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Materials Express
2158-5849/2021/11/627/007
Copyright © 2021 by American Scientific Publishers
All rights reserved. doi:10.1166/mex.2021.1961
Printed in the United States of America www.aspbs.com/mex
Polylactic acid block copolymer grafted
temozolomide targeted nano delivery in the
treatment of glioma
Maokai Wang1 , Rongyan Kuang1 , Baoqing Huang1 , and Defeng Ji2, ∗
1
Department of Neurosurgery, Jiaozhou Central Hospital, Qingdao 266000, Shandong, PR China
2
Department of Neurosurgery, Jiaozhou People’s Hospital, Qingdao 266000, Shandong, PR China
ABSTRACT
Gliomas are tumors of the central nervous system; they can be invasive and are commonly treated by surgical
Article
resection, chemo, and radiotherapy. Removal of a glioma is dangerous and not always successful. Temozolo-
IP: 192.168.39.210
mide (TMZ), the first-line chemotherapy drug for On: Fri, 19inhibit
gliomas, Nov 2021
tumor03:03:43
recurrence, and metastasis to some
Copyright: American Scientific Publishers
extent. TMZ is often accompanied by side effects such as anemia, fever, constipation, and more. Here using a
Delivered by Ingenta
double-targeted Kunitz domain Angiopep-2 (ANG) modified block copolymer poly(lactic acid)-polyethylene gly-
col (PEG-PLA) coated with TMZ, we constructed a nano-delivery system (ANG@PLA-PEG/TMZ) that crosses
the blood-brain barrier (BBB) to treat gliomas.
Keywords: Glioma, Polylactic Acid, Temozolomide, Blood-Brain Barrier, Delivery System.
1. INTRODUCTION effects (thrombocytopenia, anemia, vomiting, increased
Neuroglioma (NG), a primary central nervous system drug resistance) [5]. Cancer drugs can be improved, work-
tumor, accounts for 45% of central nervous system malig- ing on ways to improve specific targeting and side effects
nant tumors [1]. Clinically, surgical resection is the main are paramount in this field.
treatment for gliomas. However, because of its high Angiopep-2 (ANG) is a Kunitz domain-derived peptide
degree of malignancy, strong invasiveness, and infiltra- that binds with low-density lipoprotein related protein-1
tive growth, surgical resection does not completely remove (LRP-1) [6]. LRP-1 is highly expressed on glioma cells,
the NG making the success rate of surgery low [2]. making them a target for ANG directed treatment. ANG
The survival time of patients is only 9–12 months, has been favored by researchers in the modification of
and the 5-year survival rate is only 0.05%–4.70% after nanomaterials, especially in the diagnosis and treatment of
surgery [3]. Currently, surgery combined with radiother- NG, because it can to carry molecules across the blood
apy and chemotherapy is the primary treatment for glioma. brain barrier (BBB) and favorably binds to LPR-1 recep-
TMZ is the first choice for adjuvant glioma chemother- tors [7]. Therefore, ANG modified drugs can better pene-
apy. A combination of radiotherapy and TMZ chemother- trate the BBB and target the glioma, reducing the damage
apy on tumor cells can help patients go into remission to normal tissue, and improving the bioavailability of the
and improve their total survival time of patients [4]. drugs [8].
While TMZ has toxic effects on tumor cells, it also The PEG-PLA block copolymer is a high molecular
polymer material. It has excellent biocompatibility and
does serious damage to noncancerous cells, causing side
is an environment-friendly biomedical material; PLA has
been widely used in various fields of medicine [9]. How-
∗
Author to whom correspondence should be addressed. ever, the weak hydrophilicity of PLA and its low adhesion
Mater. Express, Vol. 11, No. 5, 2021 627
Materials Express Polylactic acid block copolymer grafted temozolomide targeted nano delivery
Wang et al.
to cells, there are many restrictions on the separate use of SpectraMax® Plus384 (Perkin Elmer instrument Co., Ltd.
