Peptide based hydrogels for cancer drug release: Modulation of stiffness, drug release and proteolytic stability of hydrogels by incorporating d-amino acid residue(s)

Article abstract of DOI:10.1039/c6cc01744d

Synthetic tripeptide based noncytotoxic hydrogelators have been discovered for releasing an anticancer drug at physiological pH and temparature. Interestingly, gel stiffness, drug release capacity and proteolytic stability of these hydrogels have been suc

Full text of DOI:10.1039/c6cc01744d

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DOI: 10.1039/C6CC01744D
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Peptide based hydrogels for cancer drug release: Modulation of
stiffness, drug release and proteolytic stability of hydrogels by
incorporating D-amino acid residue(s)
Received 00th January 20xx,
Accepted 00th January 20xx
Kingshuk Basu,a Abhishek Baral,a Shibaji Basak,a Ashkan Dehsorkhi,b Jayanta Nanda,c Debmalya
DOI: 10.1039/x0xx00000x
Bhunia,d Surajit Ghosh,d Valeria Castelletto,b Ian W. Hamley,b and Arindam Banerjee *a
www.rsc.org/
Synthetic tripeptide based noncytotoxic hydrogelators have been are important delivery vehicle for targeted delivery of
discovered for releasing an anticancer drug at physiological pH Doxorubicin into cancer affected areas, where intravenous
and temparature. Interestingly, gel stiffness, drug release capacity administration is not very promising (in the case of
and proteolytic stability of these hydrogels has been sucessfully osteosarcoma patients).9 Here, we study the slow and
modulated by incorporating D-amino acid residues, indicating sustained release of Doxorubicin from
a
peptide-based
their potential use for drug delivery in future.
thixotropic hydrogel Boc-(L)Phe-(L)Phe-(L)Phe-COOH P1).
(
However, the homochiral triphenylalanine system containing
only α-L protein amino acid residues has a serious shortcoming
due to its proteolytic instability,10 this is because α-L amino
acid residues can be easily recognized and cleaved by the
proteolytic enzymes present inside the cell. So, in addition to
the drug release ability, it is essential to optimise the
proteolytic stability of the hydrogel by incorporating D-amino
acid residues into the parent gelator molecule. The parent
gelator molecule P1 has three chiral centres in its structure,
therefore alternation of chirality of Phe residue(s) might
change the orientation of the corresponding aromatic ring and
the direction of π-π stacking interaction, which can have a
profound effect on the macroscopic properties of the
corresponding gel. It is also of great interest to investigate how
alternation of chiral residue(s) around the chiral centre(s) in
the parent peptide affects the self-assembly, gelation,
mechanical strength, proteolytic stability and drug release
capacity of these gels. We have synthesized(detailed synthetic
procedure and characterization data are given in the ESI) all
possible stereoisomers of the parent compound and
investigated their self assembly, drug release and mechanical
properties as well as proteolytic stability in order to optimise
their properties in future use.
Peptide based hydrogels1 continue to attract attention
among researchers due to their potential applications in
various research fields.2 Peptide molecules are not only good
gelators due to the presence of various self-assembling units in
their structures but also possess inherent biocompatibility
which enhances their applicability.3 The orientation of
different functional groups in proper configuration is crucial to
trigger an entropically disfavoured process like gelation.1n
Amino acids, the basic building blocks of peptide molecules,
are inherently chiral with at least one stereogenic centre
dictating the spatial arrangement of various functional groups
attached to them. So, all peptide based gelator molecules are
examples of chiral gelator molecules,4 whose chirality can be a
tool for tuning the physical properties of the corresponding
gels to make them smarter.5 Furthermore, the simplicity and
low cost of synthesis make these peptide-based materials a
wonderful platform for studying chirality induced effects.
