inhibit the proliferation of
trophoblastic cells, thereby effectively preventing the progression
of ectopic pregnancies.
Further investigations have highlighted the potential of NPs
for selective therapeutic delivery to the placenta in animal models.
This can be achieved through the infusion of NPs into the umbilical
cord, amniotic sac, or directly into the placenta. For instance, a
peptide that binds to placental chondroitin sulfate A has been
utilized to guide drug-loaded NPs to the placenta, minimizing
adverse effects on the embryo while enhancing drug efficacy and
absorption by placental tissues [
23].
4.2 Liposomes
Liposomes, which are a type of nanocarrier, improve the stability
and distribution of therapeutic agents by forming phospholipid
vesicles that consist of a lipid bilayer encasing an aqueous core.
They are characterized by their biocompatibility, customizable features, and the ability to achieve targeted delivery through the
attachment of specific ligands [
In reproductive
health care, liposomes play a crucial role in
24].
enhancing drug bioavailability and extending half-life by acting as
a shield against immune detection [
25]. They hold significant
potential for targeted therapies in cancers such as breast, ovarian,
and prostate, as well as in HIV treatment and the management of
preterm labor. For instance, immunoliposomes have been
380 Dhaval J. Kamothi et al.
developed to deliver doxorubicin (DOX) specifically to malignant
breast cells that overexpress the human estrogen receptor (HER2),
utilizing conjugation with anti-HER2 antibodies. This strategy has
shown effectiveness in selectively targeting HER2-positive breast
cancer cells and promoting efficient intracellular drug delivery in
animal studies [
ticularly EndoTAG-1, which is loaded with paclitaxel for the treatment of advanced triple-negative breast cancer (TNBC). This
technique has yielded encouraging results in Phase II clinical trials
with 140 TNBC patients, where the use of paclitaxel (Taxol) via
EndoTAG-1 led to significant tumor growth inhibition and was
well-tolerated by the subjects [
oxytocin receptor (OTR) have a strong affinity for these receptors,
which are abundant in placental decidual tissues [28]. This discovery has enabled the creation of immunoliposomes conjugated with
OTR antibodies for the treatment of preterm labor, allowing for
the targeted delivery of anti-contraction medications such as nifedipine, salbutamol, and rolipram [
tive in pregnant mouse models, facilitating precise drug targeting
to the placenta, delaying delivery, and showing no signs of transplacental transport to the fetus [
26].
Moreover, a novel approach involves cationic liposomes, par-
27].
Additionally, studies have shown that antibodies targeting the
29]. This method has been effec-
30].
4.3 Hydrogels and Biodegradable Polymers
Polymer gels are solid conjugates of polymers and electrolytes that
possess mechanical properties similar to traditional polymers while
also maintaining the ionic conductivity typical of liquid electrolytes.
One notable application of polymer gels is in the treatment of
ovarian cancer in animal models, where a hydrogel depot made
from photocured glycol chitosan and loaded with paclitaxel was
utilized. This hydrogel was able to release paclitaxel steadily over
7 days while preserving its structural integrity and effectively inhibiting tumor growth [
31].
Moreover, polymer gels are also utilized in addressing erectile
dysfunction, particularly in the form of microemulsion gels. These
gels are considered effective DDS due to their ease of preparation,
thermodynamic stability, capability to penetrate cell membranes,
high bioavailability, and significant drug-loading capacity [
In a
research, a microemulsion gel containing sildenafil citrate
32].
was created using isopropyl myristate for transdermal delivery
33]. When evaluated on a human skin fibroblast cell line, the gel
[
demonstrated substantial skin permeation without causing cytotoxicity. Additionally, the sildenafil-loaded gel maintained good physical and chemical stability over a 6-month duration, suggesting its
potential as a promising option for the topical treatment of erectile
dysfunction.
Advances in Drug Delivery to the Reproductive System 381
4.4 Injectable and Implantable Devices
Nanomaterials exhibit significant potential in the domains of contraception and fertility regulation. NPs can serve as carriers for
contraceptive agents, thereby enhancing the efficacy of birth control methods. By encapsulating or modifying these agents with
NPs, it is possible to establish controlled release mechanisms that
improve drug stability and bioavailability.