PLA in many fields [10]. To break through these limita- (Shanghai, China)), and a Cyto-FLEX flow cytometer
tions, using effective technical means to graft hydrophilic (Beckman Coulter, Inc. U.S.A) was used to detect cell
groups or segments on the main chain of PLA is a way apoptosis.
to improve its hydrophobicity of PLA [11]. Polyethylene
glycol (PEG) is able to improve the hydrophobicity of 2.3. Synthesis of Block Copolymers
PLA based on its good hydrophilicity and softness. PEG
The PEG2000 -PLA block copolymer was prepared using
modified PLA (PEG-PLA) has low toxicity and can travel
through the bloodstream [12]. PEG-PLA can be quickly a simple hydrothermal method [15], in which 10.0 g of
excreted after entering the body and rarely accumulates in lactic acid, stannous octanoate (1.0% wt), and PEG2000
the human body. More importantly, when PEG modifies were added to a 150 mL flask, degassed, and sealed
PLA, it can still be used as a biomedical material [13]. in an argon (Ar) environment and placed in a 100 C
After the drug is loaded with the PEG-PLA block poly- reaction bath. The mixture was continuously stirred at
mer, it can also be used to control the release of the drug, 800 rpm, and the reaction lasted for four days. The
it is associated with further improving the bioavailability obtained reaction mixture was filtered and washed with
of the drug [14]. N -N -dimethylformamide (DMF). After dissolving in chlo-
In this work, we use ANG bipolar targeting modified
roform and recrystallizing in an ethanol solution, the pure
PEG-PLA to carry TMZ in a nano-drug targeted delivery
PEG2000 -PLA block copolymers were obtained, filtered,
system (ANG@PEG-PLA/TMZ). With the help of ANG’s
targeted navigation function, we can break through the and dried with P2 O5 .
limitation of the BBB and realize the accumulation of
TMZ in brain NG lesions. While further improving the 2.4. Preparation of Targeted Nano-Pharmaceuticals
efficacy and bioavailability of TMZ, reducing the toxic- PEG2000 -PLA (20 mg/mL), TMZ (20 mg/mL), and
ity and side effects, and improving the quality of life of Angiopep-2 were dissolved in DMF and magnetically
patients. This study explored the pharmacological activity
Article
stirred (800 rpm) for 20 min, then the mixture was sealed
and biosafety of ANG@PEG-PLA/TMZ through in vitro in a dialysis bag and dialyzed in living water for 24 h,
and in vivo experiments to provide IP: 192.168.39.210
new strategies On:
and Fri,and
19 Nov 2021 03:03:43
Copyright: American Scientificthe Publishers
uncoated TMZ and Angiopep-2 were vacuum
choices for the treatment of NG. Delivered bylyophilized
Ingenta and set aside.
2. MATERIALS AND METHODS 2.5. Cell Culture and Collection
2.1. Materials Rat glioma C6 cells were cultured in DMEM/F12 mixed
L-lactide (C6 H8 O4 , 99.99%), PEG-2000, and thiazolyl medium (10% FBS), DMEM/F12 mixed medium plus
blue (MTT, C18 H16 BrN5 S, 98%) were purchased from 0.2 mM L-glutamine, 100 g/mL of streptomycin, and
Sigma–Aldrich (St. Louis, Missouri, U.S.A). Stannous 100 U/mL of penicillin. The cells were incubated in 37 C,
octanoate (C16 H30 O4 Sn, 95.0%), ethanol (CH3 CH2 OH,
5.0% CO2 (95% Air) at constant temperature for 24 h, the
95%), methanol (CH3 OH, 99.5%), trichloromethane
culture medium was changed and sub-cultured in dishes.
(CHCl3 , Analytical purity), and acetone were pro-
vided by Shanghai Maimeer Chemical Technology Co., After three days of culture, 80% of the cells were collected
Ltd. (Shanghai, China). Kunitz-type domain Angiopep-2 for follow-up experiments.
