Paclitaxel-initiated, controlled polymerization of lactide for the formulation of polymeric nanoparticulate delivery vehicles

Article abstract of DOI:10.1002/anie.200800491

(Chemical Equation Presented) Paclitaxel-polylactide nanoconjugates were prepared by the site-specific polymerization of lactide mediated by a paclitaxel-metal complex followed by nanoprecipitation (see scheme). The resulting nanoconjugates have nearly 100% paclitaxel incorporation efficiencies and predefined drug loadings, and are less than 100 nm in diameter. The drug burst release effect is completely eliminated with this drug delivery vehicle.

Full text of DOI:10.1002/anie.200800491

Communications
DOI: 10.1002/anie.200800491
Drug Delivery
Paclitaxel-Initiated, Controlled Polymerization of
Lactide for the Formulation of Polymeric
Nanoparticulate Delivery Vehicles**
Rong Tong and Jianjun Cheng*
Angewandte
Chemie
4830
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Chemie
Paclitaxel (Ptxl) is a potent chemothera-
peutic agent. However, clinical applica-
tion of Ptxl is often accompanied by
severe, undesirable side effects.[1] To
reduce the side effects, various nanopar-
ticulate delivery vehicles have been devel-
oped and investigated in the past
decade.[2–5] Of the various nanoparticles
(NPs) being studied, polymeric nanoen-
capsulates (NEs), NPs prepared by copre-
cipitating hydrophobic polymers and
drugs, hold particular promise because
of their ease of formulation and the
potential control of drug release through
the degradation of polymers.[6,7] However,
current NEs typically have low drug
loadings, uncontrolled encapsulation effi-
ciencies, and significant drug burst release
effects when used in vivo.[8–11] These
formulation challenges significantly limit
their potential clinical applications. Here,
we report the use of living polymerization
to facilitate the controlled preparation of
Ptxl–polylactide(PLA)-conjugated NPs
with predefined drug loadings, nearly
quantitative loading efficiencies, and con-
trolled release kinetics without burst
release effects.
Figure 1. Preparation of poly(ethyleneglycol)ated (PEGylated) Ptxl–PLA NCs by means of Ptxl-
initiated LA polymerization in the presence of [(BDI)MN(TMS)2] (M=Mg, Zn), followed by
nanoprecipitation and noncovalent surface modification with poly(glycolide-co-lactide)-b-
methoxylated PEG (PLGA-mPEG) (PLGA-mPEG).
Metal alkoxides (MORs) are well-known initiators for the
living polymerizations of cyclic esters, such as dl-lactide (LA)
used in this study (Figure 1).[12] They can be prepared in situ
by mixing a hydroxy-group-containing compound with an
active metal complex, such as a metal–amido complex.[13] If
well designed, the MORs formed in situ can initiate con-
trolled polymerization of LA, resulting in quantitative
incorporation of the alkoxide (OR) to the PLA terminals
with 100% monomer conversion.[12] Since Ptxl has multiple
hydroxy groups, we postulated that it may be incorporated
into polyesters through the metal–Ptxl-mediated polymeri-
zation of LA (Figure 1). Drug loadings can thus be precisely
controlled by adjusting the LA/Ptxl ratio. The incorporation
efficiency of Ptxl into the resulting PLA should be 100% as
the formation of the metal complex is usually quantitative.
After polymerization, Ptxl molecules are covalently linked to
the terminals of PLA through a hydrolyzable ester linker and
are subject to sustained release upon hydrolysis. Followed by
nanoprecipitation (Figure 1), polymeric NPs containing cova-
lently linked Ptxl should be readily obtained.
