High Drug Loading and Sub-Quantitative Loading Efficiency of Polymeric Micelles Driven by Donor-Receptor Coordination Interactions

Article abstract of DOI:10.1021/jacs.7b12776

Polymeric micelles are extensively used for the delivery of hydrophobic drugs, which, however, suffer from unsatisfactory drug loading, colloidal uniformity, formulation stability, and drug release. Herein, we demonstrate a convenient strategy to prepare micelles with ultrahigh drug loading via the incorporation of polymer-drug coordination interactions. An amphiphilic copolymer containing pendant phenylboronic acid as electron acceptor unit was synthesized, which afforded donor-acceptor coordination with doxorubicin to obtain micelles with ultrahigh drug loading (～50%), nearly quantitative loading efficiency (>95%), uniform size, and colloidal stability. Besides, the encapsulated drug can be effectively and selectively released in response to the high reactive oxygen species levels in cancer cells, which potentiated the anticancer efficacy and reduced systemic toxicity. Apart from doxorubicin, the current platform could be extended to other drugs with electron-donating groups (e.g., epirubicin and irinotecan), rendering a simple and robust strategy for enabling high drug loading in polymeric micelles and cancer-specific drug release.

Full text of DOI:10.1021/jacs.7b12776

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Communication
High Drug Loading and Sub-Quantitative Loading Efficiency of
Polymeric Micelles Driven by Donor-Receptor Coordination Interactions
Shixian Lv, Yuchen Wu, Kaimin Cai, Hua He, Yongjuan
Li, Min Lan, Xuesi Chen, Jianjun Cheng, and Lichen Yin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12776 • Publication Date (Web): 13 Jan 2018
Downloaded from http://pubs.acs.org on January 13, 2018
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High Drug Loading and Sub-Quantitative Loading Efficiency of Pol-
ymeric Micelles Driven by Donor-Receptor Coordination Interactions
Shixian Lv,†,‡ Yuchen Wu,† Kaimin Cai,‡ Hua He,† Yongjuan Li,† Min Lan,† Xuesi Chen,§ Jianjun
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Cheng,‡ Lichen Yin*,†
† Jiangsu Key Laboratory for CarbonꢀBased Functional Materials and Devices, Institute of Functional Nano and Soft Materiꢀ
als (FUNSOM), Collaborative Innovation Center of Suzhou Nano Science and Technology, Joint International Research
Laboratory of CarbonꢀBased Functional Materials and Devices, Soochow University, Suzhou, 215123, China
‡ Department of Materials Science and Engineering, University of Illinois at UrbanaꢀChampaign, Urbana, Illinois, 61801,
United States
§
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun, 130022, China
Supporting Information Placeholder
drug loading, and controlled drug release via the introduction of
ABSTRACT: Polymeric micelles are extensively used for the
coordination interactions between the drug and polymeric carrier.
delivery of hydrophobic drugs, which however, suffer from unsatꢀ
isfactory drug loading, colloidal uniformity, formulation stability,
and drug release. Herein, we demonstrate a convenient strategy to
prepare micelles with ultraꢀhigh drug loading via the incorporaꢀ
tion of polymerꢀdrug coordination interactions. An amphiphilic
copolymer containing pendant phenylboronic acid as electron
acceptor unit was synthesized, which afforded donorꢀacceptor
coordination with doxorubicin to obtain micelles with ultraꢀhigh
drug loading (~50%), nearly quantitative loading efficiency
(>95%), uniform size, and colloidal stability. Besides, the encapꢀ
sulated drug can be effectively and selectively released in reꢀ
sponse to the high reactive oxygen species levels in cancer cells,
which potentiated the antiꢀcancer efficacy and reduced systemic
toxicity. Apart from doxorubicin, the current platform could be
extended to other drugs with electronꢀdonating groups (e.g., epiꢀ
rubicin and irinotecan), rendering a simple and robust strategy for
enabling high drug loading in polymeric micelles and cancerꢀ
specific drug release.
