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102 J. Aparicio-Blanco and A. I. Torres-Suárez
https://t.me/med1917
versus three times a week) and low systemic toxicity (neither significant
myelosuppression nor significant depletion in alkaline phosphatase in comparison
with the control saline group).
Subsequently, Gem-C12-LNC-based hydrogels have been thoroughly tested for
the local treatment of glioblastoma. Tolerability studies show ed that these Gem-C12LNC-based hydrogels administered by intracerebral injection at a dose of 5.5 mg
GemC12 per kg of body weight are suitable for local application in the brain of
healthy mice (Bastiancich et al.
10 μL (maximal injectable volume in the mice brain) of GemC12-LNC-based
hydrogel, no increase in inflammation, apoptosis or microglia activation was
observed in comparison with control.
Furthermore, the local treatment of glioblastoma with the GemC12-LNC hydrogel has been shown to delay tumour onset in various mouse and rat preclinical
models.
First, the antitumour efficacy of the GemC12-LNC-based hydrogel at a dose of
3 mg GemC12 per kg of body weight has been tested in the U-87 MG human
xenograft orthotopic model in nude mice following intratumoural administration by
stereotactic injection (Bastiancich et al.
significantly prolonged median survival was observed in mice treated with the
hydrogel in comparison with the other treatments (i.e. intratumoural injection of
unloaded LNC, intratumoural injection of free GemC12 and intravenous injection of
free GemC12).
Then, to closely mimic the local delivery clinical scenario for glioblastoma
therapy, a second antitumour efficacy study was performed using an orthotopic
subtotal resection model in mice (Bastiancich et al.
the tumour resection cavity immediately after surgery of 5 μL of the GemC12-LNCbased hydrogel (corresponding to a dose of 3 mg GemC12 per kg of body weight), a
significant increase in the median survival of mice was observed compared with
controls. Interestingly, the curves of the free drug (GemC12) and GemC12-LNCbased hydrogel groups almost overlapped in this orthotopic resection tumour model,
while in the previous orthotopic non-resected tumour model, a significant difference
between the curves could be observed. However, in this subtotal resection model,
recurrence of the tumours, which lead to mouse death, occurred in all animals.
Analogously, the efficacy of the GemC12-LNC-based hydrogel has been tested in
an orthotopic subtotal resection model in Fisher rats, where the hydrogel was used to
fill the resection cavity given its mechanical properties adapted for brain implantation (Bastiancich et al. 201 8 ). In the syngeneic immunocompetent rat orthotopic 9L
gliosarcoma model, the perisurgical injection of 10 μL of the GemC12-LNC-based
hydrogel (corresponding to a dose of 1.4 mg GemC12 per kg of body weight)
delayed or even prevented tumour recurrences, with 50% of animals being longterm survivors (i.e. survived >150 days post-tumour inoculation).
Even if, altogether, strong preclinical evidence has been provided for the
GemC12-LNC-based hydrogel to delay recurrence onset in distinct orthotopic
resection rat and mouse glioblastoma models; however, GemC12-LNC-based
hydrogels without other chemotherapeutic agents might not be enough to fully
2016a, 2017). Up to 6 months, after the injection of
2017). In this orthotopic xenograft model, a
2017). Aft er injection within
5 Lipid Nanocapsules: Latest Advances and Applications 103
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prevent recurrences from occurring. To address this last issue, GemC12-LNC-based
hydrogels have also been used as a scaffold to co-encapsulate a second drug
(paclitaxel (Bastiancich et al. 2019) or salinomycin (Bozzato et al. 2022
)) in the
oily core of the LNCs, opening new avenues for combination therapies that might
lead to
increased therapeutic efficacy. The lack of differences between loaded and
unloaded GemC12-LNC-based hydrogels in terms of stability, degradability, physicochemical properties and rheological behaviour indicates that the second drug is
most likely located inside the oily core of the LNC and does not take part in the
gelation process, unlike GemC12. Nonetheless, the eval
these
LNC-bas
hydroge
ed
exploiti
ls
ng
combi
nation
thera
uat
ion of the effi
in
pies
preclinic
cacy
al
models
of
of glioblastoma is still pending.