To demonstrate this concept, we utilized [(BDI)MgN-
(TMS)2](BDI
= 2-((2,6-diisopropylphenyl)amino)-4-((2,6-
diisopropylphenyl)imino)-2-pentene, TMS = trimethylsilyl)
(Figure 1), an active catalyst developed by Coates and co-
workers for the polymerization of LA.[13] After Ptxl was
mixed with 1 equiv of [(BDI)MgN(TMS)2], the (BDI)Mg–
Ptxl complex formed in situ (structure uncharacterized;
tentatively illustrated as a monomeric Mg–Ptxl complex in
Figure 1) initiated and completed the polymerization of LA
within hours at room temperature; the resulting PLA had
nearly quantitative incorporation of Ptxl (entries 1–4,
Table 1). The incorporated Ptxl was released in its original
form along with degradation species after the Ptxl–PLA was
treated with 1m NaOH (see Figure 1 in the Supplementary
Information), which demonstrated that Ptxl was linked to
PLA through an ester bond. Nanoprecipitation of the Ptxl–
PLA conjugates resulted in NPs less than 100 nm in diameter
(Table 1). To differentiate these from NEs, these NPs derived
from nanoprecipitation of Ptxl–PLA conjugates are called
nanoconjugates (NCs); PLA is denoted as LAn where n is
derived from the LA/Ptxl ratio.
[*] R. Tong, Prof. Dr. J. Cheng
Department of Materials Science and Engineering
University of Illinois at Urbana-Champaign
Urbana, IL 61801 (USA)
Fax: (+1)217-333-2736
E-mail: jianjunc@uiuc.edu
[**] This work was supported by the University of Illinois at Urbana-
Champaign (UIUC), the Siteman Center for Cancer Nanotechnology
Excellence (SCCNE, Washington University)-Center for Nanoscale
Science and Technology (CNST, UIUC), the Prostate Cancer
Foundation Competitive Award, and the National Science Founda-
tion Career Award Program (DMR0748834). R.T. acknowledges a
student fellowship from SCCNE-CNST. We thank Dr. Jian-guo Wen
and Prof. Jian-Min Zuo for their help on TEM analysis, Prof. Martin
Burke and Prof. Jeffrey Moore for providing anhydrous solvents, and
Dr. Daniel Pack for letting us use his ZetaPals particle-size analyzer.
NEs prepared from nanoprecipitation are usually poly-
disperse with multimodal distributions.[7,10] Interestingly, NCs
with monomodal particle distributions and low polydisper-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Formation of drug–PLA nanoconjugates with high loadings, high incorporation efficiencies,
solution of the Ptxl–PLA conjugate in
DMF is typically in a range of 60–
100 nm; these particles are 20–30 nm
smaller than those prepared with acetone
or THF as solvent (data not shown).[10]
When the nanoprecipitation was carried
out with DMF as the solvent and a DMF/
water ratio of 1:20 (v/v), the size of Ptxl–
LA200 NCs showed a linear correlation
with the concentration of Ptxl–LA200
conjugate and can be precisely tuned
from 60 nm to 100 nm by changing the
concentration of Ptxl–LA200 (see
Figure 2 in the Supporting Information).
Drug burst release is a long-standing
formulation challenge of NEs and leads
small particle sizes, and low particle distributions.[a]
Entry
NC[b]
M/I
Loading
[wt%]
LA conv.
[%][c]
Incorp.
NC size [nm]
PDI
eff. [%][d]
1
2
3
4
5
6
Ptxl–LA100
Ptxl–LA50
Ptxl–LA25
Ptxl–LA15
Dtxl–LA10
CPT–LA10
100
50
25
15
10
10
5.6
10.6
19.2
28.3
35.9
19.5
>99
>99
>99
>99
>99
>99
>99
>99
97
95
95
95.1Æ2.7
80.6Æ0.2
55.6Æ0.5
85.5Æ1.4
77.9Æ1.5
72.5Æ0.7
0.04Æ0.01
0.05Æ0.01
0.04Æ0.01
0.09Æ0.03
0.06Æ0.02
0.06Æ0.02
96
[a] Abbreviations: M/I=monomer/initiator ratio, NC=nanoconjugates, LA conv.=lactide conversion,
Incorp. eff.=incorporation efficiency, PDI=polydispersity derived from particle sizing using dynamic
light-scattering, Ptxl=paclitaxel, Dtxl=docetaxel, CPT=camptothecin. [b] NCs are named as drug–
LAM/I. [c] Determined by analyzing the unreacted lactide using FTIR (band at 1771 cmÀ1) or using
1H NMR spectroscopy; [d] Based on reversed-phase HPLC analysis of unincorporated drug.