Scheme 1. Schematic illustration of the encapsulation of hydroꢀ
phobic drugs into polymeric micelles. (a) Unwanted formation of
drug aggregates during drug loading via hydrophobic interactions.
(b) Quantitative and high drug loading enabled via specific drugꢀ
polymer coordination interactions.
Polymerꢀdrug interaction dominates the formulation of drugꢀ
incorporated micelles. Hydrophobic interaction between the drug
and polymer is the major driving force for drug encapsulation.
However, the hydrophobic interaction is nonꢀspecific, which also
occurs among free drug molecules. Therefore, undesired drug
aggregation happens during the selfꢀassembly process, which
decreases the drug loading efficiency and heterogeneity of the
formulation (Scheme 1a). Altering the molecular structure of
chemoꢀdrugs serves as an efficient approach to achieve high drug
loading via inhibition of drug aggregation, which, however, inꢀ
volves complicated chemical synthesis.8 As an alternative, enꢀ
hancing the drugꢀpolymer interaction may provide a more conꢀ
venient way (Scheme 1b). To this end, introduction of suitable
molecular forces that can specifically enhance the polymerꢀdrug
interaction is highly demanded.
Micellar nanoparticles (NPs) formed via the selfꢀassembly of
amphiphilic polymers represent an important delivery platform for
hydrophobic chemoꢀdrugs.1 Micelles with coreꢀshell nanostrucꢀ
ture encapsulate the hydrophobic drug in the core, and the hydroꢀ
philic shell enhances the colloidal stability in physiological fluꢀ
ids.2 While polymeric nanomedicine (NM) has been extensively
studied, their clinical translation is still hurdled by the various
formulation challenges including drug loading, release profile,
size distribution, and stability.3 Micellar NMs usually demonstrate
unsatisfactory drug loading,4 exemplified by the typical low drug
loading capacity (< 5%) for chemoꢀdrugs, such as doxorubicin
(DOX) and camptothecin (CPT).5 Although few highꢀdrugꢀ
loading micelles have been prepared from drugꢀdrug conjugate or
prodrug, it is still of great difficulty to achieve high drug loading
for most polymeric micelles.6 In addition, unsatisfactory drug
release and formulation stability greatly limit the application of
polymeric micelles.7 We herein report a facile approach to prepare
polymeric micelles with quantitative loading efficiency, ultraꢀhigh
Donorꢀacceptor interaction, also known as coordination bondꢀ
ing, is a common molecular force between electron donors and
acceptors including πꢀdonor/organometallics or Lewis baꢀ
ses/acids. This interaction widely exists in material systems and is
extensively utilized for catalysis or assembly.9 The donorꢀ
acceptor bond energy is usually weaker than covalent bonds while
stronger than hydrophobic interactions. As such, we hypothesize
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that the donorꢀacceptor coordination could be incorporated into
was first studied by 11B NMR in deuterated dimethylformamide
(DMFꢀd7). PBA showed the typical chemical shift of aryl boronic
acid/ester at 29ꢀ30 ppm (Figure 1b). After interaction with DOX,
peak shift to high field (~20 ppm) appeared due to coordination of
PBA with the nitrogen atom of DOX.10 The peak shift remained
after addition of water, indicating aqueous stability of the coordiꢀ
nation interaction. Subsequently, drug loading by PꢀCBZ and Pꢀ
PBA micelles was studied using the nanoprecipitation method.
Upon coꢀprecipitation of DOX with PꢀCBZ at 1:1 (w/w), micromꢀ
eterꢀsized drug precipitates immediately appeared and multiple
distributions were observed in the dynamic light scattering (DLS)
diagrams. Such formulation heterogeneity was still observed
when the drug/polymer ratio was decreased to 1:5 (w/w) (Figure
1c). On the contrary, no largeꢀsized precipitate was observed for
PꢀPBA micelles, obtaining homogeneous micelles with small size
(< 50 nm) and monomodal distributions at various DOX/PꢀPBA
feeding ratios (Figure 1d and Table S2). Due to excessive drug
aggregation, PꢀCBZ micelles showed low drug loading content
(DLC, ~3%) and drug loading efficiency (DLE, 7~20%). Comꢀ
paratively, PꢀPBA micelles demonstrated dramatically improved
DLC (~50%) along with ~100% DLE (Table 1). Such discrepancy
clearly evidenced the advantage of coordination interactionꢀ
mediated drug loading over traditional mechanisms via hydrophoꢀ
bic interactions.
