Light-controlled active release of photocaged ciprofloxacin for lipopolysaccharide-targeted drug delivery using dendrimer conjugates

Article abstract of DOI:10.1039/c6cc05179k

We report an active delivery mechanism targeted specifically to Gram(-) bacteria based on the photochemical release of photocaged ciprofloxacin carried by a cell wall-targeted dendrimer nanoconjugate.

Full text of DOI:10.1039/c6cc05179k

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2016, DOI: 10.1039/C6CC05179K.
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DOI: 10.1039/C6CC05179K
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Light-Controlled Active Release of Photocaged Ciprofloxacin for
Lipopolysaccharide-Targeted Drug Delivery using Dendrimer
Conjugates
Received 00th January 20xx,
Accepted 00th January 20xx
Pamela T. Wong,ab* Shengzhuang Tang,ab Jhindan Mukherjee,ab Kenny Tang,a Kristina Gam,a
DOI: 10.1039/x0xx00000x
Danielle Isham,a Claire Murat,a Rachel Sun,a James R. Baker Jr.,ab and Seok Ki Choiab*
www.rsc.org/
We report an active delivery mechanism targeted specifically to by NPs through the multivalent conjugation of cell wall-
18
Gram(−) bacteria based on the photochemical release of photocaged targeting small molecule ligands including vancomycin2-5,
19
ciprofloxacin carried by a cell wall-targeted dendrimer nanoconjugate. and polymyxin,16,
as well as cationic antimicrobial
peptides.20, 21 Such multivalent NPs were shown to adsorb to
the cell wall very tightly, and could be further modified with
Drug delivery for the effective treatment of bacterial infections
is still an unmet need for certain localized wounds and for
ocular infections.1 Poor blood perfusion to these infected sites
limits the utility of oral or systemic routes of anti-infective
drug administration. Additionally, the non-selective effects of
certain anti-infective agents upon topical application on the
wound healing process and on non-infected tissues also
hinders treatment.1 Targeted delivery of antibacterial
therapeutics with multifunctional nanoparticles (NPs)
16
additional functionalities for fluorescence detection,3,
5, 19
magnetic bacterial isolation4,
and promotion of
opsonisation by macrophages.18
Despite their tight and specific cell wall adsorption, most of
these targeted NPs show suboptimal bactericidal activities4, 5,
largely due to their poor intracellular uptake.8 Thus, a
16, 18
conjugate in which the advantages of a tightly binding delivery
vehicle that acts to focus on a high local concentration of drug
at the bacterial surface in combination with a mechanism that
enables drug release at the bacterial surface is of high value.
conjugated with bacteria-specific ligands constitutes
a
promising strategy for treating localized infections.2-7 However
the challenge of overcoming the thick cell wall structure8
which poses a barrier to both passive and active modes of NP
uptake still poses a significant hurdle to these methods for
antibacterial use. Here we report a proof of concept study for
a novel, stimulus-controlled delivery strategy in bacteria that
enables light triggered, targeted release of an antimicrobial
payload at the bacterial cell wall surface.
Release
mechanisms
currently
developed
for
nanoconjugates are largely based on reactions that occur in
mammalian cells by endogenous factors such as low pH in
endosomes,22 differences in intracellular and extracellular
thiol/disulfide redox potential,23 and hydrolytic enzymes24 in
lysosomes.25 These mechanisms are not directly applicable to
antibiotic delivery due to their irrelevance to bacterial systems
and to the poor uptake of NPs in bacteria. Use of UV light has
been well validated for various controlled-release applications
including the spatiotemporal control of gene expression in
vivo,26 and tumor targeted drug delivery.25, 27, 28 Further, light
only-based therapies which include photodynamic therapy and
UVB (280–315 nm) irradiation are already in use clinically as
Multivalent strategies9-12 have played a fundamental role in
the design of NPs for the targeted delivery of therapeutic
agents, genes and imaging molecules to a broad range of cell
types and pathogens.13-15 In particular, multivalent attachment