(ANG) was purchased from National Peptide Biotechnol-
ogy Co., Ltd. (Hefei, China). Temozolomide (TMZ) was 2.6. Establishment of Animal Model
purchased from Beijing Bellingway Technology Co., Ltd. The cultured C6 cells were dispersed in serum-free
(Beijing, China). All reagents were able to be used without DMEM/F12 medium at 3.0 × 107 cells/mL. After SD mice
further purification. were anesthetized with 10.0% chloral hydrate and disin-
Rat glioma C6 cells were purchased from Tongpai fected, an incision of about 1.00 mm was made in the
(Shanghai) Biotechnology Co., Ltd. (Shanghai, China). SD brain, and 10 L of glioma C6 cells were injected with
rats were purchased from Tianqin Biotechnology Co., Ltd.
a needle at the junction of the cortex and white matter.
(Changsha, China). The feeding and treatment of the ani-
mals involved in this study all meet international ethical The injection time was 5.0 min, the needle retention time
and moral standards. was 3.0 min, and then the wound was sutured. SD rats
were intravenously injected with penicillin (10 U) for three
2.2. Instrument consecutive days to avoid postoperative infection and were
Transmission electron microscopy (TEM, JEM-1400Flash, reared in cages. MRI imaging was performed on the SD
JEOL, Japan) was used to characterize the morphology rats two weeks after the operation to observe the growth
of the nanodrugs. C6 cell activity was measured on a of solid tumors in the brain.
628 Mater. Express, Vol. 11, pp. 627–633, 2021
Polylactic acid block copolymer grafted temozolomide targeted nano delivery
Wang et al.
Materials Express
2.7. Physicochemical Properties of 2.7.4. Clone Formation Experiment
ANG@PLA-PEG/TMZ The monodispersed cell suspension was obtained after
2.7.1. Entrapment Efficiency and Drug Loading the C6 cells were in the logarithmic phase and digested
The absorption value of TMZ in the ANG@PLA- with trypsin (0.25%). The dispersed cells were inocu-
PEG/TMZ polymer was determined by an enzyme lated in a 96-well plate, with DMEM/F12 (10% FBS)
labeling instrument, which was used to calculate the medium, and cultured at 5% CO2 , 37 C in a constant
loading rate and drug loading of polymer to TMZ. In temperature incubator for 24 h. The medium was changed
after the cells were attached, and the newly configured
brief, ANG@PLA-PEG/TMZ was completely dispersed in
PBS, ANG@PLA-PEG, and ANG@PLA-PEG/TMZ were
0.10% DMSO solution, and the obtained dispersion was added and mixed evenly. In the same environment, the
added to a 96-well plate of 1.00 mL per well. After shak- cells were cultured for 4 h, and the new medium was
ing and mixing, the absorbance value was measured on changed for continuous culture until a clone appeared.
the enzyme meter. By setting the gradient concentration of After the original culture medium was removed, the cells
TMZ, the corresponding absorbance value was obtained, were washed with aseptic PBS, and 2.0 mL paraformalde-
and a standard curve was drawn. The entrapment efficiency hyde was added to each well. After being treated with-
and drug loading rate in ANG@PLA-PEG/TMZ were cal- out light for 15 min at room temperature, the cells were
culated according to the following formula: washed. Each well was stained with 2.0 mL crystal violet
for 20 min and washed. The cells were dried in the nat-
Amount of drug loaded ural environment, and the clone formation rate (FR) and
Loading rate = × 100% (1) cell survival rate (SR) were calculated according to the
Total drug
following formula:
Drug loading Clone number
Drug loading rate = × 100% (2) FR = × 100% (3)
Empty carrier mass Number of inoculated cells
2.7.2. ANG@PLA-PEG/TMZ Morphology Clone formation rate of experimental group
Article
Characteristics SR =
Clone formation rate of control group
The morphology of ANG@PLA-PEG/TMZ IP: 192.168.39.210 On: Fri, 19 Nov 2021 03:03:43
and the par- × 100% (4)
ticle size distribution of the polymerCopyright: American
were measured by Scientific Publishers
Delivered by Ingenta
TEM, and the distribution of polymer nanoparticles was 2.8. Antitumor Effect of ANG@PLA-PEG/TMZ
observed. Each sample was tested three times. In brief, the In Vivo
suspension obtained by ANG@PLA-PEG/TMZ dispersion Tumor-bearing rats were randomly divided into a PBS
was added to a 200 mesh carbon film and re-stained with (n = 5), TMZ (n = 5), ANG@PLA-PEG (n = 5), and
2.0% phosphotungstic acid to observe the morphology of ANG@PLA-PEG/TMZ group (n = 5). 10 mg/kg of
polymer nanoparticles under TEM. ANG@PLA-PEG, and 40 mg/kg, of TMZ or ANG@PLA-
PEG/TMZ were injected into the rat from its respected
2.7.3. ANG@PLA-PEG Toxicity Test group once a day for 20 days. The in vivo imaging obser-
Based on the traditional MTT assay, the inhibition of the vation was carried out on the 5, 10, 15, 20, 25, and 30th
ANG@PLA-PEG polymer carrier on cell proliferation was day after drug injection, and the actual tumor volume and
analyzed to evaluate whether it has a toxic effect on cells. the inhibition rate of each nanodrug on solid tumors were
measured.
