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92 J. Aparicio-Blan co and A. I. Torres-Suárez
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Fig. 5.1 Distinct formulation approaches exploited so far with LNCs: (a) Oily core LNCs. (b)
Reverse micelle-loaded LNCs. (c) LNC-based hydrogels. (d) LNCs as a cargo
Commonly, LNCs prepared by the phase inversion temperature method have a
particle size of between 20 and 100 nm with a very low polydispersity index (<0.1),
which eventually enables the sterilization of the formulations by filtration.
In summary, LNCs are core-shell structures composed of an oily liquid triglyceride core surrounded by a surfactant rigid membrane (Heurtault et al. 2002, 2003).
As a result, LNCs are usually used to encapsulate lipophilic substances in their oily
core, with the oily core acting as a drug reservoir. However, alternative formulation
strategies have also been developed to produce LNCs with an aqueous core that can
encapsulate hydrophilic substances. Additionally, LNCs have been used to formulate LNC-derived hydrogels to improve their extended-release properties and have
finally been used as a cargo for inclusion in other dosage forms (such as gels,
microparticles or microneedles). Altogether, these formulation strategies make
LNCs a versatile platform for drug delivery (Fig. 5.1). All these four distinct
formulation approaches and their main explored applications are described in detail
in the following sections.
5.2 Latest Advances and Applications in Oily Core LNCs
As mentioned, LNCs are primarily well suited for the encapsulation of hydrophobic
drugs within their oily core with high encapsulation efficiencies reported in nearly all
cases (Table 5.1).
For example, various hydrophobic cytotoxic drugs have been encapsulated within
the oily core of LNCs to be tested in preclinical cancer models following distinct
routes of administration (i.e. intravenous, intracarotid or convection enhanced
5 Lipid Nanocapsules: Latest Advances and Applications 93
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Table 5.1 Latest advances and applications in oily – core LNCs in animal models
Formulation description Route of administration Animal model Ref.
Combination regimen of
SN38-loaded LNCs (1 mg/
kg) and regorafenib-loaded
LNCs (10 mg/kg)
Combination regimen of
SN38-loaded LNCs (1 mg/
kg) and salinomycin-loaded
LNCs (2 mg/kg)
Triamcinolone-acetonideloaded LNCs
Cannabidiol-decorated
LNCs
Retinoic acid-loaded
NFL-targeted LNCs
Prostaglandin
D2-TAT-targeted-loaded
LNCs
Tetrathiatriarylmethyl
radical-loaded LNCs
Blank LNCs Intravenous and stereo-
Intravenous administration (3 weekly cycles of
two doses of each drug
on alternate days)
Intravenous administration (3 weekly cycles of
two doses of each drug
on alternate days)
Subconjunctival
administration
Intravenous Healthy ICR mice Aparicio-
Intraventricular injection Lysolecithin-induced rat
Nasal Lipopolysaccharide-
Intratumoural Subcutaneous FSaII
tactic injection,
respectively
Subcutaneous CT26
mouse colon tumour
model in Balb/C mice
Subcutaneous HCT116
colorectal human xenograft model in nude mice
Endotoxin-induced uveitis rabbit model
model of white matter
focal demyelination
induced
neuroinflammation
mouse model Experimental autoimmune
encephalomyelitis mouse
model
tumours in mice
Subcutaneous FSaII
fibrosarcoma and intracerebral C6 glioblastoma
models in mice
Tsakiris
et al.
(
2019)
Tsakiris
et al.
(2020)
Formica
et al.
(2020)
Blanco
et al.
2019c)
(
Carradori
et al.
(2020)
Mwema
et al.
2023)
(
Nel et al.
2019a)
(
Nel et al.
(
2019b)
delivery) as already reviewed elsewhere (Aparicio-Blanco and Torres-Suarez 2015).
More recently, combination therapies with drug-loaded LNCs have also been tested
in murine models of colorectal cancer following intravenous admi nistration (Tsakiris
et al. 2019, 2020). Notably, these studies were enabled because the encapsulation of
SN38 (i.e. the active form of irinotecan) or salinomycin within LNCs significantly
reduced their intrinsic drug-induced haemolysis.