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the polymerꢀdrug interaction to yield micelles with high drug
loading and uniform distribution (Scheme 1b). Because of the
reversible nature of the coordination bond, it will not alter the
molecular structure of drugs.10 A wide range of Lewis acids/bases
can be incorporated, which features synthetic simplicity and
chemical diversity to manipulate the polymer structure for conꢀ
trolled drug release.
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Table 1. DLC and DLE of different micelles
Drug/poly
mer (w/w)
1:5
DLC
(%)
3.3
DLE
(%)
19.8
11.1
8.8
Micelles
Polymer
PCꢀDOXꢀ1
PCꢀDOXꢀ2
PCꢀDOXꢀ3
PCꢀDOXꢀ4
PBꢀDOXꢀ1
PBꢀDOXꢀ2
PBꢀDOXꢀ3
PBꢀDOXꢀ4
PꢀCBZ
PꢀCBZ
PꢀCBZ
PꢀCBZ
PꢀPBA
PꢀPBA
PꢀPBA
PꢀPBA
Figure 1. (a) Design of a typical amphiphilic copolymer containꢀ
ing electron accepter. (b) 11B NMR spectra of PBA and
PBA&DOX. Intensity size distributions of DOXꢀloaded PꢀCBZ (c)
and PꢀPBA (d) micelles.
1:2
3.7
1:1.5
1:1
3.5
3.3
6.6
In support of such hypothesis, boronic acid, a common Lewis
acid, is of particular interest due to its ability to form reversible
interactions with donor atoms (e.g., oxygen and nitrogen).9a,11
More importantly, the boronic acids/esters such as phenylboronic
acid (PBA) are sensitive to reactive oxygen species (ROS) that are
overꢀproduced in cancer cells.12 As such, PBAꢀincorporated amꢀ
phiphilic copolymers would afford specific and strong coordinaꢀ
tion interactions with electronꢀdonating chemoꢀdrugs to enhance
their loading. In cancer cells, the excessive ROS could selectively
release the drug, thus potentiating their antiꢀtumor efficacy while
reducing systemic toxicity.
1:5
17.4
33.4
40.0
49.0
>99
>99
>99
98
1:2
1:1.5
1:1
The distinct drug loading performance of PꢀCBZ and PꢀPBA
micelles might be largely attributed to their different interactions
with drug molecules. The donorꢀacceptor coordination between
drug and PꢀPBA can stabilize the polymerꢀdrug complex, elimiꢀ
nate drug aggregation, and thereby drive the quantitative drug
loading (Scheme 1b). One possible concern was whether covalent
bonds would form, which would otherwise inhibit the drug release
(Scheme S2). To answer this question, we analyzed the mass
spectrum of the PBAꢀDOX mixture in DMF, which revealed no
stable covalent bonding (Figure S7). Highꢀperformance liquid
chromatography (HPLC) analysis further confirmed such finding.
DOX/PBA mixture and PBꢀDOXꢀ2 micelles showed similar eluꢀ
tion peaks (Figure S8 and S9), probably due to destruction of the
PBAꢀDOX coordination in the acidic mobile phase, which further
demonstrated reversibility of the coordination interaction. These
results collectively indicated that coordination interaction rather
than covalent bonding contributed to the high drug loading, withꢀ
out altering the chemical structure of the drug payloads.