of bacterial cell wall or outer membrane specific ligands to NPs
improved their functional activity in the detection and rapid
isolation of bacterial cells, and enhanced the antimicrobial
activities of NPs carrying therapeutic payloads.2, 4-7, 16, 17 We
and others have reported on the specific targeting of bacteria
a.Michigan Nanotechnology Institute for Medicine and Biological Sciences,
University of Michigan, Ann Arbor, Michigan 48109, United States. Email:
ptw@umich.edu; Tel: (734) 615-2192; Fax: (734) 615-2506; E-mail:
skchoi@umich.edu; Tel: (734) 647-0052; Fax: (734) 936-2990
b.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
48109, United States
Fig. 1 Scheme for light-controlled, targeted delivery of photocaged ciprofloxacin
(Cipro*) carried by a lipopolysaccharide (LPS)-binding dendrimer G5(Ligand)(Cipro*)
adsorbed to the outer membrane (OM) of the Gram(−) cell wall. Internalized Cipro
inhibits DNA gyrase. Abbreviations: PMB = polymyxin B; EA = ethanolamine, a PMB-
†
Electronic Supplementary Information (ESI) available: synthetic details and
spectral copies of 2–4; photorelease studies and turbidity assay. See
DOI: 10.1039/x0xx00000x
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mimicking lower affinity but more biocompatible ligand; PG = peptidoglycan; IM = inner
membrane.
suggest that these conjugates are more cationic than
View Article Online
unmodified G5(NH2)114 as expected forDcOoIn: 1ju0.g1a0t3i9o/nC6wCCit0h51t7h9Ke
cationic EA residues, and tend to form smaller aggregates
upon co-conjugation with ONB-Cipro.
alternative antibacterial therapies.29, 30 In the present study,
we expand the scope of light-based therapy by combining the
functionalities of light-controlled release of an antibiotic
payload with the specificity of bacterial cell wall targeting on
the same NP. This nanoconjugate could potentially augment
current photodynamic therapy regimens.
Photocaged ciprofloxacin, a broad-spectrum antibiotic, was
attached
to
a
lipopolysaccharide
(LPS)-binding
poly(amidoamine) (PAMAM) dendrimer nanoconjugate for cell
wall targeted delivery (Fig. 1). The delivery system was
designed using a fifth generation (G5) PAMAM31 dendrimer
parent, conjugated with excess outer-membrane targeted
ligands, polymyxin B (PMB, a polycationic cyclic peptide) or a
PMB-mimicking molecule, ethanolamine (EA) as the carrier for
Fig. 2 Structure of ciprofloxacin, photocaged ciprofloxacin (ONB-Cipro), and G5 PAMAM
dendrimers 3–4 conjugated with ONB-Cipro and a cell wall targeting ligand (L) such as
ethanolamine (EA) (3) or polymyxin B (PMB) (4).
1
ciprofloxacin (Cipro), an inhibitor of DNA gyrase (Fig. 2). Use
of these ligands with the dendrimer system for bacterial
targeting has been validated in our previous study16 which
demonstrated their tight and specific adsorption to a model
surface immobilized with lipopolysaccharide (LPS) (KD = 2.1–
1.4 nM)16 and to E. coli cells in vitro. First, an N-Boc protected
The binding avidity of these two conjugates to the bacterial
surface was evaluated with a Gram(−) cell wall model by
surface plasmon resonance (SPR) spectroscopy as described
16
previously.4,
Each conjugate showed tight binding to the
form of
2 ONB-Cipro was synthesized by derivatization of
sensor chip surface containing immobilized LPS in a dose-
dependent manner (Fig. 3). Sensorgram kinetic analysis
showed markedly slow dissociation rates for both dendrimers,
reflecting the tight association imparted by multivalent ligand
binding.9-11 Langmuir fitting analyses38 performed for each
sensorgram set yielded dissociation constant (KD) values of 7.0
ciprofloxacin at the secondary amine through a carbamate
bond with a photocleavable ortho-nitrobenzyl (ONB) linker32-35
(Scheme S1) and its structural identity was characterized by ESI
mass spectrometry (HRMS: calcd for C35H42FN6O12 [M+H]+
757.2839, found 757.2844), UV–vis absorption (
= 3101 M-1cm-1; 271 nm, = 7679 M-1cm-1) and 1H NMR (Fig.
S1).
max = 340 nm,


nM (
and
150 nM16), with a multivalent enhancement (
3
4
) and 5.7 nM (
thus bounnd tighter than free monovalent PMB (KD
4
) (KD = koff/kon; Table S3). Conjugates
3
=
2
ONB-Cipro was modified at its amine terminus by