First, the antitumour efficacy of the combination regimen of SN38-loaded LNCs
at a dose of 1 mg of SN38 per kg of body weight and regorafenib-loaded LNCs at a
dose of 10 mg of regorafenib per kg of body weight has been tested in a subcutaneous tumour model initiated by CT26 mouse colon cancer cell s in Balb/C mice
following intravenous administration (Tsakiris et al. 2019). The mice were treated
with 3 weekly cycles of two doses of SN38 on days 1 and 3 and/or two doses of
regorafenib on days 2 and 4. In this model, the combination regimen significantly
slowed tumour growth and significantly extended the median survival time
94 J. Aparicio-Blanco and A. I. Torres-Suárez
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(32.6 days) in comparison with all other groups (including the monotherapy SN38loaded LNCs or regorafenib-loaded LNC groups). Altogether, and although the
efficacy of the free drugs in combination was not evaluated in this study, these
results seemed to indicate that this combination therapy may help overcome the
resistance to specific cytotoxic drugs. These results were explained both by the
distinct mechanism of action of both drugs (i.e. SN-38 is a topoisomerase I i
while regora
serve as an adjuvant therapy since it also inhibits key enzymes (UGT1A1 and
UGT1A9) that are respon sible for the metabolism of SN-38 to its inactive
glucuroconjugate form, thereby ultimately increasing SN-38 concentration
over time.
To gain further insight, an alternative combination regimen that rationally targets
both quiescent (i.e. dormant cancer stem cells) and proliferating cells was subsequently tested (Tsakiris et al. 2020). For this purpose, SN38-loaded LNCs, which
mainly act on proliferating cancer cells, were combined with salinomycin-loaded
LNCs given the activity of the latter against cancer stem cells. The antitumour
efficacy of the combination regimen of SN38-loaded LNCs at a dose of 1 mg of
SN38 per kg of body weight and salinomycin-loaded LNCs at a dose of 2 mg of
salinomycin per kg of body weight has been tested in a subcutaneous HCT116
colorectal human xenograft model in nude mice following intravenous administration. The administration scheme was analogous to that of the previous study. The
combination of SN38-loaded LNCs and salinomycin-loaded LNC significantly
delayed tumour growth and increased the median survival time (49.6 days) in
mice, even in comparison with the combination of free drugs, which was ev aluated
in this case. Nonetheless, the evaluation of the efficacy of combination therapies
encapsulated within a single LNC formulation is still pending. The co-encapsulation
would represent an added value to overcome potential differences in biodistribution
of each drug when loaded and administered separately.
Alternatively, anti-inflammatory drugs have also been encapsulated within the
oily core of LNCs to be tested in preclinical models of uveitis following
subconjunctival administration (Formica et al.
of LNCs loaded with triamcinolone acetonide has been tested in an endotoxininduced uveitis rabbit model. Importantly, a single dose of the triamcinolone-loaded
LNCs significantly alleviated the clinical signs of the inflammatory response
(i.e. slight conjunctival redness and iris vessel congestion and a significant attenuation of the fogginess of the aqueous humour) 24 h after administration in comparison with both the untreated rabbits and the rabbits treated with an equipotent
marketed triamcinolone acetonide suspension following also subconjunctival
administration. This demonstrated the formulation’s therapeutic efficacy in this
ocular inflammatory in vivo model. These improved results were attributed both to
the high solubilization of the triamcinolone acetonide, which could result in a more
available dose than in the case of the drug administered as suspension and to the
small size of the LNCs, which could enhance drug access to the target site.
Co-loading of two distinct drugs in LNCs has also been described for combination
therapy in ocular pathologies that entail both inflammation and neovascularization.
fenib is a multikinase inhibitor) and by the fact that regorafenib could
). In fact, the therapeutic efficacy
2020
nhibitor
5 Lipid Nanocapsules: Latest Advances and Applications 95
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The therapeutic antibody bevacizumab was added to the LNC surface using click
chemistry and the corticosteroid triamcinolone acetonide in the oily core (Formica
et al. 2021). However, the evaluation of the in vivo efficacy of this formulation has
not yet been explored.
