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Journal of Peking University(Health Sciences) ›› 2019, Vol. 51 ›› Issue (3): 477-486. doi: 10.19723/j.issn.1671-167X.2019.03.015

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Preparation and characterization of paclitaxel microspheres in situ gel and its antitumor efficacy by local injection

Ying ZHAN1,Yi-tian DU1,Zhen-zhen YANG1,Chun-li ZHANG2,Xian-rong QI1△()   

  • Received:2019-03-22 Online:2019-06-18 Published:2019-06-26
  • Supported by:
    Supported by the National Natural Science Foundation of China (81673365) and the Fundamental Research Funds for the Central Universities: Peking University Medicine Seed Fund for Interdisciplinary Research (BMU2018MX009)

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Abstract: Objective: The current difficulties in the treatment of tumor include repeated administration and high recurrence rate after tumor resection. In order to reduce the number of doses, avoid side effects of chemotherapeutic drugs, suppress tumor growth and delay tumor recurrence after surgery, a temperature-sensitive in situ gel with paclitaxel microspheres (PTX/M gel) was prepared. PTX/M gel was administered by intratumoral injection once a month.Methods: First of all, paclitaxel microspheres (PTX/M) were prepared by emulsion solvent evaporation method. A laser particle size distribution analyzer was used to investigate the size, distribution, specific surface area of microspheres. Paclitaxel content was determined by high performance liquid chromatography (HPLC). Then encapsulation efficiency of paclita-xel was calculated and in vitro release characteristics were studied. Secondly, PTX/M gel was prepared by cold dissolution method. The phase transition temperature, elastic modulus, dissolution curve, correlation between dissolution and release were measured. Finally, U87 MG and 4T1 subcutaneous tumor mo-dels were established respectively to study the efficacy of PTX/M gel in suppressing tumor growth and delaying tumor recurrence after surgery.Results: The median diameter of the selected PTX/M was (32.24±1.09) μm, the specific surface area was (206.61±10.23) m 2/kg, the encapsulation efficiency was 85.29%±1.34%, and the cumulative release percentage of paclitaxel from PTX/M was 33.56%±3.33% in one month. Phase transition temperature of PTX/M gel was 33 ℃. The elastic modulus of PTX/M gel at 25 ℃ and 37 ℃ were 4.2×10 3 Pa and 18×10 3 Pa, respectively. The gel could stay in the body for up to 48 hours. It could be seen from the results of animal experiments that were compared with the saline group and the Taxol group, and the tumor-bearing mice of the PTX/M gel group had the slowest tumor growth (P<0.05). Similarly, in the tumor recurrence experiments, the mice of PTX/M gel group had the latest tumor recurrence after surgery. Conclusion: As a local sustained-release preparation, PTX/M gel can effectively suppress tumor growth and delay postoperative recurrence of tumors. It has potential advantages in tumor treatment.

Key words: Paclitaxel, Microspheres, In situ gel, Delayed-action preparations, Treatment outcome

CLC Number: 

  • R944.1

Figure 1

The particle diameter distribution of PTX/M 16 (A), PTX/M 10 (B), PTX/M 06 (C) Blue line represents cumulative distribution and red line reresents difference distribution."

Table 1

Comparison of particle diameter, SSA, EE, DL among PTX/M 16, PTX/M 10 and PTX/M 06"

Items PTX/M 16 PTX/M 10 PTX/M 06
Size/μm 23.17±0.6 32.24±1.09 99.74±21.61
SSA/(m2/kg) 227.97±5.78 206.61±10.23 113.68±9.94
EE/% 74.55±2.26 85.29±1.34 95.82±1.95
DL/% 15.71±0.40 17.57±0.23 19.32±0.32

Figure 2

Percentage of accumulated release of PTX from PTX/M 16, PTX/M 10 and PTX/M 06, respectively PTX, paclitaxel; PTX/M, paclitaxel microspheres. Data are presented as the x?±s (n=3)."

Figure 3

SEM micrographs of PTX/M (A, B) and degraded PTX/M after 30 days (C, D)"

Table 2

Phase transition temperature of gel when the concentration of Poloxamer 188 was changed"

Concentration of Poloxamer 188/% Phase transition temperature/℃
Blank gel PTX/M gel
1.8 32 ≤25
2.2 35 30
2.6 37 33
3.0 39 36
3.4 40 37
3.6 42 39

Figure 4

Modulus of blank gel and PTX/M gel at 25 ℃, 37 ℃"

Figure 5

Accumulated erosion of blank gel and PTX/M gel PTX/M, paclitaxel microspheres. Data are presented as the x?±s (n=3)."

Figure 6

Percentage of cumulative release of PTX/M from PTX/M gel (A) and correlation between PTX/M gel release and dissolution (B) PTX/M, paclitaxel microspheres. Data are presented as the x?±s (n=3)."

Figure 7

Changes of saline (A) and gel (B) labeled with trypan blue were injected into water at 37 ℃; Photographs of gel injected into the back of the mouse for 2 h, 4 h, 6 h, 12 h, 24 h, 48 h and control for 2 h (C)"

Figure 8

A, tumor growth curve of U87MG-bearing mice (*P=0.02, **P=0.002, vs. Control); B, relative body weight curve; C, percent of organ relative weight (Normal represents the organ index of normal nude mice[12]); D, HE staining of major organ tissues (100×) Data are presented as the x?±s (n=10). Data are presented as the x?±s (n=6)."

Figure 9

A, tumor growth curve of 4T1-bearing mice (*P=0.003, vs. Control); B-D, tumor growth curve of each mouse in Control, PTX/M gel, Taxol groups; E, relative body weight-time curve of mice; F, proportion of different degrees of lung metastasis in mice"

Figure 10

A, tumor free rate after surgery in different drug-administered groups; B-D, tumor growth curve of each mouse after surgery in control, PTX/M gel, Taxol groups; E, survival curve of mice with surgery; F, proportion of different degrees of lung metastasis in mice"

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