Doxorubicin is a potent anticancer drug routinely used in
the advanced stage of breast cancer, gastric carcinoma and
leukaemia. However, it has many side effects when it is
administered in high dose.7 Thus, selection of a delivery
vehicle is very important to overcome this problem.8 Hydrogels
Fig. 1 shows structures of peptides and images of the
peptide-based gels in their respective vials. P1 (LLL), P2 (DLL),
P3 (LDL) and P4 (LLD) are four diastereomers (chirality
sequence in brackets) and P5 (DDD), P6 (LDD), P7 (DLD) and P8
(DDL) are their respective enantiomers. It can be noticed that
a.Department of Biological Chemistry, Indian Association for The Cultivation of
Science, Jadavpur, Kolkata, 700032 (India) Fax: (+ 91) 33-2473-2805, E-mail:
bcab@iacs.res.in.
b.
Department of Chemistry,University of Reading, Whitenights, Reading, RG6, 6AD,
UK.
c. Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel
d.Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick
Road, Jadavpur, Kolkata-700032, India.
P1 (and its enantiomer P5) and P2 (and its enantiomer P6
form gels instantaneously, whereas P3 (and its enantiomer P7
)
)
Electronic Supplementary Information (ESI) available: [Details of synthesis and
characterization of peptides, gelation study, FT-IR, CD, proteolytic and cytotoxicity
studies, FE-SEM and injectability images, SAXS, XRPD and step-strain rheological
takes 12 hours to form a gel and P4 and its enantiomer P8 are
nongelator at physiological pH (7.46) and temperature. So
plots,
proposed
model
and
detailed
instrumentation].
See
DOI: 10.1039/x0xx00000x
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chirality has some extensive effect on the gelation or non- at d= 3.7 Å (2θ = 23.5) corresponding to theViπew-πArtpiclaecOknilninge
gelation of the tripeptides.
interaction9a is only prominent for the DPO1I:x1e0.r1o0g39e/lC, 6wChCi0le174t4hDe
intensity of the peak is much weak for P2 P3 and P4 in their
dried form. Fig. S30 summarizes the XRPD pattern of gelator
molecules P1 P2 P3 and the nongelator molecule P4 and their
,
,
,
corresponding enantiomers. So, we can notice a poor π-π
interaction in the molecular packing of peptides containing
residues of mixed chirality. It confirms that molecular packing
is significantly perturbed for the heterochiral sytems where
molecules pack less efficiently than that for the homochiral
systems. On the basis of FT-IR, SAXS and XRPD data a
schematic model can be proposed for P1 and P2 (Fig. S31).
Circular dichroism (CD) measurements were performed to
examine the chiroptical behaviour of all compounds in
Fig. 1 Chemical structures of tripeptides and their gelation nature in pH 7.46 phosphate
buffer.
aggregated state (Fig. S32). P1, P2 and their enantiomers show
two peaks at 203 nm and 223 nm, whereas P3 and P4 show
only one weak peak at 220 nm, indicating that P1 and P2 may
have a slightly more ordered structure in comparison with P3
Gel morphology was examined using field emission
scanning electron microscopy (FE-SEM). FE-SEM images of all
xerogels and dried aggregated solutions of all tripeptides show
similar fibrillar morphology (Fig. S26). However it is difficult to
predict gelation (or non-gelation) ability just from a fibrillar
morphology observed from microscopic experiments, rather
efficient 3D networks formed by these fibres leads to gelation
which needs entanglement of fibres to a long range.
Comparison of FT-IR spectra of xerogels and dried solutions
provides information on the difference in H-bonding
interactions for different tripeptides. All the enantiomeric pair
show a similar pattern (as shown in Fig. S27 of ESI), so
and P4 5a
.
Interestingly, it has been found that the intensity of
the peak at around 220 nm decreases gradually from P1 to P4
This indicates that the π-π interaction prevails in the order P1
P2 P3 P4. Moreover, the chirality of the terminal amino
acid residue (whether it is “D” or “L”) dictates the directions of
the CD signals at 220 nm(positive or negative). For P1 P2 P3
and P8, the terminal amino acid residue has (L)-configuration
and the peak is oriented in positive direction, whereas for P4
P5 P6 and P7, the terminal amino acid residue has (D)-
.