Last, LNCs have also been applied to enhance drug delivery to the central
nervous system (Moura et al. 2020). Diseases affecting the central nervous system
remain one of the greatest unmet medical needs because the blood-brain barrier
(BBB) prevents efficient drug delivery to the central nervous system (AparicioBlanco et al.
administration, active targeting strategies have been applied to LNCs with the
purpose of boosting the transcellular delivery across the BBB. In this regard, the
adsorption of the non-psychotropic cannabinoid, cannabidiol, on the LNC surface
enhanced by 2.5-fold the passage of LNCs across the BBB in vivo in healthy mice
following intravenous administration (Aparicio-Blanco et al.
port extent across the BBB conditions the efficacy of treatments for brain diseases,
cannabinoid-decorated LNCs seem a promising platform for the development of
novel therapies for these diseases. However, in vivo efficacy testing of this strategy
for brain drug delivery has not been reported.
Another active targeting strategy intended to boost drug delivery to certain areas
of the central nervous system has been applied, but in this case, following a
stereotactic injection (i.e. an invasive local administration). In this regard, the
adsorption of the peptide NFL-TBS.40-63 on the LNC surface system was able to
target neural stem cells from the subventricular zone following stereotactic administration in the lateral ventricle of rats (Carradori et al.
targeting strategy has been tested in a lysolecithin-induced rat model of white matter
focal demyelination to induce neural stem cell differentiation upon loading of
retinoic acid within LNCs (Carradori et al.
NFL-targeted LNCs were injected into the lateral ventricle directly below the lesion
site. Five days after a single injection of this formulation, mature oligodendrocyte
repopulation was enhanced in comparison with vehicle-treated rats, stimulating
oligodendrogenesis nearly to the prelesion levels. However, similar therapeuti c
effects were observed for both targeted and untargeted LNCs, which raised some
doubt on the beneficial effect of NFL grafting. Altogether, these data support the use
of LNCs for stimulation of endogenous differentiation of neural stem cells to restore
neurological function in distinct neurodegenerative diseases, but less invasive routes
of administration must be investigated to boost their trans lational potential.
Alternatively, the nasal administration route has also been explored with LNCs
for non-invasive nose-to-brain drug delivery (Formica et al.
route of administration enables direct brain drug delivery because, unlike with
systemic administration routes, the BBB is avoided. Delivery along both the trigeminal and olfactory nerves have been proposed to account for the direct transport from
the nasal cavity to the brain. Through this route, the efficacy of prostaglandin
D2-glycerol ester-loaded LNCs has been tested in distinct in vivo
neuroinflammation models (Mwema et al.
2016). To enhance brain distribution following systemic intravenous
2019c). As the trans-
2016). Subsequently, this
2020). For that, retinoic acid-loaded
2022). The intranasal
2023).
96 J. Aparicio-Blan co and A. I. Torres-Suárez
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First, the impact of intranasal administration of prostaglandin D2-loaded LNCs
was tested after a single nasal administration at a dose of 0.4 mg of prostaglandin
D2-glycerol ester per kg of body weight on a lipopolysaccharide-induced
neuroinflammation mouse model. This single administration reduced the expression
of proinflammatory cytokines like monocyte chemoattractant protein-1 (MCP-1) in
several regions of the brain (olfactory bulb, prefrontal cortex, brainstem) in comparison with their unloaded LNCs counterparts and to a similar extent to the free drug.
Then, the impact of prostaglandin D2-loaded LNCs, functionalized in this case
with the cell penetrating peptide transactivator of transcription (TAT) to increase
accumulation in the central nervous system, was tested on an experiment al autoimmune encephalomyelitis (EAE) mouse model to evaluate the effect of these LNCs on
a chronic form of neuroinflammation. Treatments were administered intranasally at a
dose of 0.4 mg of prostaglandin D2-glycerol ester per kg of body weight once every
2 days. Treatments started in all cases 10 days after immunization once the symptoms of the disease had appeared. Although neither the mice clinical score or the
extent of demyelination were significantly reduced with the treatment, intranasal
administration of TAT-targeted prostaglandin D2-loaded LNCs significantly
reduced the expression of the most common inflammatory markers associated to
the pathology (MIP-1α and MIP-1β mRNA) and increased the expression of a
cytokine known to influence recovery and promote myelin repair (IL-33) in the
lumbar spinal cord. Nonetheless, these effects were also observed for the blank
TAT-targeted LNCs. This latter finding deserves further research on the potential
therapeutic action on neuroinflammation of the carrier itself together with other
therapeutic regimens in order to find the most efficient dose and administration
scheme in this experimental setting.