To realize such design strategy, we synthesized amphiphilic
copolymer bearing pendant PBA moieties on the sideꢀchain terꢀ
minals of the hydrophobic segment. A nonꢀcharged and biocomꢀ
patible scaffold, methoxy poly(ethylene glycol)ꢀbꢀpolyꢀ[(Nꢀ2ꢀ
hydroxyethyl)ꢀaspartamide] (mPEG113ꢀbꢀPHEA21) was obtained
through the aminolysis of mPEGꢀb-poly(γꢀbenzylꢀLꢀaspartate)
(mPEGꢀbꢀPBLA) with ethanolamine (Scheme S1, Figure S1ꢀ
S2).13 mPEGꢀbꢀPHEA was modified with 4ꢀ(hydroxymethyl)
phenylboronic acid pinacol carbonylimidazole to obtain amꢀ
phiphilic copolymer, PꢀPBA (Figure 1a). The pendant PBA moieꢀ
ties could serve as electron acceptors for coordination interactions
with chemoꢀdrugs. As a control, mPEGꢀbꢀPHEA was also modiꢀ
fied by benzyl carbonylimidazole to obtain PꢀCBZ that contained
the hydrophobic benzyl side groups with no electron accepting
capability (Figure 1a). PꢀPBA and PꢀCBZ had similar amount of
hydrophobic groups on the side chains (9~10 benzyl or PBA moiꢀ
eties per polymer, Figure S3ꢀS6 and Table S1), and the only difꢀ
ference was the electron accepting/donating capability.
We next studied the lyophilization stability and serum stability
of the drugꢀloaded micelles, two important requirements for NM.
Lyophilized PBꢀDOXꢀ2 micelles were well dispersed in phosꢀ
phate buffered saline (PBS) at 10 mg DOX/mL (Figure S10),
affording small size (< 50 nm) and monomodal distribution (Taꢀ
ble S2). Transmission electron microscopy (TEM) observation
further revealed unaltered morphology and dispersity of micelles
DOX was selected as a model hydrophobic drug which posꢀ
sessed electron donor groups (primary amine) to interact with
boronic acid on PꢀPBA. The interaction between DOX and PBA
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after lyophilization (Figure S11). In addition, size of the PBꢀ
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DOXꢀ2 micelles maintained constant upon 48ꢀh incubation in
PBS with or without 10% serum (Figure S12), revealing desired
colloidal stability.
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Figure 3. (a) 11B NMR spectra of the mixture of PBA and differꢀ
ent amines (molar ratio = 1:2) in DMFꢀd7/D2O (v/v = 1:2). (b)
Drug loading of PꢀPBA micelles for different chemoꢀdrugs (N.D.,
not determined due to excessive drug aggregation).
We next investigated whether the current strategy can be utiꢀ
lized for other chemoꢀdrugs with electron donors. Firstly, PBA
was allowed to interact with various amines. 11B NMR spectra
showed that the chemical shift of PBA in DMFꢀd7/D2O moved to
high field after addition of primary, secondary, or tertiary amine,
indicating formation of donorꢀacceptor interaction (Figure 3a). No
obvious change of the chemical shift was observed in the case of
phenylamine or pyridine, probably due to their weak electron
donating ability. Such result thus indicated the selectivity of donor
type toward coordination interaction. Three representative chemoꢀ
drugs, epirubicin (EPI), irinotecan (IR), and CPT, were then tested
for drug loading in PꢀPBA micelles. As an analogue of DOX, EPI
could be encapsulated with quantitatively high loading (~51%,
Figure 3b). IR, a CPT derivative with tertiary amine, can also be
encapsulated with high drug loading. As expected, CPT that lacks
electron donors cannot be encapsulated.
Figure 2. (a) Schematic illustration of H2O2ꢀtriggered removal of
PBA moiety from the polymer. (b) H NMR spectra of PꢀPBA
micelles after H2O2 treatment. (c) In vitro drug release profiles of
PBꢀDOXꢀ2 micelles (n = 3). (d) Cytotoxicity of DOXꢀloaded
micelles toward HeLa cells after 48ꢀh incubation (n = 3).
