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pH-responsive Virus-like Nanoparticles with Enhanced Tumour-targeting Ligands for Cancer Drug Delivery

View Article: PubMed Central - PubMed

ABSTRACT

Multifunctional nanocarriers harbouring specific targeting moieties and with pH-responsive properties offer great potential for targeted cancer therapy. Several synthetic drug carriers have been studied extensively as drug delivery systems but not much information is available on the application of virus-like nanoparticles (VLNPs) as multifunctional nanocarriers. Here, we describe the development of pH-responsive VLNPs, based on truncated hepatitis B virus core antigen (tHBcAg), displaying folic acid (FA) for controlled drug delivery. FA was conjugated to a pentadecapeptide containing nanoglue bound on tHBcAg nanoparticles to increase the specificity and efficacy of the drug delivery system. The tHBcAg nanoparticles loaded with doxorubicin (DOX) and polyacrylic acid (PAA) demonstrated a sustained drug release profile in vitro under tumour tissue conditions in a controlled manner and improved the uptake of DOX in colorectal cancer cells, leading to enhanced antitumour effects. This study demonstrated that DOX-PAA can be packaged into VLNPs without any modification of the DOX molecules, preserving the pharmacological activity of the loaded DOX. The nanoglue can easily be used to display a tumour-targeting molecule on the exterior surface of VLNPs and can bypass the laborious and time-consuming genetic engineering approaches.

No MeSH data available.


Cumulative release profile of doxorubicin packaged in tHBcAg nanoparticles in different pH conditions.(a) Release profile of free doxorubicin (DOX), tHBcAg nanoparticles loaded with PAA-DOX (tHBcAg-PAA-DOX), folic acid (FA)-conjugated tHBcAg nanoparticles loaded with PAA-DOX (FA-tHBcAg-PAA-DOX), and FA-conjugated tHBcAg nanoparticles using the nanoglue and loaded with PAA-DOX (FA-N-tHBcAg-PAA-DOX) at pH 5.4 and 7.4. Approximately 80% of the DOX packaged in tHBcAg nanoparticles was released after 2 days at pH 5.4. However, at pH 7.4, only approximately 19% of the DOX was released from the particles after 2 days, demonstrating slow release of DOX at physiological pH. (b) Enlargement of the free DOX release profile. More than 80% of the free DOX was released after 6 h, at pH 5.4 and pH 7.4. Data are expressed as the mean ± standard deviation (n = 3).
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f6: Cumulative release profile of doxorubicin packaged in tHBcAg nanoparticles in different pH conditions.(a) Release profile of free doxorubicin (DOX), tHBcAg nanoparticles loaded with PAA-DOX (tHBcAg-PAA-DOX), folic acid (FA)-conjugated tHBcAg nanoparticles loaded with PAA-DOX (FA-tHBcAg-PAA-DOX), and FA-conjugated tHBcAg nanoparticles using the nanoglue and loaded with PAA-DOX (FA-N-tHBcAg-PAA-DOX) at pH 5.4 and 7.4. Approximately 80% of the DOX packaged in tHBcAg nanoparticles was released after 2 days at pH 5.4. However, at pH 7.4, only approximately 19% of the DOX was released from the particles after 2 days, demonstrating slow release of DOX at physiological pH. (b) Enlargement of the free DOX release profile. More than 80% of the free DOX was released after 6 h, at pH 5.4 and pH 7.4. Data are expressed as the mean ± standard deviation (n = 3).

Mentions: An in vitro drug release experiment was performed under simulated physiological (pH 7.4, 37 °C)27 and tumour tissue and endosomal conditions (pH 5.4, 37 °C)28 at various time points. The drug release profiles of the tHBcAg-PAA-DOX, FA-tHBcAg-PAA-DOX and FA-N-tHBcAg-PAA-DOX particles were compared with free DOX (Fig. 6). After 6 h of incubation, approximately 80% of the free DOX was released into the receptor chamber, and almost all of it was released within 24 h (Fig. 6a and b). No significant difference was observed in the cumulative release rate of free DOX in the different pH solutions. In contrast, tHBcAg-PAA-DOX, FA-tHBcAg-PAA-DOX and FA-N-tHBcAg-PAA-DOX nanoparticles did not exhibit any significant release of DOX in the initial hours, resulting in more sustained DOX release patterns over the subsequent 2 days at pH 5.4 (Fig. 6a). In addition, the cumulative release of DOX from tHBcAg-PAA-DOX, FA-tHBcAg-PAA-DOX and FA-N-tHBcAg-PAA-DOX nanoparticles was significantly higher at pH 5.4 (P < 0.01) compared with pH 7.4, indicating that DOX is released more efficiently and in a controlled manner in tumour tissue and endosomal conditions.