After the C6 cells were in the logarithmic phase, they were
digested by enzyme, and the cell suspension was obtained.
A cell suspension of 5.0 × 103 cells/well was added to
a 96-well plate and cultured in DMEM/F12 (10% FBS)
medium for 24 h (5% CO2 , 37 C). Then, the serum-
free medium was changed, and the ANG@PLA-PEG was
added to the cells at a gradient concentration (0, 100,
200, 200, 300, 400, 500, 500, 1,000, 1,200 g/mL). After
adding 100 L of the above-mentioned specific concentra-
tions of ANG@PLA-PEG to each well, the C6 cells were
cultured in the gradient concentrations of ANG@PLA-
PEG for 12 h, and then the fresh medium (10% FBS) was
changed and cultured for 24 h. At the end of the culture
period, 20 L MTT solution was added and incubated for Fig. 1. 1 H-NMR spectrum of the poly(lactic acid)-polyethylene glycol
4 h, and the absorbance was measured at 490 nm. (PEG2000 -PLA) block copolymers.
Mater. Express, Vol. 11, pp. 627–633, 2021 629
Materials Express Polylactic acid block copolymer grafted temozolomide targeted nano delivery
Wang et al.
Fig. 2. Technical route for synthesis of the poly(lactic acid)-polyethylene glycol (PEG2000 -PLA) block copolymers.
3. RESULTS AND DISCUSSION According to formulas (1) and (2), the entrapment effi-
3.1. Physicochemical Properties of Block Copolymers ciency of ANG@PLA-PEG to TMZ was 88.24%, and the
The NMR spectrum of the PEG2000 -PLA block copoly- drug loading rate was 63.2%.
mers synthesized by the hydrothermal method is shown in
Figure 1. And the synthesis route of PEG-PLA is shown in 3.4. Cytotoxicity of ANG@PLA-PEG Vector
Figure 2. The strong proton peak at = 2.24 is the –CH3 In this study, an amphiphilic block copolymer PEG2000 -
segment in the PEG2000 unit, while the peak at = 3.3 PLA was loaded with targeted ANG as the carrier of TMZ
belongs to the proton peak of –CH3 in the PLA structural chemotherapeutic drugs, which has excellent biocompati-
unit, and the peak at the chemical shift = 3.65 is formed bility. Therefore, the carrier’s toxicity needed to be tested
by the –CH splitting in the PEG unit. As a result, it can be to ensure the reliability of the follow-up experiments. The
proven that the PEG2000 -PLA block copolymer was suc- cytotoxicity of ANG@PLA-PEG polymer carrier detected
cessfully synthesized.