5.5 Latest Advances and Applications in Alternative
Formulation Strategies with LNCs: LNCs as a Cargo
Finally, to broaden the range of routes of administration through which LNCs can be
applied, alternative formulation strategies that utilize LNCs as a cargo have been
described. Indeed, this has been the case to enable their pulmonary delivery
(Umerska et al.
Following pulmonary administration, particle aerodynamic diameter is highly
correlated with the lung deposition pattern. To achieve deposition into deep lung, the
inhaled particles must be small enough to avoid deposition by inertial impaction in
the upper airways, but large enough to prevent exhalation. Hence, particles with a
mass median aerodynamic diameter ranging from 1 to 5 μm are preferred for
pulmonary administration given their higher likelihood of sedimentation by gravitational force in the smaller airways (Aparicio-Blanco et al. 2022). Altogether, this
makes the use of nanomedicines themselves severely restricted for pulmonary
delivery. To address the challenge of finding a larger carrier with suitable aerodynamic diameter for pulmonary delivery of nanomedicines, LNCs have been
entrapped within carbohydrate-based microparticles prepared via spray drying
(Umerska et al.
2020) and topical administration (Fernandes et al. 2021) (Table 5.4).
2020).
Table 5.4 Latest advances and applications in alternative formulation strategies with LNCs as a
cargo in animal models
Formulation description
Lidocaine and prilocaine
co-loaded LNCs dispersed in a
2.5% Carbopol 940 gel
Hypericin-loaded LNCs (25 μg/
kg) delivered by hollow
microneedles
Route of
administration Animal model Ref.
Topical Tail-flick assay in mouse model Fernandes
Intradermal Subcutaneous tumour model
initiated by CT26 mouse colon
cancer cells in mice
et al.
2021)
(
Abd-El-
Azim et al.
(
2022)
104 J. Aparicio-Blan co and A. I. Torres-Suárez
https://t.me/med1917
The encapsulation within microparticles requires that the LNCs retain their size
and individual nature within the dried microparticles. The LNCs were successfully
reconstituted from all tested microparticles upon dispersion in water. Among the
various carbohydrates tested (i.e. raffinose, trehalose, sucrose, lactose and mannitol),
raffinose was the preferred choice to obtain LNC-loaded microparticles because it
was the most effective carbohydrate in preserving the LNCs size after spray drying
(78 nm after versus 59 nm before spray drying). Moreover, the mixture of raffinose
and LNCs remained amorphous, which ultimately eases their homogeneous mixing
for spray drying. Finally, LNC-loaded raffinose microparticles showed suitable
aerodynamic diameter for deep lung deposition (i.e. 5.3 ± 0.1 μm). Indeed, in vitro
aerosol deposition studies using the Next Generator Impactor (NGI, Ph. Eur.)
showed a fine particle fract ion and a total emitted dose of approximately 23.4%
and 64%, respectively.
Altogether, raffinose-based microparticles can be useful carriers for pulmonary
delivery of LNCs loaded with a wide variety of drugs using dry powder inhalers,
although the evaluation of their therapeutic potential in in vivo preclinical models
remains.
In a distinct approach, to enable their buccal topical administration through
enhancement of mucoadhesive properties, LNCs loaded with the local anaesthetics
prilocaine and lidocaine have been dispersed in a polymer matrix to form a 2.5%
Carbopol 940 gel network (Fernandes et al. 2021). The in vivo anaesthetic effect of
the LNC-loaded Carbopol gel has been tested in a mouse model through the tail-flick
assay. Notably, the hybrid formulation extended by fourfold the anaesthesia duration
in comparison with an equipotent Carbopol gel formulated without LNCs in agreement with the more prolonged release provided by the inclusion of the LNCs. These
results seem to support the topical use of this hybrid formulation in dental procedures
prior to infiltrative anaesthesia to reduce the pain of needle stick.