Apart from therapeutic purposes, LNCs have also been designed to serve as
diagnostic tools (Nel et al.
2019a, b). For example, the assessment of hypoxia is a
key feature in oncolo gy that often preludes more aggressive tumours and resistance
to chemotherapy. Therefore, several techniques have been used to assess the hypoxic
tumour environment. In this context, LNCs loaded with hydrophobic paramagnetic
spin probes have been used to measure tissue oxygenation through electron paramagnetic resonance oxim etry (Nel et al.
2019a). The encapsulation of lipophilic
oxygen sensors in LNCs is of particular interest because it can enhance the sensitivity of spin probes to oxygen given the high solubility of oxygen in lipids. The
performance of tetrathiatriarylmethyl radical-loaded LNCs as oxygen sensors was
evaluated in subcutaneous FSaII tumours in mice following intratumoural administration. The encapsulation of the probes within LNCs significantly extended their
half-life, which ultimately enabled the sensitivity of LNCs loaded with the spin
probe to be assessed during 20-min carbogen respiratory challenges (i.e. exposure to
a mixture of carbon dioxide and oxygen gas, 95% O
, 5% CO2). Overall, LNCs
2
responded well to changes in the oxygen environment in terms of increased electron
paramagnetic resonance line width. Analogously, LNCs have been used to measure
tissue oxygenation through magnetic resonance imaging in two murine tumour
models (i.e. subcutaneous FSaII fibrosarcoma and intracerebral C6 glioblastoma
models) (Nel et al.
2019b). These models were chosen to represent two types of
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severely hypoxic tumours together with two distinct administration routes of LNCs:
intravenous and stereotactic injection, respectively. LNCs were able to probe the
oxygen level of both tumoural tissues after a carbogen challenge with a significant
global longitudinal relaxation time (R1) increase (3% and 6% mean change for the
subcutaneous and intracranial tumour, respectively). In both cases, LNCs increased
the lipid content of tumours to enable the mapping of ox
signal-to-noise ratio.
theranostic platforms (Aparicio-Blanco and Torres-Suarez
Finally, LNCs have also been exploited for the co-encapsulation of a pair of
fluorescent carbocyanine dyes, which enabled the biodistribution of the intact LNCs
following intravenous administration in rats to be directly tracked using quantitative
Förster resonance energy transfer (FRET) (Kaeokhamloed et al. 2022). FRET relies
on the interaction between the co-encapsulated dyes to monitor intact LNCs because
the FRET signal can only be detected while both dyes remain together inside the
intact LNCs. As shown by population pharmacokinetics modelling, this approach
resulted in the observation that the elimination of intact LNCs is non-linear and
dependent on particle size, with reduced maximum elimination rate for bigger LNCs
(Lebreton et al. 2022).
Altogether, these results illustrate the potential of LNCs also as
ygen with an improved
2018).
5.3 Latest Advances and Applications in Reverse
Micelle-Loaded LNCs
The use of LNCs is no longer restricted to the encapsu lation of lipophilic drugs since
the phase inversion method has been repurposed to obtain LNCs with an aqueous
core so that the encapsulation of hydrophilic drugs is eventually enabled (Tsakiris
2019; Vrignaud et al. 2012; Groo et al. 2018). This alternative formulation
et al.
procedure is based on the initial development of reverse micelles within which the
hydrophilic drug is encapsulated. Reverse micelles are micellar entities in which the
non-polar and polar phases are inverted so that the head groups of a low HLB
amphiphilic surfactant point towards the encased volume containing the polar phase
wherein water-soluble mol ecules can be solubilized. Then, reverse micelle-loaded
LNCs are prepared by adding a reverse micelle nonaqueous dispersion during the
cooling step of the phase inversion method before the final water quench, so that the
reverse micelles with their hydrophilic cargo are encapsulated within the oily core of
the LNCs.