sities (entries 1–4, Table 1), exemplified by the Ptxl–LA25 NC
(Figure 2a), were consistently obtained through the nano-
precipitation of Ptxl–PLA conjugates. As the multimodal
distribution of NEs is due in part to the aggregation of the
non-encapsulated free drug,[10] the monomodal distribution
observed with NCs is likely related to the unimolecular
structures of Ptxl–PLA conjugates.
Both the solvent and the concentration of the polymer
have dramatic effects on the size of the NPs prepared by
nanoprecipitation. At a fixed concentration of the Ptxl–PLA
conjugate, the size of the NCs prepared by precipitating a
to undesirable side effects and reduced therapeutic efficacy.[11]
Conventional NEs typically “burst release” 60–90% of their
payloads within a few to tens of hours because the release of
drug is controlled solely by diffusion.[14] Since the Ptxl release
kinetics of Ptxl–PLA NCs is determined not only by diffusion
but also by the hydrolysis of the Ptxl–PLA ester linker, the
release of Ptxl from NCs is more controllable and with a
significantly reduced burst release effect (Figure 2b). The
amount of Ptxl released from Ptxl–LA50 (10.6 wt%) and Ptxl–
LA25 (19.2 wt%) was 7.0% and 8.7% at day 1, and 43% and
70.4% at day 6, respectively. In comparison, 82% of Ptxl was
released within 24 h from Ptxl–PLA NE
(Figure 2b). The release of Ptxl from
Ptxl–LA50 NC was slower than that from
Ptxl–LA25 NC, presumably because of the
higher molecular weight of Ptxl–LA50 and
more compact aggregation in the particle.
The in vitro toxicities of NCs are
correlated to the amount of Ptxl released;
they show strong correlation with drug
loadings (Figure 2c). The IC50 values of
Ptxl–LA15, Ptxl–LA25 and Ptxl–LA50 NCs
with similar sizes ( ꢀ 100 nm), which were
determined by MTT (MTT= 3-(4,5-dime-
thylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) assays in PC-3 cells, are 111,
370, and 855 nm, respectively. The IC50
value of Ptxl–LA15 NC is nearly identical
to that of free Ptxl (87 nm), while the IC50
value of the Ptxl–LA50 NC is an order of
magnitude higher. As a result, the toxicity
of the NCs can be tuned in a wide range
simply by controlling NC drug loading.
Surface modification of NPs with
poly(ethylene glycol) (PEG) is widely
used for prolonged systemic circulation
Figure 2. Characterization and properties of Ptxl–PLA NCs. a) Ptxl–LA25 (paclitaxel–PLA NC
prepared at a LA/Ptxl ratio of 25:1) analyzed by scanning electron microscopy (SEM) and
dynamic light scattering (DLS, inset). Scale bar=150 nm. b) Release kinetics of Ptxl from
Ptxl–PLA NCs and Ptxl–PLA NE (prepared by nanoprecipitating a mixture of Ptxl and PLA
(Ptxl/PLA (wt/wt)=1:12) at 378C in 1”PBS. c) Toxicity evaluation of Ptxl–LA50 NC, Ptxl–LA25
NC, Ptxl–LA10 NC, and Ptxl using MTT assay in PC-3 cells after incubation for 24 h.