) factor of 21
attachment of an oxirane group (Scheme S2) which allowed
covalent coupling to partially acetylated (Ac)60G5(NH2)
dendrimer derived from G5(NH2)114 (Mw = 26,600 gmol-1,
polydispersity index (PDI) = Mw/Mn ~1.010)36 (Scheme S3). The
remaining primary amines of the resulting dendrimer were
capped with epibromohydrin for ligand conjugation with
and 26 over PMB, respectively. These values are consistent
with previous results16 observed for the dendrimer modified
with only PMB ligand and/or excess EA as an auxiliary ligand
excess ethanolamine (EA) and PMB which yielded conjugates
3
G5(EA)n(ONB-Cipro)m (n = 40; m = 8.5) and G5(PMB)n(ONB-
4
Cipro)m (n = 1.1; m = 8.5). After purification by membrane
dialysis (MWCO 10 kDa), each conjugate was fully
characterized for its polymer purity (UPLC; >95%), molar mass
(MALDI-TOF: Mr = 31,300 (
absorption (ONB-Cipro: max
max ) = 335 nm (
= 3,857 M−1cm−1) in PBS, pH 7.4) as
summarized in the Supplementary Information. The valency of
attached ONB-Cipro (m) and PMB (n) on and was
3
(
), 31,500 (
4
) gmol-1), and UV–vis
= 3,315 M−1cm−1);
3
) = 337 nm (

