Zhao Xinghua,Ding Shi,Li Shengnan,Wang Yang,Jiang Mingjun,Liu Ju,Chen Ye
Aim: An active-passive dual-targeting gambogic acid HPMA Copolymer Coupling drug system with high efficiency, low toxicity and high selectivity was constructed. Methods: The gambogic acid HPMA copolymer coupling drug system was constructed and its structure was characterized. The
cytotoxicity of gambogic acid HPMA copolymer was detected by MTT assay. The pharmacokinetics of gambogic acid HPMA copolymer was evaluated in mice. Targetability of gambogic acid HPMA copolymer was evaluated by tissue distribution experiment. The in vitro antitumor activity of gambogic acid
HPMA copolymer was evaluated by pharmacodynamics experiment in mice. Results: Two copolymers of gambogic acid HPMA were successfully prepared. The copolymers showed reduced cytotoxicity and a certain sustained release effect and targeting property. In vivo pharmacodynamic experiments
also showed better anti-tumor effects than GA. Discussion: In this study, gambogic acid was combined with HPMA polymer and the targeting molecule D-galactose/folic acid to form a polymer micelle with high efficiency, low toxicity and high selectivity for active-passive dual targeting.
The construction of the drug system provides new ideas for future formulation research and development.
The balance between systemic toxicity and circulation time for a polymeric nanocarrier to deliver antitumor drugs has been trialed. A new approach to break the balance was proposed in this study by significantly improving its biosafety and prolonging the circulation time, hence, to
enhance its anti-tumor efficacy. A matrix metalloproteinases (MMPs)-sensitive peptide (PVGLIGK) was introduced to cross-link the N-(2-hydroxypropyl) methylacrylamide polymer-doxorubicin conjugates (HPMA-Dox) conjugate to construct a nano-size polymeric nanocarrier-Dox assembly (PMD) with a
molecular weight (MW) of 73 kDa and this modification has resulted in a prolonged circulation time (a half-time of 20.1 h) and enhanced accumulation of PMD at the tumor site, while negligible systemic toxicity and excellent biocompatibility were displayed after injection of PMD into the mice.
The cross-linked nanoassembly was unpacking in the presence of MMPs in the extracellular microenvironment, and the conjugated Dox was released from the nanoassembly in the lysosome/endosome due to an intracellular low pH microenvironment. The released Dox from PMD inhibited tumor cells very
efficiently with a tumor growth inhibition of around 70%. The outstanding performance of the dual stimuli-responsive biodegradable polymeric nanocarriers may open a door for other hydrophobic anti-tumor drugs.
Thanks to the enhanced cancer cell affinity, modification of polymeric drug carriers with an active targeting ligand has been one of the most effective strategies to achieve better therapeutic efficacy. However, hydrophobic ligands (e.g. folate), when conjugated to hydrophilic carriers, encounter the problem of reduced targeting effectiveness due to the fact that the ligand may be buried inside the carrier. In the present study, we studied the impact of the hydrophilic polymer structure on the targeting efficiency of the conjugated folate (FA). After modification with folate, the linear N-(2-hydroxypropyl)-methacrylamide (HPMA) polymer (P-FA, 27.3 kDa) exhibited a neutral surface charge (1.5 mV), while the graft HPMA polymer (GP-FA, 117.4 kDa) possessed a mild negative charge (−7.2 mV), which suggests different exposure levels of negatively charged folate on the surface of P-FA and GP-FA. Notably, on folate receptor positive MCF-7 cells, P-FA exhibited comparable cell uptake with the unmodified linear polymer, whereas GP-FA resulted in 2-fold higher cell internalization over the untargeted graft polymer. Meanwhile, the involvement of folate receptor mediated endocytosis and augmented folate binding affinity of GP-FA were observed in comparison with P-FA. Moreover, GP-FA exhibited significantly enhanced tumor accumulation relative to GP, while marginally improved tumor accumulation was observed for P-FA compared with P. In summary, the structure of the hydrophilic polymer plays a vital role in the targeting efficiency of the conjugated hydrophobic ligand.
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