Finally, LNCs have also been incorp orated into hollow microneedles for minimally invasive intradermal drug delivery (Abd-El-Azim et al.
effect of the LNCs loaded with hypericin and delivered by the hollow microfibres
has been tested in a mouse tumour model subcutaneously implanted with the CT-26
mouse colon cancer cell line. Notably, upon irradiation to trigger local photodynamic therapy, above an 85% tumour destruction level was observed after administering four doses of 25 μg of hypericin per kg of body weight in an undisclosed
dosing frequency. The combination of photodynamic therapy with the microneedleenabled delivery outperformed the tumour volume reduction observed with either of
them applied separately (i.e. microneedle-enabled delivery of hypericin-loaded
LNCs in the absence of light or photodynamic therapy in the absence of
microneedle-enabled delivery of LNCs).
2022). The therapeutic
5 Lipid Nanocapsules: Latest Advances and Applications 105
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5.6 Conclusion
LNCs are versatile carriers that can be obtained by a single-step phase inversion
temperature method and be finely tuned in terms of particle size with prolonged
colloid stability in suspension. They can exploit distinct formulation strategies to
include both lipophilic and hydrophilic cargoes or to improve their extended-release
properties by gelling. More recently, LNCs have also been used as a cargo themselves to be included into supra-d rug delivery systems. As a proof of their versatility
in the drug delivery field, LNCs have been tested following administration by
multiple routes (such as intravenous, subconjunctival, intranasal, oral, pulmonary,
topical or intradermal to name a few), where their potential use as not only a
therapeutic but also as a diagnostic tool has been tested. This gained experience
augurs very well for the future of LNC research in the field of drug delivery.
Acknowledgements This work was supported by the Spanish State Research Agency, Ministry of
Science and Innovation (grant number PID2019-105531RB-I00/AEI/10.13039/501100011033).
The authors would like to thank Pablo Jiménez-Romero for providing assistance with the figures.
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Chapter 6
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Polymer-Drug Conjugates
Cristina Fante, María J. Vicent, and Francesca Greco
6.1 Materials Chemistry
6.1.1 Definition of Polymer-Drug Conjugates and General
Background to This Technology
Polymer-drug conjugates are a drug delivery technology where a polymer carrier is
used to improve the performance of a drug (e.g. improve drug selectivity towards the
target site) as a single agent or in a combination regimen. Unlike other systems, such
as liposomes or nanoparticles where the drug is physically entrapped within the
carrier, in a polymer-drug conjugate, the drug is covalently attached to the polymer
via a linker, which is generally biodegradable (Fig. 6.1).
The concept of conjugation of a drug to a polymeric carrier was first introduced in
the 1970s by Helmut Ringsdorf as a strategy to enhance the selectivity, cellular
uptake and solubility of a drug (Ringsdorf
been carried out which has resulted in polymer-drug conjugates reaching clinical
evaluation (Vasey et al.
Canal et al. 2011; Ekladious et al. 2019).
The rationale for conjugating a drug to a polymer stems from the fact that the
biological behaviour of the drug can be significantly altered by increasing the
molecular weight (MW) of the active pharmaceutical ingredient. Covalent conjugation to a polymer results in a number of advantages as outlined below.
1999; Seymour et al. 2009, also reviewed in Duncan 2006;
1975). Since then, extensive work has
C. Fante · F. Greco (✉)
Reading School of Pharmacy, University of Reading, Reading, UK
e-mail: f.greco@reading.ac.uk
M. J. Vicent
Polymer Therapeutics Lab, Prince Felipe Research Center (CIPF) and CIBERONC, IISCIII,
Valencia, Spain
© The Editor(s) (if applicable) and The Author(s), under exclusive license to
Springer Nature Switzerland AG 2024
I. F. Uchegbu et al. (eds.), Fundamentals of Pharmaceutical Nanoscience,
https://doi.org/10.1007/978-3-031-59478-6_6
109
110 C. Fante et al.
https://t.me/med1917
Polymer
Linker
Drug
Polymer-Drug Conjugate
Polymeric Nanoparticle
Fig. 6.1 Schematic representation of a polymer-drug conjugate and other drug delivery technologies. In polymer-drug conjugates, the drug is covalently attached to the polymer via a biodegradable linker
Ta rg e ti n g
group
Polymeric micelleLiposome
. Prolonged circulation time of the drug. The polymer can protect the conjugated
drug from premature inactivation during its delivery to the site of action. In
addition, the macromolecular size of the conjugate prevents the early elimination
of the drug through renal filtration, thus typically increasing half-life and decreas-
ing administration frequency.