pH-responsive Virus-like Nanoparticles with Enhanced Tumour-targeting Ligands for Cancer Drug Delivery
Cumulative release profile of doxorubicin packaged in tHBcAg nanoparticles in different pH conditions.(a) Release profile of free doxorubicin (DOX), tHBcAg nanoparticles loaded with PAA-DOX (tHBcAg-PAA-DOX), folic acid (FA)-conjugated tHBcAg nanoparticles loaded with PAA-DOX (FA-tHBcAg-PAA-DOX), and FA-conjugated tHBcAg nanoparticles using the nanoglue and loaded with PAA-DOX (FA-N-tHBcAg-PAA-DOX) at pH 5.4 and 7.4. Approximately 80% of the DOX packaged in tHBcAg nanoparticles was released after 2 days at pH 5.4. However, at pH 7.4, only approximately 19% of the DOX was released from the particles after 2 days, demonstrating slow release of DOX at physiological pH. (b) Enlargement of the free DOX release profile. More than 80% of the free DOX was released after 6 h, at pH 5.4 and pH 7.4. Data are expressed as the mean ± standard deviation (n = 3).
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f6: Cumulative release profile of doxorubicin packaged in tHBcAg nanoparticles in different pH conditions.(a) Release profile of free doxorubicin (DOX), tHBcAg nanoparticles loaded with PAA-DOX (tHBcAg-PAA-DOX), folic acid (FA)-conjugated tHBcAg nanoparticles loaded with PAA-DOX (FA-tHBcAg-PAA-DOX), and FA-conjugated tHBcAg nanoparticles using the nanoglue and loaded with PAA-DOX (FA-N-tHBcAg-PAA-DOX) at pH 5.4 and 7.4. Approximately 80% of the DOX packaged in tHBcAg nanoparticles was released after 2 days at pH 5.4. However, at pH 7.4, only approximately 19% of the DOX was released from the particles after 2 days, demonstrating slow release of DOX at physiological pH. (b) Enlargement of the free DOX release profile. More than 80% of the free DOX was released after 6 h, at pH 5.4 and pH 7.4. Data are expressed as the mean ± standard deviation (n = 3).
Mentions: An in vitro drug release experiment was performed under simulated physiological (pH 7.4, 37 °C)27 and tumour tissue and endosomal conditions (pH 5.4, 37 °C)28 at various time points. The drug release profiles of the tHBcAg-PAA-DOX, FA-tHBcAg-PAA-DOX and FA-N-tHBcAg-PAA-DOX particles were compared with free DOX (Fig. 6). After 6 h of incubation, approximately 80% of the free DOX was released into the receptor chamber, and almost all of it was released within 24 h (Fig. 6a and b). No significant difference was observed in the cumulative release rate of free DOX in the different pH solutions. In contrast, tHBcAg-PAA-DOX, FA-tHBcAg-PAA-DOX and FA-N-tHBcAg-PAA-DOX nanoparticles did not exhibit any significant release of DOX in the initial hours, resulting in more sustained DOX release patterns over the subsequent 2 days at pH 5.4 (Fig. 6a). In addition, the cumulative release of DOX from tHBcAg-PAA-DOX, FA-tHBcAg-PAA-DOX and FA-N-tHBcAg-PAA-DOX nanoparticles was significantly higher at pH 5.4 (P < 0.01) compared with pH 7.4, indicating that DOX is released more efficiently and in a controlled manner in tumour tissue and endosomal conditions.

View Article: PubMed Central - PubMed

ABSTRACT

Multifunctional nanocarriers harbouring specific targeting moieties and with pH-responsive properties offer great potential for targeted cancer therapy. Several synthetic drug carriers have been studied extensively as drug delivery systems but not much information is available on the application of virus-like nanoparticles (VLNPs) as multifunctional nanocarriers. Here, we describe the development of pH-responsive VLNPs, based on truncated hepatitis B virus core antigen (tHBcAg), displaying folic acid (FA) for controlled drug delivery. FA was conjugated to a pentadecapeptide containing nanoglue bound on tHBcAg nanoparticles to increase the specificity and efficacy of the drug delivery system. The tHBcAg nanoparticles loaded with doxorubicin (DOX) and polyacrylic acid (PAA) demonstrated a sustained drug release profile in vitro under tumour tissue conditions in a controlled manner and improved the uptake of DOX in colorectal cancer cells, leading to enhanced antitumour effects. This study demonstrated that DOX-PAA can be packaged into VLNPs without any modification of the DOX molecules, preserving the pharmacological activity of the loaded DOX. The nanoglue can easily be used to display a tumour-targeting molecule on the exterior surface of VLNPs and can bypass the laborious and time-consuming genetic engineering approaches.

No MeSH data available.