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Arylboronic esters could be oxidized by ROS (e.g., H2O2) and
then undergo rearrangement to unmask the modified group (Figꢀ
ure 2a).12a,14 Thus, we investigated the H2O2ꢀtriggered removal of
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PBA groups by H NMR. Due to the coreꢀshell structure, PꢀPBA
micelles in D2O only showed the PEG peak (Figure 2b). After
H2O2 treatment, peaks of 4ꢀ(hydroxymethyl)phenol and mPEGꢀbꢀ
PHEA appeared, demonstrating disassembly of the micelles. The
peak intensity of the degraded products increased with incubation
time (Figure 2b), leading to removal of ~80% PBA groups after
60ꢀh incubation. H2O2 treatment (100 µM) significantly increased
the size of DOXꢀloaded PꢀPBA micelles, and almost no DLS
signals were detected after 48ꢀh incubation, indicating disassemꢀ
bly of the micelles (Figure S13). Consistently, H2O2 (100 µM)
also promoted DOX release, leading to an accumulative drug
release of ~75% within 48 h (Figure 2c). As a nonꢀresponsive
analogue, DOX release from PꢀCBZ micelles were not affected by
H2O2 (Figure S14). Acidic pH also accelerated the drug release
from PꢀPBA micelles, presumably due to the protonation of DOX
that destroyed the coordination interaction (Figure 2c).
In conclusion, we for the first time reported a convenient stratꢀ
egy to prepare micelles with high drug loading via the incorporaꢀ
tion of coordination interactions between electron acceptorꢀ
containing polymers and electron donorꢀcontaining chemoꢀdrugs.
The micelles afforded ultraꢀhigh drug loading (up to 50%) and
nearly 100% loading efficiency for various chemoꢀdrugs, along
with uniform distribution and desired lyophilization stability.
Additionally, the encapsulated drug can be selectively released in
response to the high ROS levels in cancer cells. To the best of our
knowledge, high drug loading with quantitative loading efficiency
has rarely been reported for polymeric micelles with such a conꢀ
venient method. Without complicated carrier design or drug modiꢀ
fication, this approach affords a simple and robust strategy for the
encapsulation of hydrophobic drugs, which will benefit further
application of polymeric NM.
The in vitro cytotoxicity of the blank and DOXꢀloaded micelles
was then investigated. mPEGꢀbꢀPHEA, PꢀCBZ, and PꢀPBA were
almost nonꢀtoxic to HeLa, B16F10, HepG2, and NIH/3T3 cells at
concentrations up to 1 mg/mL (Figure S15 and S16). In compariꢀ
son, PBꢀDOXꢀ2 micelles demonstrated doseꢀdependent cytotoxiꢀ
city to HeLa cells (Figure 2d), achieving an IC50 value of 0.60
ꢁg/mL, similar to that of free DOX (0.43 ꢁg/mL). As a nonꢀ
responsive analogue, PCꢀDOXꢀ1 micelles showed notably higher
IC50 (1.22 ꢁg/mL). Such discrepancy was further noted in other
two cancer cell lines (HepG2 and B16F10), which was largely
attributed to the ROSꢀmediated rapid release of DOX from PBꢀ
DOXꢀ2 micelles but not PCꢀDOXꢀ1 micelles (Figure S18). In
support of such observation, PBꢀDOXꢀ2 micelles only showed
slightly stronger cytotoxicity than PCꢀDOXꢀ1 micelles in
NIH/3T3 cells (normal cell), due to the lack of intracellular ROS
to trigger DOX release from PBꢀDOXꢀ2 micelles (Figure S18).
Because of the cancer cellꢀselective drug release, PBꢀDOXꢀ2
micelles showed desired animal tolerance at the maximal tolerated
dose (MTD) of ~40 mg DOX/kg (Figure S19), 8ꢀfold higher than
that of free DOX (Figure S20).
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterizations are included in
supporting information. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
lcyin@suda.edu.cn.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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This work was supported by National Natural Science Foundation
of China (51403145, 51573123, and 51603137), the Ministry of
Science and Technology of China (2016YFA0201200), China
Postdoctoral Science Foundation (7131705316), and Priority Acꢀ
ademic Program Development of Jiangsu Higher Education Instiꢀ
tutions (PAPD).
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