. Restricted body distribution. An intravenously administered drug is generally
able to diffuse throughout the body, with no selectivity towards the target tissue.
On the other hand, the macromolecular size of a conjugate prevents extravasation
of the drugs in areas where the vascular endothelium is continuous. In fact,
conjugation to a polymer restricts drug access to those tissues where the vascu-
lature presents fenestrations and gaps of appropriat e size (>20 nm). The tumour
tissues, for instance, are characterised by a defective vasculature which is perme-
able to the conjugate. This and other features (discussed in Sect. 6.4.1) make the
tumour tissue a particularly good target for polymer-drug conjugates.
. Improved drug solubility in water. The conjugation of a hydrophobic drug to a
hydrophilic carrier improves drug solubility in water (see, e.g. Piao et al. 2019).
.
Selective drug release. Polymer conjugation can also alter the cellular pharma-
cokinetics of the drug. Due to their large size and hydrophilicity, polymer-drug
conjugates cannot enter the cell via passive diffusion across the cellular mem-
brane as many small drugs do. Instead, they are taken up typically by endocytosis
and routed towards the lysosomes (lysosomotropic delivery). The lysosomal
6 Polymer-Drug Conjugates 111
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compartment has two peculiar characteristics: an acidic pH (4–5) and a high
concentration of proteolytic enzymes (e.g. cathepsin B). This unique environment
can be turned into a useful trigger for drug release from the conjugate. Indeed,
polymer-drug conjugates have been designed with biodegradable linkers either
sensitive to acidic pH or selectively degraded by proteolytic enzymes. This allows
the drug to be released exclusively intracellularly and to effectively reach its
biological target (such as the cytosol or the nucleus depending on the drug). In
addition to pH and enzymes, other environmental triggers have been explored to
promote drug release, for example the reductive environment (exploited for
redox-sensitive linkers) (Giraldo et al. 2021).
. Bypassing some mechanisms of drug resistance. Because of the polymer
‘masking’ the drug and also changing its cellular pharmacokinetics, polymer
conjugation has been reported to bypass certain mechanisms of drug resistance
(Ke et al. 2014).
The biological behaviour of a polymer-drug conjugate is strongly affected by
each of its constituents and by the overall physico-chemical properties of the
system (e.g. water solubility, conformation in solution). The next section will
look at each component of a polymer-drug conjugate.
6.1.2 Composition of a Polymer-Drug Conjugate
As previously described, a polymer-drug conjugate is constituted of three (to four)
components: a drug, a polymeric carrier, a linker and, optionally, a targeting group.
In this section we will look at each component, individually.
Drug(s)
Polymer-drug conjugates that have been traditionally designed for application in
cancer therapy (see Sect. 6.4), but more recently they have also been applied to
diseases other than cancer (see Sect. 6.4.2). Examples of drugs that have been
incorporated in polymer-drug conjugates include doxorubicin, paclitaxel and
camptothecin (as antic ancer agents), docosahexaenoic acid (DHA) and fasudil (for
other applications).
With the help of an example (doxorubicin) we are now going to look at what
characteristics make a drug suitable for conjugation to a polymeric system (also
summarised in Fig. 6.2).
Doxorubicin is a potent anticancer agent used for the treatment of metastatic
breast cancer (Paridaens et al.
doxorubicin is its cardiotoxicity, which is a result of the lack of selec tivity of this
drug (Jensen 2006). Such lack of selec tivity makes it an ideal candidate for polymer
conjugation, as the polymer will promote drug accumulation in the tumour tissue.
The chemical structure of doxorubicin also makes it a suitable candidate for conjugation. In particular, this molecule contains a primary amino group and a hydroxyl
group. Both these functional groups can be exploited for linking the drug onto a
2000). The main issue with the therapeutic use of
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