>
>
>
,
,
,
,
configuration and the peak is oriented in the negative
direction.5a So, this observation indicates how chirality of the
terminal residue (whether it is “D” or “L”) governs the
supramolecular assembly of all these peptides.
To check how the different self-assembly patterns are
reflected in the macroscopic properties of these gelator
properties of only four diastereomeric peptides P1, P2, P3 and
P4 are discussed here. The peak around 1649 cm-1 corresponds
to the hydrogen bonded stretching frequency of the amide
carbonyl groups which are present in all four cases,9a while the
peak for hydrogen bonded urethane C=O which appears at peptides, rheological measurements for all hydrogels were
1690 cm-1 is prominent only for P1 and P2 xerogels. However,
carried out to measure the gel strength keeping the gelator
it is weak for P3 and almost non-existent for dried P4 solution.
This indicates the absence of hydrogen bonding for the
urethane carbonyl group of P4 and only weak H-bonding
interaction for P3. The amide stretching peaks corresponding
to 3343 and 3422 cm-1 are assigned to hydrogen bonded and
non-hydrogen bonded amide N-H respectively.11 Interestingly,
in this study P1 and P2 show both types of peaks, suggesting
the presence of both hydrogen bonded and free N-H, while P3
and P4 do not show any significant peak at 3343 cm-1
indicating the presence of free N-H groups only. P4 is unable to
form H-bonding at both urethane and amide N-H sites
resulting in its inability to form a gel.
concentration the same [1 % (w/v)]. From a frequency sweep
experiment (at constant strain of 0.1%) (Fig. 2 and Fig. S33 in
ESI), it is
Small angle X-ray scattering (SAXS) is a useful technique to
obtain information on molecular packing. For P1 gel and its
enantiomer P5 a broad peak was observed at d= 28 Å, (Fig.
S28) which is double the calculated length of a single molecule
(calculated from Chem-Draw 3D Ultra software).
Wide-angle X-ray powder diffraction (XRPD) studies were
done for all samples in xerogel form. A characteristic peak at
Fig. 2 Frequency sweeps of dynamic shear modulus for hydrogels P1, P2 and P3 (gels
4.7 Å (2θ= 18 Å) can be assigned to a β-sheet like arrangement made at 1 % (w/v), G’ and G’’ values for the enantiomers are given in the ESI Fig. S27).
Inset: Comparison of mechanical strength with change in chirality of residues at
constant frequency 12.595 rad/sec.
in the molecular packing of gelator molecules which is
revealed by the diffraction pattern of all the xerogels. The peak
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observed that all hydrogels formed by P1
modulus (G') > loss modulus (G'') and also G' and G'' values are
weakly dependent on angular frequency over the range
studied indicating the formation of a stable gel. Again the
enantomeric counterpart of each tripeptide shows similar
rheological data, and therefore we are focusing only on
COMMUNICATION
,
P2
,
P3 show storage
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DOI: 10.1039/C6CC01744D
diastereomers P1
strength as indicated by G' decreases gradually in the series
P1 P2 P3 P4 does not gel) (Fig. 2). It is evident from the
, P2, P3 and P4. It is notable that mechanical
>
>
(
study that gel strength (G') gradually decreases as the D-Phe
residue is moved from the N to the C terminus. This agrees
well with previous observations which shows the decreasing
trend of H-bonding and π-π stacking interaction in the order
P1 ~ P2 > P3 > P4. This remarkable observation shows that it is
possible to modulate the mechanical strength of a particular
gelator by changing molecular chirality and placing the D-
residue in the proper position (at or towards the C terminus).
All the hydrogels are thixotropic in nature, and have been
checked by repetitive shaking and resting cycles. Thixotropy of
the gels have been confirmed by using time dependent step-
strain rheology experiments, keeping the gelator
concentration fixed in all cases. At first the strain on the gel
was kept constant at 0.1% then after 200 seconds it was
rapidly increased to 10%, at this point the gel was broken
which is indicated by crossover of G'' values over G'. Again
after 200 seconds strain was decreased to 0.1% where
reformations of the gels was observed. The relative strength
recovery of gels of P1, P2, P3, P5, P6 and P7 is near 100% and
recovery times lies in the range 410-440 seconds range (Fig.