by MTT assay is shown in Figure 5. When ANG@PLA-
PEG reached 1,000 g/mL, the survival rate of the C6
3.2. Morphology Characteristics of
cells was 92% or more. With the extension of the co-
ANG@PLA-PEG/TMZ
incubation time between the carrier and the C6 cells, the
The morphology of ANG@PLA-PEG/TMZ was tested
survival rate of C6 cells decreased to a certain extent,
by TEM, as shown by Figure 3. The particle size and
Article
and the higher the concentration of ANG@PLA-PEG, the
Zeta potential (Table I) were measured with a Malvern
longer the action time, the greater the effect on the activ-
particle size analyzer. It can be IP: seen
192.168.39.210 On: Fri, 19 Nov 2021 03:03:43
from the TEM
diagram that the ANG@PLA-PEG/TMZ Copyright: ity of C6Publishers
American Scientific
polymer nanopar- cells. Therefore, when the concentration of the
Delivered
ticles have a similar ball-stick-like structure and are uni- by Ingenta
ANG@PLA-PEG vector was 200 g/mL, it did not cause
formly distributed. a greater toxic effect on the C6 cells with the prolongation
of incubation time.
3.3. Entrapment Efficiency and Drug Loading
Rate of Nanodrugs
The standard curve of the TMZ gradient concentra- Table I. Size and zeta potential distribution of nanopharmaceuticals.
tion is shown in Figure 4, and the standard curve is Nanometer material Size (nm) Zeta (mV)
as follows:
PEG2000 -PLA 123.56 28.9 ± 0.62
Fluorescence value = 0.0481CTMZ − 0.0084R2 = 0.997 ANG@PLA-PEG 162.41 12.36 ± 1.6
ANG@PLA-PEG/TMZ 198.23 −5.63 ± 2.1
(5)
Fig. 3. Transmission electron microscope (TEM) image of angiopep-
2@poly(lactic acid)-polyethylene glycol/temozolomide (ANG@PLA-
PEG/TMZ). Fig. 4. Standard curve of temozolomide (TMZ).
630 Mater. Express, Vol. 11, pp. 627–633, 2021
Polylactic acid block copolymer grafted temozolomide targeted nano delivery
Wang et al.
Materials Express
of ANG@PLA-PEG/TMZ treatment time, the C6 cells
showed apoptosis and dissolution, and the difference was
statistically significant (P < 0.05).
3.6. Antitumor Effect of ANG@PLA-PEG/TMZ
In Vivo
An in vivo imaging technique was used to detect the
growth of gliomas in the brains of the tumor-bearing
SD rats. Among all the experimental groups, the glioma
growth rate with PBS was the fastest. In addition, the
growth rate of glioma in the ANG@PLA-PEG group was
similar to the PBS group. Compared with the TMZ group,
the growth rate of NG in the ANG@PLA-PEG/TMZ group
was stagnant, indicating that the ANG@PLA-PEG/TMZ
polymer nanodrugs had a significant inhibitory effect on
the growth of NG. More importantly, the fluorescence
Fig. 5. Effect of gradient concentration of angiopep-2@poly(lactic
intensity of TMZ in the cancer foci detected by MRI in
acid)-polyethylene glycol (ANG@PLA-PEG) polymer empty carrier on
the activity of c6 cells at different times. (A) 4 h. (B) 8 h. (C) 12 h. vivo imaging was much higher than TMZ alone. The solid
tumor volume and weight of each group are shown in
Figure 6.
Table II. Clone formation rate of C6 cells in each drug group. In addition, the inhibition rate of each nanodrug on solid
Material Clone formation rate (%) tumor tissue is shown in Figure 7. The inhibition rates
of the ANG@PLA-PEG and PBS groups were 178.3 and
PBS 59.1 ± 2.0
54.0 ± 5.0
198.1, respectively. The tumor inhibition rate of the TMZ
Article
ANG@PLA-PEG
ANG@PLA-PEG/TMZ 10.4 ± 10.0 group was 82.3, which was significantly higher than the
IP: 192.168.39.210 On: Fri,PBS 19 Nov 2021 03:03:43 groups (P < 0.01). The results
and ANG@PLA-PEG
Copyright: American Scientific
showed thatPublishers
TMZ could inhibit tumor growth to a certain
Delivered byextent.