Subcutaneous contraceptive implants, which utilize biodegradable materials, involve the integration of hormones with various
biomaterial configurations, such as capsules or rods. These implants
are placed beneath the skin to facilitate continuous and stable drug
release, providing a long-lasting contraceptive effect with notable
reversibility. A single implant can offer effective contraception for
up to 5 years [
34], exhibiting a very low failure rate, and allowing
for the complete restoration of fertility upon removal.
Another example of an implantable contraceptive is the
extended-release delivery system known as Implanon, which
employs ethyl vinyl acetate (EVA) as the carrier matrix [
35]. EVA
is characterized by its exceptional elasticity, flexibility, water resistance, and corrosion resistance, as well as its superior compatibility
with fillers compared to silicone rubber.
Additionally, research has demonstrated the effectiveness of a
hydrogel delivery system composed of a blend of polyethylene vinyl
acetate (PEVA) and polylactic acid (PLA), which incorporates
hydrophilic tenofovir. By carefully adjusting the ratio of PLA to
PEVA, researchers achieved optimal performance for long-acting,
slow-release applications aimed at contraception, pregnancy prevention, and the inhibition of HIV transmission [
36].
4.5 Micro- and Nano-Needles
Microneedle (MN) delivery systems present a viable alternative to
traditional subcutaneous injections, offering a painless application
method and the potential for self-administration [37]. MNs, which
have diameters ranging from 50 to 2000 μm, can penetrate the
stratum corneum without causing pain and are particularly effective
for transdermal drug delivery, especially for biomolecules
[
38]. Polymeric MNs, which can be loaded with therapeutic agents,
have been extensively researched due to their high drug-loading
0
capacity and biodegradability [39, 4
]. H
owever, drug-loaded
MNs alone do not completely prevent the enzymatic degradation
of peptides within the skin.
Recent advancements
in drug delivery technologies have introduced nanoparticles (NPs) as protective carriers that can shield
drugs from enzymatic degradation [41]. Nanoparticleencapsulated microneedles (NPs-MNs) have emerged as innovative
tools for the combined treatment of various conditions, including
diabetes, cancer, dermatological disorders, and for enhancing
immune responses [
42, 43]. In these systems, NPs are typically
synthesized using polymers, freeze-dried, and then incorporated
into a water-soluble polymer matrix to form the MNs. However,
382 Dhaval J. Kamothi et al.
the stability of the NPs can be compromised by high temperatures
or interactions with polymers during the manufacturing process
[44, 45].
utilized in assisted reproductive technology (ART) [
less, the low bioavailability and the frequent requirement for subcutaneous injections of triptorelin can adversely affect the quality of
life for women preparing for pregnancy. The study suggests the use
of silk fibroin (SF)-based microneedles (MNs) for the transdermal
delivery of triptorelin-loaded NPs, which may enhance the bioavailability of the medication and facilitate safe and effective selfadministration.
A study highlighted that triptorelin is a critical medication
46]. Nonethe-
4.6 Spermbots
In 2013, the initial sperm-based biohybrid micro-robot was engineered by integrating a motile sperm cell with a rolled-up magnetic
microtube, which can be manipulated via an external magnetic field
47]. This innovation, referred to as the “spermbot,” has paved the
[
way for the exploration of novel applications within the domain of
assisted reproductive technology (ART). Over the last decade,
significant advancements have been made in the design and optimization of various spermbots or sperm-like nanorobots. The term
“spermbot” is defined as a biohybrid microrobot propelled by
sperm cells [
48]
ive fundamental types of nano-components
. F
have been developed for the fabrication of spermbots, which
include microtubes, microhelices, tetrapod microtubes, rice grainshaped (or spindle-type) nanoparticles, and complex nanocarriers
2).
(Fig.
Spermbot
signify a notable progression in ART. These sophisticated devices harness the natural motility of sperm cells, combining them with artificial structures to form hybrid micromotors
capable of targeted delivery and improved fertilization techniques.