(4

3
4
determined on an average basis by UV–vis analysis (m = 8.5
(mean), and 9 (median) by Poisson distribution,37 Fig. S5) and
by NMR integration (n = 1.1).16 Further characterization by gel
permeation chromatography (GPC) led to the determination of
their polymer distribution (PDI = 1.081 (3), 1.131 (4)). The basis
for such increased dispersity after drug conjugation is partially
attributable to the distribution of ONB-Cipro molecules
Fig.
3
(A, B) Overlaid SPR sensorgrams of
3 G5(EA)40(ONB-Cipro)8.5 and 4
G5(PMB)1.1(ONB-Cipro)8.5 binding to
a
LPS-immobilized cell wall model surface.
attached to the dendrimer (Fig. S5). Hydrodynamic size (Zave
)
Experimental (solid line); simulated global fit (dotted line). (C, D) Confocal fluorescence
and zeta potential (ZP) measurements of
3 and 4 (Table S2)
images of E. coli treated with the control dendrimer FITC-G5(GA)16 (C) or with FITC-4
2 | J. Name., 2012, 00, 1-3
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G5(PMB)1.1(ONB-Cipro)8.5 (D). Inset: an enlarged view. FITC fluorescence is shown
(green). Bacterial cells were also stained with SYTO59 (red).
AUC analysis of each UPLC trace. (C, D) UPLC and UV–vis traces (inset, top) measured
for the release kinetics of 3 and 4 (31.7 M in water) as a function of UV exposure time.
DOI: 10.1039/C6CC05179K
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without the photocaged ciprofloxacin (ONB-Cipro), 8.2 × 10−4 s−1. After 30 min of irradiation, 80% release of
demonstrating that the attached ONB-Cipro does not affect ciprofloxacin from ONB-Cipro was achieved.
the binding avidity. In addition, SPR experiments performed Light-controlled ciprofloxacin release was next investigated
using a model surface for Gram(+) bacteria (immobilized with for conjugates G5(ONB-Cipro)8.5 and G5(PMB)1.1(ONB-
2
3
4
(D)-Ala-(D)-Ala) demonstrated a lack of binding by conjugate
or , supporting their LPS-targeting specificity (Fig. S6).
3
Cipro)8.5 and monitored by UPLC and UV–vis spectrometry (Fig.
4C, 4D). Overlaid UPLC traces acquired for each conjugate after
4
We investigated the binding of fluorescein 5(6)- UV exposure showed a sharp peak for free ciprofloxacin (tR =
isothiocyanate (FITC)-labeled conjugate to Escherichia coli 7.2 min) which grew within the broad dendrimer peak.
(XL-1) by confocal fluorescence microscopy (Fig. 3C, 3D). E. coli Ciprofloxacin release was also evidenced by the shift in the
treated with FITC-labeled showed intense areas of green broad dendrimer peaks to faster retention times over the
4
4
fluorescence, indicating adsorption of conjugate to the cell course of UV exposure, reflecting their reduction to smaller
wall. In contrast, a negatively charged control dendrimer FITC- NPs due to the loss of the drug payload. No significant fraction
G5(GA)16 lacking
adsorption. Treatment with
a
targeting ligand did not show any of intact
3 was observed after ≥15 min of irradiation. UV–vis
4
led to aggregates of E. coli which spectral traces (top, inset) acquired over the irradiation time
might be attributable to crosslinking of the multivalent course showed a notable change in the absorbance at 280 nm
dendrimers with multiple cells.4, 16
which reflects photocleavage of the ONB linker (quantum
The photochemical release of ciprofloxacin from
2
ONB- efficiency Φ = 0.29)32 as observed in other drug release
Cipro was evaluated by exposing it to UVA light (365 nm; systems.32-34 These analyses demonstrate the effectiveness of
exposure time = 0–30 min) followed by reversed phase UPLC UV in the active control of ciprofloxacin release from its ONB
analysis of the photolysed product as a function of exposure photocaged form on LPS-targeted dendrimers
time (Fig. 4A). After brief irradiation, a new peak appeared We then investigated the light-controlled bactericidal
with a retention time of tR = 7.2 min which was identical to activity of conjugates and
using a turbidity assay.16 The
3 and 4.
3
4
that of free ciprofloxacin. The peak grew as a function of optical density at 650 nm (OD650) of E. coli cultures treated
exposure time with the concomitant consumption of ONB- with the conjugates was measured over time. A drop in OD
Cipro
2 (tR = 9.5 min). Area under the curve (AUC) analysis (Fig. reflects a decrease in bacterial viability. Fig. 5A shows control
4B) provided a half-life (t1/2) of 15 min for the decay of ONB- experiments involving free ciprofloxacin, photocaged
Cipro which occurred with a first-order rate constant of
ciprofloxacin (2) and a control dendrimer. Free ciprofloxacin
displayed potent antibacterial activity with an MIC50 value of
80 nM (lit. MIC50 = 94 nM39). In contrast, a glutarate-
terminated control dendrimer lacking the conjugated drug
G5(GA) showed no significant effect on the cell viability at
concentrations of up to 2.5
the activity of free ciprofloxacin or the dendrimer control.
However ONB-Cipro showed bactericidal activity as potent as
M. UVA exposure did not impact
2
free Cipro after UVA exposure, demonstrating the efficient
release of drug in a functional form by long wavelength UV
(365 nm). Fig. 5B summarizes the viability of E. coli treated
with conjugates 3 or 4, each carrying photocaged ciprofloxacin.
Unlike bactericidal UVC (200–280 nm), exposure to longer
wavelength UVA (315–400 nm) alone had no effect on the
viability of untreated bacterial cells (Fig. 5B).30 Likewise
treatment of bacterial cells with each conjugate without UV
exposure (−UV) led to minimal changes in viability. These
results suggest that tight LPS binding by each conjugate is
insufficient for cytotoxicity, likely due to poor penetration of
the conjugate into the inner cell wall structure and/or to the
lack of intracellular ciprofloxacin release if uptake occurs (Fig.
1). In contrast, treatment of bacteria with
3 and 4 with
concomitant UVA irradiation for 30 min dramatically increased
the antibacterial efficacy of the conjugates. This decrease
occurred as a function of dose with an MIC50 value of ≈ 230 nM
Fig. 4 Light-controlled release of ciprofloxacin from ONB-Cipro 2 (top) or from the ONB-
Cipro conjugated G5 dendrimer 4 (bottom) through cleavage of the ONB cage. (A) UPLC
traces for release kinetics of Cipro by UVA (365 nm) irradiation of 2 (0.13 mM in 10%
aq. MeOH), and (B) a plot of Cipro release (%) against exposure time determined by
(2.0
M) on a dendrimer (or Cipro) basis. Although this
antibacterial activity is lower than that of free ciprofloxacin,
perhaps in part due to incomplete drug release, these results
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A Graphical and Textual Abstract
DOI: 10.1039/C6CC05179K
We report a light-controlled release mechanism for photocaged
ciprofloxacin carried by a cell wall-targeted dendrimer nanoconjugate.
Validation of this bacteria-targeted strategy adds a novel modality to
existing light-based therapies for wound treatments.
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