Even if the formulation of reverse micelle-loaded LNCs has been applied to
encapsulate various hydrophilic drugs, only reverse micelle-loaded LNCs encapsulating the incretin-mimetic peptide exenatide have been tested in preclinical models
of disease to evaluate their suitability for oral peptide delivery, namely, one of the
greatest unmet challenges in the pharmaceutical technology (Table 5.2).
Xu et al. utilized a Span 80 (as low HLB surfactant):Labrafac WL 1349
(as nonpolar dispersion phase) mixture (1:5 w/w) to form the reverse micelles
98 J. Aparicio-Blanco and A. I. Torres-Suárez
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Table 5.2 Latest advances and applications in reverse micelle-loaded LNCs in animal models
Route of
Formulation description
Exenatide-reverse micelle-loaded LNCs
(500 μg/kg single dose or daily administration in chronic treatment)
Exenatide-loaded reverse micelle
PEGylated LNCs (500 μg/kg single dose or
once every 2 days administration in chronic
treatment)
administration
Oral High-fat diet-induced
Oral High-fat diet-induced
Animal model Ref.
type 2 diabetes mouse
model
type 2 diabetes mouse
model
Xu
et al.
(2020a)
Xu
et al.
(2020b)
upon addition of an aqueous exenatide solution for subsequent encapsulation within
200-nm-sized LNCs following the modified phase inversion formulation strategy
previously described (Xu et al. 2020a). The drug delivery system was designed to
synergize the intrinsic stimulating effect on endogenous glucagon-like peptide
1 (GLP1) secretion of 200-nm-sized LNCs themselves (Xu et al.
2018) with the
GLP-1 analogue exenatide.
The resulting exenatide-reverse micelle-loaded LNCs were tested in a murine
high-fat diet-induced type 2 diabetes model follow ing oral administration (Xu et al.
2020a). The study was conducted following both acute and chronic treatment.
In the acute treatment, a single oral dose of 500 μg/kg exenatide encapsulated
within reverse micelle-loaded LNCs administered 1 h before conducting an oral
glucose tolerance test displayed equivalent glycaemia in diabetic mice to that
observed in norm oglycemic control mice upon oral glucose challenge. These results
were reproducible in 3-, 8- and 10-week high-fat diet-fed mice, that is, regardless of
the chronicity of the disease. Moreover, total GLP-1 levels were significantly
increased with both empty and exenat ide-reverse micelle-loaded LNCs (confirming
the ability of the nanocarrier per se to stimulate GLP-1 release under pathological
conditions), although only the exenatide-reverse micelle-loaded LNCs significantly
reduced the insulin resistanc e index in comparison with the untreated group. Additionally, a pharmacokinetic study in diabetic mice confirmed the increased relative
bioavailability of exenatide (4.32%) when orally administered within reverse micelle
LNCs compared with exenatide in solution. Altogether, these data demonstrated the
efficacy of reverse micelle LNCs in ameliorating glycaemia by simultaneously
increasing endogenous GLP-1 levels and exenatide bioavailability.
In the chronic treatment, a daily oral dose of 500 μg/kg exenatide encapsulated
within reverse micelle LNCs was compared with a daily administration of a
marketed subcutaneous exenatide solution at a dose of 10 μg/kg for 5 weeks.
Notably, after the 5 weeks of treatment, only the exenatide-reverse micelle-loaded
LNCs were able to display equivalent glycaemia in diabetic mice to that observed in
normoglycemic control mice. Furthermore, mice treated orally with the exenatidereverse micelle-loaded LNCs exhibited insulin plasma levels and insulin resistance
values comparable to those of both the normoglycemic control mice and the mice
treated subcutaneously with the marketed exenatide solution.
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Altogether, the oral treatment with exenatide-reverse micelle-loaded LNCs
allowed not only normalized glycaemia and insulin levels to be achieved following
either acute or chronic treatment, but also comparable effects to those observed for
marketed products given subcutaneously to be obtained, with the added benefitof
administration via the oral route, more suitable for chronic treatments. As a result,
the reverse micelle LNC formulation strategy seems to be promising to enable oral
incretin-mimetic delivery for diabetes treatment.
Subsequently, exenatide-reverse micelle-loaded LNCs have been further modified to strengthen their GLP-1 secretory effect and prolong their antidiabetic effect to
boost their clinical translation in oral type 2 diabetes treatment. The previous
exenatide-reverse micelle-loaded LNCs were surface modified with polyethylene
glycol (PEG) (Xu et al.