The potential applications of spermbots in assisted reproduction are
extensive, encompassing enhancements in fertilization rates and the
direct delivery of therapeutic agents to reproductive tissues. A key
advantage of spermbots is their capacity to traverse the female
reproductive tract, utilizing the inherent propulsion abilities of
sperm. This characteristic facilitates precise targeting of oocytes,
which is particularly advantageous in instances of male infertility
characterized by compromised sperm motility. Research has indicated that spermbots can be remotely controlled through external
magnetic fields, allowing for the directed movement of sperm to
specific sites within the reproductive system [
This functionality
49].
not only improves fertilization efficiency but also creates opportunities for drug delivery to address conditions such as ovarian cancer,
where sperm-hybrid micromotors have demonstrated efficacy in
transporting therapeutic agents [
50].
Advances in Drug Delivery to the Reproductive System 383
Fig. 2 Different types of spermbots fabricated for assisted fertilization and
treatment of diseases
5 Route-Specific Delivery Approaches
Significant advancements have been made globally in enhancing the
delivery of therapeutics, particularly through various administration methods and delivery systems. The vaginal route has emerged
as a promising option due to its unique anatomical and physiological properties. A primary advantage of vaginal drug delivery systems
(VDDS) is their ability to avoid first-pass metabolism, which is
particularly beneficial for medications targeting disorders of the
female genital tract [
of therapeutics to the uterus, leveraging the uterine first-pass effect.
This mechanism is advantageous for treating various conditions of
the reproductive tract while minimizing systemic absorption of the
drugs, thereby reducing potential side effects [
tion of the different delivery systems used for different reproductive
disorders is shown in Fig. 3.
5.1 Vaginal and Cervical Delivery
Anatomically, the vagina provides a large surface area and is rich in
blood vessels, which supports efficient systemic circulation
[53]. Upon absorption, drugs enter the venous plexus, draining
into the internal iliac veins and subsequently passing through the
hemorrhoidal veins before reaching the peripheral circulation. This
51]. VDDS facilitate the direct administration
52]. The representa-
384 Dhaval J. Kamothi et al.
Fig. 3 Representation of the different delivery systems used for different reproductive disorders
pathway enhances drug concentrations in the bloodstream, thereby
improving therapeutic efficacy.
A diverse array of drug formulations has been developed for
vaginal delivery, targeting conditions such as microbial infections,
sexually transmitted diseases, cancers, endometriosis, and
pregnancy-related disorders. These formulations are also employed
in hormonal therapy, contraception, labor induction, and vaginal
lubrication [
Recent i
54].
nnovations i
n VDDS have focused on prolonging the
retention time of drugs within the vaginal cavity. Researchers have
utilized smart bioadhesive polymers that respond to environmental
stimuli, such as pH and temperature changes, within the vaginal
milieu. These polymers effectively adhere to vaginal mucus and
regulate the release of therapeutics from nanoformulations. Current developments in novel VDDS include nanoemulsions, vaginal
films, liposomes, polymeric nanoparticles, nanofibers, and mucoadhesive polymers (Table
Cervical
cancer remains a leading cause of mortality among
1)
.
women, with conditions such as cervicitis and cervical erosion
identified as significant risk factors. Although local treatments can
be effective, the deep anatomical location of the cervix, along with
its mucus-covered and smooth mucosal surface, presents challenges
for the effective administration of therapeutic agents. Conventional
Advances in Drug Delivery to the Reproductive System 385
Table 1
Novel VDDS used in different vaginal infections
Sr.
Reproductive
no.
tract infections
Novel VDDS Reference
1 Bacterial and
fungal
infections
2 Parasitic
infections
3 Viral infections HIV infection Chitosan-based nanoparticles loaded with
E. coli Cefixime vaginal microspheres with chitosan
and alginate
N. gonorrhoeae Chitosan nanoparticles made with
tripolyphosphate (TPP)
Most bacterial
infections
Bacterial vaginosis
(Gardnerella
vaginalis)
C. albicans Miconazole-loaded microsponge gel [59]
Trichomonas
vaginalis
HIV infection and
contraception
HIV infection pH-responsive polyurethane membranes were
Chitosan nanoparticle-loaded nanofiber hybrid
system for vaginal con- trolled release of
benzydamine
Hydrogels with metronidazole-loaded gel
flakes
Microporous matrices for vaginal delivery of
the drug tinidazole
HIV-1 fusion inhibitor
Fabricated bioad hesive vaginal film for delivery
of dapivirine and levonorgestrel
fabricated for the intravaginal release of
cargo [antivirals/CCR5 small-interfering
RNA (siRNA)]
[55]
[56]
[57]
[58]
[60]
[61]
[62]
[63]
4 Other
reproductive
disorders
Human
papillomavirus
(HPV)
Cervical cancers
Endometriosis Mucoadhesive 3D-printed
Preterm birth Liposomes with oxytocin inhibitors [67]
Nanopar
Polymer–
Vaginal ring
Muco-inert nanosuspension of histone
Silk p
ticles with siRNA
vaginal ovules
incorporating
with miRNA
deacetylase inhibitors
rotein hydrogel (increases cervical
volume)
pirfenidone
nucleic acid complexes conjugated
was fabricated
with anastrozole [66]
[64]
[65]
[68]
[69]