Significance at 95% confidence interval is marked with an asterisck (*). d) Stability of Ptxl–
LA200 NC in PBS at 378C before and after being treated with PLGA–mPEG5k or mPEG5k.
and reduced aggregation of NPs in
blood.[15] To reduce the efforts of remov-
ing unreacted reagents and by-products,
we attempted to use
a noncovalent
approach to PEGylate the NC surface
instead of covalently conjugating PEG to
the NCs.[5,7] We used poly(glycolide-co-
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lactide)-b-methoxylated PEG (PLGA-mPEG), an amphi-
philic copolymer that has a 13 kDa PLGA and a 5 kDa PEG
segment,[16] to PEGylate the NCs. It is expected that the
PLGA block forms strong hydrophobic interactions with the
NC to create a stable PEG shell (Figure 1). A similar
approach has been used previously for the surface PEGyla-
tion of NPs.[17] Sequential addition of 0.4 to 2 equiv (in mass)
of PLGA-mPEG to Ptxl–LA200 resulted in a linear increase in
particle size from 54.5 nm to 100.3 nm (see Figure 3 in the
Supporting Information).
Ptxl–LAn NCs have negative surface zeta potential and thus
remain nonaggregated in water as a result of surface charge
repulsion. However, aggregation of NCs occurred immediately
after they were added to phosphate-buffered saline (PBS),
presumably because of the salt-induced screening of the
repulsive forces.[18] The PLGA-mPEG modified Ptxl–LA200
NCs were significantly more stable in PBS than the untreated
NCs or NCs treated with mPEG (Figure 2d), indicating the
importance of the hydrophobic PLGA segment to the non-
covalent interaction between PLGA-mPEG and NCs.
Ptxl has hydroxy groups at its C2’, C1, and C7 positions
(Figure 3a). Any of these three hydroxy groups can poten-
tially initiate LA polymerizations, resulting in Ptxl–PLA
conjugates with one to three PLA chains attached to Ptxl. To
reduce the heterogeneity of Ptxl–PLA, we investigated
whether the initiation can be controlled at a specific hydroxy
group of Ptxl to make a Ptxl–PLA conjugate containing a
single PLA chain (as illustrated in Figure 1).
The steric environments of the three hydroxy groups of
Ptxl differ in terms of steric hindrance in the order of 2’-OH <
7-OH < 1-OH. The tertiary 1-OH group is least accessible and
typically inactive.[19] The 7-OH group, however, could poten-
tially compete with the 2’-OH group,[20] the most accessible
and active hydroxy group of Ptxl, for coordination with metal
catalyst. We postulated that a metal catalyst with a bulky
chelating ligand may differentiate between the 2’-OH and
7-OH groups, and thus preferentially or even specifically form
a Ptxl–metal complex through the 2’-OH group for site-
specific LA polymerization.
Figure 3. a) Bu4NBH4-induced site-specific degradation of Ptxl for the
formation of PDB and baccatin (BAC). b) Reductive degradation of 13-
ester linkage of Ptxl–PLA; c) HPLC traces of 1. Ptxl, 2. Ptxl treated with
Bu4NBH4, 3. Ptxl–LA5 , 4. Ptxl–LA5 prepared using [Mg(N(TMS)2)2]
followed by treatment with Bu4NBH4, 5. same as trace 4 except that
[(BDI)MgN(TMS)2] was used, 6. same as trace 4 except that
[(BDI)ZnN(TMS)2] was used. The PDB and partial BAC degradation
products detected and marked with an asterisk (*) in traces 5 and 6
were from the free Ptxl that was not completely consumed during the
polymerization at a very low M/I ratio (M/I=5). Separation of Ptxl was
not attempted. If one compares the BAC and PDB patterns in traces 6
and 2, it is clear that the BAC in trace 6 arose partially from
Magri et al,[21] reported that tetrabutylammonium boro-
hydride (Bu4NBH4) could selectively and quantitatively
reduce the 13-ester bond of Ptxl to give baccatin III (BAC)
and (1S,2R)-N-1-(1-phenyl-2,3-dihydroxypropyl)benzamide
(PDB) (Figure 3a). We attempted to use this reduction
reaction to disassemble the Ptxl–LA5 derived from metal/
Ptxl-mediated polymerization and then to analyze whether
PLA is attached to these fragments (Figure 3b). It was
anticipated that [Mg(N(TMS)2)2], a catalyst without a chelat-
ing ligand, would initiate polymerization nonpreferentially at
both the 2’-OH and the 7-OH groups. As expected, both
PDB–PLA and BAC–PLA were obtained after the resulting
Ptxl–LA5 was treated with Bu4NBH4 (trace 4 in Figure 3c).