2020b). A post-insertion PEGylation method which involved
incubating reverse micelle LNCs with 1,2-distearoyl-sn-glycero-3phosphoethanolamine (DSPE)-PEG
was used to ensure that the PEG chains
2000
were located on the LNC surface.
Analogously, the resulting exenatide-reverse micelle-loaded PEGylated LNCs
were tested orally in a murine high-fat diet-induced type 2 diabet es model following
both acute and chronic treatment.
In the acute treatment, a single oral dose of 500 μg/kg exenatide encapsulated
within PEGylated reverse micelle LNCs administered 1 h before conducting an oral
glucose tolerance test significantly decreased glycaemia throughout the glucose
tolerance test in comparison with untreated diabetic mice. Besides, exenatide-reverse
micelle-loaded PEGylated LNCs significantly increased the active GLP-1 levels and
reduced the insulin resistance index in comparison with untreated diabetic mice.
Moreover, a pharmacokinetic study in chronic diabetic mice indicated that
PEGylation extended by 3.5-fold the half-life and doubled the systemic absorption
of the encapsulated peptide in comparison with exenatide-reverse micelleloaded LNCs.
Notably, as a proof of the prolonged effect of the exenatide administered in the
PEGylated LNCs, in the chronic treatment over 1 month, PEGylation enabled the
oral administration frequency of exenatide-reverse micelle-loaded LNCs (at a dose
of 500 μg/kg of exenatide) to be reduced from once daily to once every 2 days.
Indeed, the exenatide-reverse micelle-loaded PEGylated LNCs following either
daily administration or administered every other day displayed equivalent glycaemia
and insulin resistance in diabetic mice to that observed in normoglycemic control
mice. Interestingly, when administered daily, the unloaded PEGylated reverse
micelle-loaded LNCs were also able to reach basal glucose levels and significantly
reduce insulin resistance, demonstrating that the increase in GLP-1 secretion
achieved with PEGylation was a sufficient stimulus for lowering glucose levels.
Altogether, these findings on reverse micelle LNCs bring hope for oral peptide
delivery strategies for the treatment of many other diseases (Xu et al.
2021).
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5.4 Latest Advances and Applications in LNC-Based
Hydrogels
Alternatively, to enhance their prolonged release properties, LNCs have been formulated as injectable hydrogels suitable for both subcutaneous and local administration (Table
polar phase immobilized within the spaces available of a three-dimensional network
that ultimately provides a platform suitable for extended drug release. Nanoparticleloaded hydrogels can combine consequently the advantages of both nanomedicines
and hydrogels.
Whereas the design of nanoparticle-loaded hydrogels conventionally consists of
the dispersion of nanoparticles in the polymeric network that forms the hydrogel
(Wu et al. 2023; Li et al. 2022; Yu et al. 2020), LNC-based hydrogels are the LNCs
themselves that form the characteristic three-dimensional network of the hydrogel
(Moysan et al.
amphiphilic molecule to the LNC mixture, which drives sol-gel transition in an
aqueous solvent through self-assembly via H-bond cross linking. Indeed, the hydrophilic part of these amphiphilic molecules spontaneously localizes at the oil–water
interphase of the LNC during the formulation process and interacts with each other
through H-bonds.
To formulate the LNC-based hydrogel, two distinct amphiphilic molecules have
been used; namely, lauroyl-gemcitabine (GemC12), composed of a lauroyl chain
covalently bound via an amide function to gemcitabine (Bastiancich et al.
palmitoyl-cytidine (CytC16), composed of a palmitic chain covalently bound via an
amide function to cytidine (Pitorre et al.
molecules was performed using a longer aliphatic chain than that of gemcitabine to
maintain a similar hydrophilic–lipophilic balance given the higher hydrophilic
character of cytidine than that of gemcitabine due to an additional hydroxyl function
on the cytidine cycle. In both cases, the non-polar alkyl chain is inserted in the LNC
structure while the nucleo side, polar in nature, is orien ted towards the aqueous phase
forming H-bond cross linkings and immobilizing the water phase to form a gel.