386 Dhaval J. Kamothi et al.
drug delivery systems often encounter difficulties in penetrating
this barrier. To address these challenges, a novel cervical positioning drug delivery system (CPDDS) has been developed utilizing
hydrogel microspheres (HMs) derived from Bletilla striata polysaccharide (BSP). The HMs leverage the hydrophilic long chains of
BSP, resulting in a microporous, circular structure that enhances
flowability and water absorption. This design facilitates improved
dis
tribution across the cervical mucosa, effectively overcoming the
mucus barrier
engineered to provide controlled drug release with minimal initial
burst and sustained delivery, making them suitable for local treatment applications. Additionally, the natural biodegradability of BSP
reduces the risk of irritation and allergic reactions, highlighting the
potential of BSP-based HMs as an effective CPDDS for clinica
implementation [
increasingly utilized for the delivery of therapeutic proteins in the
treatment of infections, genetic disorders, and cancers. Traditional
drug-loading techniques, such as soaking or encapsulation, frequently result in rapid drug release. To overcome this limitation, a
strategy for controlled, long-term protein release has been developed. This approach involves the use of custom 3D-printed scaffolds embedded with drug-laden microspheres to deliver antihuman papillomavirus (anti-HPV) proteins following cervical cancer surgery. These scaffolds not only provide structural support but
also facilitate localized drug release, while the microspheres protect
the proteins from degradation and ensure sustained release
throughout the necessary treatment duration [
and promoting optimal mucoadhesion. The HMs are
l
70].
In the realm of personalized medicine, 3D-printed scaffolds are
71].
5.2 Uterine and Intrauterine Delivery
Intrauterine devices (IUDs) and intrauterine balloon systems represent established methodologies for intrauterine drug delivery.
Among these, hormonal and copper IUDs are extensively
researched for their efficacy in addressing various conditions affecting the female urogenital tract (UGT), including unintended pregnancies, dysmenorrhea, endometriosis, uterine fibroids, and
adenomyosis [
72]. Hormonal IUDs are generally constructed
from polymers featuring a core-sheath or matrix design, often
incorporating a rate-limiting polymer that functions as a semipermeable barrier or is integrated within the matrix. These devices are
engineered for prolonged drug release, which can extend from
typically exhibiting an initial phase
several months to years [
73],
of linear release followed by a gradual decline. Copper and
levonorgestrel-releasing IUDs are frequently utilized as long-acting
contraceptive methods. Additionally, levonorgestrel IUDs have
been applied in the management of various UGT disorders, including endometriosis, endometritis, dysmenorrhea, and adenomyosis
[74]. Other therapeutic agents, such as steroids, anti-inflammatory
drugs, and chemotherapeutic agents, have also been administered
Advances in Drug Delivery to the Reproductive System 387
via IUDs. For instance, using 3D printing technology to develop
IUDs that contain progesterone (P4) and fluorouracil to treat
ovarian and endometrial malignancies enables customized drug
combinations and dosages to meet the needs of each patient [
75].
In addition to IUDs, balloon uterine systems, such as Foley
catheters, have been employed as physical barriers to mitigate intrauterine adhesions (IUAs). These systems are available in various
configurations, including heart-shaped designs [
76], to facilitate
optimal placement within the uterine cavity. They can also be
infused with drugs, cells, and growth factors (GFs) to promote
wound healing and enhance clinical outcomes. However, these
delivery systems are not without limitations, which include the
necessity for insertion by healthcare professionals, difficulties in
drug loading, potential patient discomfort, risks of device expulsion, migration to adjacent pelvic organs, and the possibility of
organ perforation [
77].
