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Drug-Polymer Interaction, Pharmacokinetics and Antitumor Effect of PEG-PLA/Taxane Derivative TM-2 Micelles for Intravenous Drug Delivery

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Abstract

Purpose

A novel polymer micelle was prepared with a high drug loading, good stability, high tolerance and better anti-tumor effect.

Methods

TM-2 was encapsulated in poly-block-poly (D, L-lactic acid) self-assembled micelles by the thin-film hydration method. From the critical micelle concentrations of the copolymers, particle size, drug loading and encapsulation efficiency of drug-loading micelles, the appropriate polymer material could be assessed. Comparisons between TM-2 solution and TM-2 micelles were done to evaluate the pharmacokinetics and toxicity in rats, compared with Taxol to evaluate the anti-tumor effect in mice.

Results

The optimized TM-2 micelles achieved a high drug loading (~20%) with the polymer material of PEG2k-PLA2.5k, with a particle size of 30 nm and no significant change in particle size after lyophilization. The result of pharmacokinetic experiment displayed that the half-life in vivo was obviously prolonged. The maximum tolerated dose of TM-2 micelles was approximately 25 mg/kg in rats, and the relative tumor growth rate of Taxol (15 mg/kg), TM-2 (10 mg/kg), TM-2 (15 mg/kg) and TM-2 (40 mg/kg) in mice were 49.35%, 49.14%, 36.44 and 9.98% respectively.

Conclusions

TM-2 micelles with high drug loading increased drug solubility, improved tolerance, antitumor effects and reduced toxicity.

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Abbreviations

A549:

Human lung xenografts

ACN:

Acetonitrile

AUC:

Concentration-time curve

BC:

Breast cancer

Clz :

Plasma clearance

Cmax :

Maximum plasma concentration

CMC:

Critical micelle concentration

CrEL:

Cremophor EL

CYP:

Cytochrome P450 proteins

DL:

Drug loading

DLS:

Dynamic light scattering

DMF:

N-N dimethylformamide

DSC:

Differential scanning calorimetry

EE:

Encapsulation efficiency

FTIR:

Fourier Transform infrared spectroscopy

GPC:

Gel permeation chromatography

KB/VCR:

Human cervical adenocarcinoma resistant to vincristine

MBC:

Metastatic breast cancer

MCF:

7/ADR-Human breast cancer resistant to adriamycin

MDR:

Multiple drug resistance

MTD:

The maximum tolerable dose

NSCLC:

Non-small cell lung cancer

OC:

Ovarian cancer

ODnc:

Negative control absorbance

ODpc:

Positive control absorbance

ODt:

Sample absorbance

PBS:

Phosphate-buffered saline

PDI:

Polydispersity index

PEG:

PLA-Poly-block-poly (D, L-lactic acid)

PSD:

Particle size distribution

PSMA:

Prostate-specific membrane antigen

PTX:

Paclitaxel

RTV:

Relative tumor volume

SD:

Male Sprague-Dawley

T/C:

Relative tumor growth rate

t1/2 :

Elimination half-life

Taxol:

Commercial name of paclitaxel solution

TEM:

Transmission electron microscopy

Tmax :

Maximum plasma concentration

Tween:

Polysorbate

XRD:

X-ray diffraction

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Authors and Affiliations

  1. School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China

    Qiao Wang, Yi Liu, Chenguang Pu, Hongjuan Zhang, Xinyi Tan, Jingxin Gou, Haibing He, Tian Yin, Yu Zhang, Yanjiao Wang & Xing Tang

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  1. Qiao Wang
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  2. Yi Liu
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  3. Chenguang Pu
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Correspondence to Yanjiao Wang.

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Wang, Q., Liu, Y., Pu, C. et al. Drug-Polymer Interaction, Pharmacokinetics and Antitumor Effect of PEG-PLA/Taxane Derivative TM-2 Micelles for Intravenous Drug Delivery. Pharm Res 35, 208 (2018). https://doi.org/10.1007/s11095-018-2477-3

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  • DOI: https://doi.org/10.1007/s11095-018-2477-3

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