5.3). Hydrogels are semi-solid drug delivery systems that consist of a
2014). Indeed, physical gelation of LNCs occurs upon addition of an
2016a)or
2021). The synthesis of modi fied cytidine
Table 5.3 Latest advances and applications in LNC-based hydrogels in animal models
Formulation
description
GemC12LNC-based
hydrogel
GemC12LNC-based
hydrogel
GemC12LNC-based
hydrogel
Route of
administration Animal model Ref.
Subcutaneous Orthotopic Ma44-3 patient-like xenograft
Intratumoral
(by stereotactic injection)/Perisurgical
Perisurgical
of mediastinal metastases in a non-smallcell lung tumor model in nude mice
Orthotopic U-87 MG human xenograft
model in nude mice Orthotopic subtotal
U-87 MG human xenograft resection
model in nude mice
Orthotopic subtotal 9L gliosarcoma
resection model in Fisher rats
Wauthoz
et al. (2015)
Bastiancich
et al. (2017)
Bastiancich
et al. (
2018)
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Overall, the viscoelastic properties of the CytC16-LNC-based hydrogels were
enhanced in comparison with those of GemC12-LNC-based hydrogels for a given
concentration of amphiphilic molecule, which might be due to the additional
hydroxyl function of the cytidine moieties at the surface of the LNCs (Pitorre et al.
2021). Regardless of the amphiphilic molecule used to induce gelation, LNCs in
suspension are recovered upon gel dilution in water, showing the physical character
of the gel association.
An advantage of these hydrogels for biomedical applications is that their subcutaneous or local injection is enabled, unlike other imp lantable devices that require
surgical procedures for implantation. Indeed, the LNC-based hydrogels retained the
gel property following extrusion through thin (18 and 21 G (Moysan et al.
down to 26 or 30 G (Bastiancich et al. 2016a; Pitorre et al. 2021)) needles with either
no loss of viscoelastic properties (in the case of GemC12-LNC hydrogels) or with
only a slight loss of the viscoelastic properties after extrusion (in the case of CytC12LNC hydrogels). The viscoelastic properties were also maintained upon storage in
syringes at 4 °C over 6 months. Nevertheless, despite its stable viscoelastic properties, one limitation of the CytC12-LNC hydroge l is the loss of stability during
storage in terms of LNC size (Pitorre et al. 2021). This increase in size and
polydispersity index, which was not observed in the case of the GemC12-LNC
hydrogel, would affect the distribution of the LNCs following disruption of the
LNC-based hydrogel structure.
Another advantage of this system is that the degradation of the gel corresponds to
the release of the LNC, as no other polymers have been added to the formulation,
reducing the risk of side effects and simplifying the formulation procedure. The
release profiles of LNCs from the hydrogels correlated with their viscoelastic
properties, that is, slower release profiles correlated with higher viscoelasticity
(Pitorre et al. 2021). Once LNC release is completed, no gel matrix remains at the
injection site.
Altogether, LNC-based hydrogels hold promise as injectable implants for pharmaceutical applications. Whereas the antimetabolite nature of gemcitabine allows
the GemC12-LNC-based hydrogels to be used for anticancer applications
(Bastiancich et al.
CytC16-LNC-based hydrogels open new therapeutic avenues for diseases other
than cancer that require subcutaneous or local injection for extended drug release.
Even though CytC16-LNC-based hydrogels showed good biocompatibility over
1 month following subcutaneous administration, with a local in flammatory response
similar to that induced by an approved excipient for parenteral injection (Pitorre et al.
2021), only GemC12-LNC-based hydrogels have been tested in preclinical models
of disease.
Gem-C12-LNC-based hydroge ls were first tested in mice bearing orthotopic
patient-like mediastinal metastases of non-small-cell lung tumour xenografts
(Ma44-3) following subcutaneous administration (Wauthoz et al.
ment (at a Gem-C12 dose of 40 mg/kg of body weight) resulted in an equivalent
survival increase in mice to that following intravenous administration of GemC12loaded LNCs in suspension with a lower administration frequency (twice a week
2016b, 2021), due to the endogenous character of cytidine,
2015). This treat-
2014)
Соседние файлы в папке Библиотека им академика М.И. Перельмана