Ingenta The ANG@PLA-PEG/TMZ group’s tumor inhi-
3.5. Clone Formation Rate
Clones of the C6 cells were observed and counted by an bition rate was 6.2, which was significantly higher than
inverted microscope, and the results are shown in Table II. the other three groups (P < 0.01). The results showed
The clone group formed by C6 cells was found in the con- that ANG@PLA-PEG/TMZ had an obvious inhibitory
trol group (PBS) and ANG@PLA-PEG. On the contrary, effect on the growth of NG. The potential mechanism
in the ANG@PLA-PEG/TMZ group, the proliferation of of ANG@PLA-PEG to deliver TMZ in the treatment of
the C6 cells was stagnated, and the cell morphology was glioma is illustrated in Figure 8. The ANG@PLA-PEG
abnormal, the cell volume increased, the cytoplasmic color polymer carries TMZ across the BBB and releases TMZ
was lighter, and the edge was irregular. With the extension to participate in antitumor effects.
Fig. 6. Tumor weight (A) and volume (B) curves in tumor-bearing SD rats at different times after caudal vein administration of PBS,
angiopep-2@poly (lactic acid)-polyethylene glycol (ANG@PLA-PEG), temozolomide (TMZ), and angiopep-2@poly(lactic acid)-polyethylene gly-
col/temozolomide (ANG@PLA-PEG/TMZ) (∗ P < 0.05, ∗∗ P < 0.001).
Mater. Express, Vol. 11, pp. 627–633, 2021 631
Materials Express Polylactic acid block copolymer grafted temozolomide targeted nano delivery
Wang et al.
such as strong magnetism, strong targeting, easy modi-
fication, penetration of the BBB, high biocompatibility,
low cytotoxicity, and more [22–26]. In this work, ANG
targeted modified PEG-PLA was used to carry TMZ to
build a nanodrug targeted delivery system (ANG@PEG-
PLA/TMZ). With the help of ANG’s targeted naviga-
tion function, it broke through the limitation of the BBB
and realized the accumulation of TMZ in brain NG
lesions. The drug delivery system improved the efficacy
and bioavailability of TMZ, reduced the toxicity and side
effects, and improve the quality of life of patients. It was
confirmed that ANG@PEG-PLA/TMZ had a significant
inhibitory effect on solid tumors in vivo and in vitro.
Fig. 7. Tumor growth inhibition of each group of drugs on the tumor-
bearing SD rats (∗∗ P < 0.01).
4. CONCLUSION
3.7. Discussion In this work, a new strategy using a block polymer nano-
preparation for the treatment of NG was developed and
Clinically, NG are treated with temozolomide (TMZ) com-
designed. The targeted ANG was loaded on the block
bined with radiotherapy; this can prolong the survival
polymer’s surface, which allowed the drug molecules to
time of patients by means of the synergistic effect of
break through the BBB and accumulate in the cancer
radiotherapy on cells and the cytotoxicity of chemothera-
peutic drugs [16]. Studies have also confirmed that radio- focus. ANG@PEG-PLA/TMZ can improve the efficacy
therapy, combined with TMZ, can prolong the survival and bioavailability of TMZ, reduce the toxicity and side
time of patients with glioma [17]. However, TMZ alone effects, and improve the quality of life of patients.
Article
can cause serious side effects (thrombocytopenia, nausea,
fatigue, loss of appetite, etc.) [18]. Research Conducted on Animals or Humans
IP: 192.168.39.210 On: Fri,Research
19 Nov 2021 03:03:43
experiments conducted in this article with ani-
Nanotechnology provides a new means for the diagnosis
Copyright: American Scientific Publishers
and treatment of tumors [19–21]. Polymer nanomaterials mals or
Delivered by Ingenta humans were approved by the Medical Ethics
show great potential in the early diagnosis and treatment of Committee of the Jiaozhou Central Hospital following
tumors because of their physical and chemical properties, all guidelines, regulations, legal, and ethical standards as
required for humans or animals.
Conflicts of Interest
There are no conflicts to declare including any competing
financial interest.
Acknowledgments: Thank all the colleagues from
Jiaozhou Central Hospital and Jiaozhou People’s Hospital
of Neurosurgery for their support and assistance to this
study, and thank all patients who participated in this study.
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