When [(BDI)MgN(TMS)2]was used, the amount of BAC–
PLA derived was significantly reduced (trace 5 in Figure 3c),
indicating polymerization of LA was preferentially initiated
at the 2’-OH group of Ptxl by Mg catalysts with a proper
chelating ligand.
degradation of unreacted Ptxl and partially from the reduction of Ptxl–
PLA, where the PLA is attached to the 2’-OH group of Ptxl. The
assignments marked with ** were verified by mass spectrosmetry (see
Figure 4 in the Supporting Information).
polymerization, the resulting Ptxl–PLAs typically have a
fairly broad molecular weight distribution (MWD) (e.g., Ptxl–
LA200 Mw/Mn = 1.47). This observation is attributed to fast
propagation relative to initiation for the polymerization
initiated by Mg catalysts.[13] To reduce the propagation rate
and transesterification side reactions, we tested [(BDI)ZnN-
(TMS)2], a zinc analogue of [(BDI)MgN(TMS)2]that gives
more controlled LA polymerization.[13] As expected, Ptxl–
PLAs with projected MWs and narrow MWDs were readily
prepared by LA polymerization mediated by the (BDI)Zn–
Ptxl complex formed in situ. For instance, Ptxl–LA200 with
Mn = 28100 Da (expected 29700 Da) and a MWD of 1.02
Although
[(BDI)MgN(TMS)2]gave
significantly
improved site-specific control in the metal/Ptxl-initiated
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FTIR or 1H NMR spectroscopy), the polymerization solution was
added to ethyl ether (25 mL) to precipitate out the Ptxl-LA100
conjugate. Ptxl–LA100 in DMF (100 mL, 10 mgmLÀ1) was precipitated
by dropwise addition to vigorously stirred nanopure water (2 mL).
PLGA–mPEG5k (MW= 18300 gmolÀ1, 5 mgmLÀ1 in DMF, 100 mL)
was added dropwise to the NCs to give PEGylated Ptxl–LA100 NC.
were obtained in the [(BDI)ZnN-Ptxl]-mediated LA poly-
merization (200 equiv). HPLC analysis of the Ptxl–LA5
prepared with [(BDI)ZnN(TMS)2]and then treated with
Bu4NBH4 showed that initiation and polymerization occurred
exclusively at the 2’-OH group of Ptxl (trace 6, Figure 3c).
Various studies suggests that the polymerization process does
not lead to deleterious effect on Ptxl (see Figures 5 and 6 in
the Supporting Information).
Received: January 30, 2008
Published online: May 19, 2008
This drug-initiated polymerization method can be applied
to the preparation of NCs of other therapeutic agents
containing hydroxy groups. For instance, docetaxel(Dtxl)–
LA10 and camptothecin(CPT)–LA10 NCs with very high drug
loading (35.9 wt% and 19.5 wt%, respectively), more than
95% loading efficiencies, and sub-100 nm sizes can be readily
prepared using this metal–drug complex initiated LA poly-
merization followed by nanoprecipitation (entries 5 and 6,
Table 1). CPT differs from both Ptxl and Dtxl as it has no
intrinsic ester bond. It was quantitatively recovered from the
CPT–PLA NC after the NC was treated with NaOH. The
CPT separated from the hydrolysis mixture of CPT–PLA in
Keywords: drug delivery · nanoparticles · nanotechnology ·
polymer–drug conjugates · ring-opening polymerization
.
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Experimental Section
General procedure for the preparation and formulation of Ptxl–PLA
[13]
nanoconjugates: [(BDI)MgN(SiMe3)2](6.2 mg, 0.01 mmol)
and
Ptxl (8.5 mg, 0.01 mmol) were mixed in 0.5 mL anhydrous THF. dl-
Lactide (144 mg, 1 mmol) in 2 mL anhydrous THF was added
dropwise. After the LA was completely consumed (monitored by
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