5.3 Penile and Testicular Delivery
The direct administration of treatments to the penis or testes for
the management of reproductive disorders is an active area of
investigation. These methodologies aim to address underlying
pathophysiological issues more effectively, minimize systemic side
effects, and improve therapeutic outcomes. Avanafil, a phosphodiesterase type 5 (PDE5) inhibitor, functions by inhibiting the degradation of cyclic guanosine monophosphate (cGMP), leading to
the relaxation of smooth muscle in the penile vasculature and
enhancement of erectile function. However, its clinical efficacy is
constrained by its low aqueous solubility [
78]. To overcome this
limitation, avanafil was encapsulated in solid nanoparticles and
incorporated them into a chitosan-based transdermal film
79]. This formulation was evaluated on rat skin and demonstrated
[
successful drug permeation, suggesting a viable alternative to oral
administration with improved bioavailability.
Nitric o
NO) plays a crucial role in the erectile process by
xide (
promoting smooth muscle relaxation and increasing blood flow to
the penis. Topical gel was developed containing three erectogenic
agents—two PDE5 inhibitors (tadalafil and sialorphin) and NO—
loaded onto NPs [
80]. In experiments using a murine model with
an anesthetized penis, the gel effectively induced erections, indicating the potential of NPs as a delivery system for multiple pharmacological agents aimed at treating erectile dysfunction through
topical application. This strategy may mitigate the adverse ef fects
associated with oral medications and avoid hepatic metabolism.
Sildenafil, another
PDE5 inhibitor, is typically administered
orally; however, it is linked to side effects such as hypotension and
arrhythmias, as well as challenges related to bioavailability and
delayed onset of action. To address these issues, researchers are
investigating alter native topical delivery methods. One study
employed bilosomes—liposomes modified with bile salts—as a
388 Dhaval J. Kamothi et al.
delivery vehicle for sildenafil. This modification enhances both
molecular stability and transdermal absorption. In ex vivo studies,
sildenafil-loaded liposomes achieved a penetration rate of 39%
within 15 min, and in murine models, a dosage of 2 mg/kg resulted
in increased potency within 10 min [
(a vasodilator), is another approach used to induce erections, particularly in men unresponsive to oral therapies for erectile dysfunction. Additionally, intracavernosal delivery of substances like stem
cells or growth factors is being explored for penile rehabilitation
following surgical procedures or for the treatment of Peyronie’s
disease, characterized by penile curvature due to fibrous scar
tissue [
testes to regulate testosterone production or spermatogenesis. For
instance, gonadotropins such as human chorionic gonadotropin
(hCG) or follicle-stimulating hormone (FSH) may be utilized in
men experiencing infertility due to hypogonadism [
more, the potential of stem cell therapy and gene therapy for
addressing testicular dysfunction is under investigation as a means
to restore fertility and enhance hormonal function in cases of
testicular injury.
81].
Intracavernosal injection of medications, such as alprostadil
82].
Hormonal therapies can also be administered directly to the
83]. Further-
6 Targeted and Precision Medicine Approaches
6.1 Hormone Replacement Therapy (HRT)
Hormone replacement therapy (HRT) plays a significant role in
managing infertility by regulating menstrual cycles, promoting
ovulation, and enhancing the likelihood of conception. A balanced
combination of estradiol (E2) and progesterone (P4) is often
employed to create an optimal environment for pregnancy, particularly in women with a uterus. The use of progesterone is crucial in
mitigating the risk of endometrial hyperplasia that may arise from
unopposed estrogen therapy [
is essential for ensuring successful implantation and the maintenance of pregnancy, as both hormones influence critical reproductive physiological processes [
An individualized
approach to HRT is necessary, taking into
account the patient’s medical history, hormone levels, and specific
reproductive goals, to optimize outcomes and minimize potential
risks [
84]. The American Menopause Society emphasizes the
importance of combining E2 and P4 in women with a uterus to
prevent complications such as endometrial hyperplasia [84]. Additionally, research underscores that the timing and dosage of HRT
can significantly impact fertility outcomes, with a proper E2 to P4
ratio associated with improved success rates in assisted reproductive
technologies [
85].
84]
85].
he balance between E2 and P4
. T