S34).
The differences in molecular level chirality and packing lead
to changes in macroscopic properties, as exemplified by
mechanical and dynamic properties of the gels. Hydrogels
Fig. 3 Release of Doxorubicin from hydrogels of (a) P1, P2 and (b) P5, P6 (in all cases gel
was loaded with 46 μg of drug and error bars are calculated after three experiments in
each case).
The proteolytic stability of the four peptides, which can
encapsulate and release Doxorubicin (P1, P2, P5 and P6) were
examined in the presence of a proteolytic enzyme Proteinase
K. Degradation of each peptide was monitored periodically
using mass spectrometry. The results (detailed procedure
given in ESI, see Fig. S36, and Fig. S37-S40) show that P1 and
P2 are proteolytically very much unstable and undergo
degradation within 24 hours, but P5 and P6 remained stable.
This stability makes P5 and P6 applicable for use in real
situations. But out of them, P6 has the greater delivery
efficacy. The results of the above studies lead to the
conclusion that among all the peptides discussed here P6 has
the optimised properties we are looking for and this makes it
the most efficient Doxorubicin delivery vehicle. Here
we
have successfully designed hydrogels for drug delivery and also
optimized their properties. To check their practical
applicability, cytotoxicity has been studied. The minimum
gelation concentrations (MGCs) of the reported hydrogels are
around ~900 μM. Cytotoxicity has been studied up to 900 μM
and no apparent cytotoxicity has been found. Fig. 4 shows the
cell viability assay and cell morphology when treated with the
proteolytically stable and most efficient drug releasing gelator
P6. Results from cytotoxicity studies with other gelators is
shown in Fig. S41. Our study vividly demonstrates that the gel
obtained from gelator P6 does not show significant toxicity
towards cancerous cells, while a Doxorubicin loaded gel of P6
kills breast cancer cells more efficiently than that of the free
drug (i.e. Doxorubicin) alone.
In summary, we have created soft biomaterials for cancer
drug release at physiological pH and temperature having no
cytotoxicity. Remarkably, the modulation of stiffness and
proteolytic stability of these hydrogels has been achieved by
replacing one or more L-Phe residue by D-Phe residue(s) and
also by changing the position of the D-residue in the
tripeptide. The incorporation and location of D-residues
determine the mechanical stability of a gel as well as its drug
release capacity. Moreover, it is the number and position of D-
amino acid residues that determines the proteolytic stability of
obtained from P1 to P3, P5 and P6 show thixotropic behavior
(Fig. S34) and this has been exploited for injectable studies.
(Fig. S35).
P1, P2, P5 and P6 hydrogels can encapsulate an anticancer
drug, Doxorubicin and their release properties have been
studied. For each gel, the same amount of drug was loaded
into the same volume of gel with same molar concentration of
gelator. Then the same volume of supernatant buffer solution
was added at the top of the drug loaded hydrogel to examine
the drug release. It is observed that though the release profile
of P1 and P2 (also of P5 and P6) are similar, the total amounts
of released drug are different for gels obtained from different
diastereomers, whereas enantiomeric pair show the same
amount of release. Anticancer drug-loaded hydrogels P2 and
P6 show the maximum release of 76% after 79 hours, then
reaching a plateau. However, both the gels P1 and P5 show a
maximum release of 65% within a total span of 52 hours and
after that each of these gels started rupturing gradually.
Interestingly, stiffer gels release less drug sustainably (because
they break down within 52 hours and after that there is a
random release) than the weaker gels(Fig. 3).
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Castelletto, M. S. Liberato, V. X. Oliveira, C. L. PV.ieOwliAvreticirleaOanlninde
the gel. After trying all possible combinations of D and L amino
acids, the most efficient gelator molecule has been identified
as P6. So, it can be concluded that by incorporating D- instead
of L-residues and by placing them in the proper position,
proteolytic stability and mechanical strength of these soft
biomaterials can be optimized for designing future drug
delivery vehicles.
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