Aptamer-modified PLGA nanoparticle delivery of triplex forming oligonucleotide for targeted prostate cancer therapy

Abstract

Presented study aimed to prepare A10 aptamer-modified poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles loaded with triplex forming oligonucleotides(TFO) for targeted prostate cancer therapy. We first synthesized a PLGA-PEG-Apt copolymer. The PLGA-PEG-Apt nanoparticles (NP-Apt) were loaded with TFO using double emulsion solvent evaporation method. Carboxy-fluorescein labeled TFO-NP-Apt, TFO-NP and TFO were prepared for cellular uptake experiments. Cell counting kit-8 (CCK-8) test was used to determine the ability of TFO-NP-Apt to inhibit LNCaP cell proliferation. RT-PCR and Western blot was conducted to analyze AR gene expressing. Then, a mouse model of prostate cancer was used to evaluate the anti-cancer effect of TFO-NP-Apt in vivo. We confirmed that the PLGA-PEG-Apt conjugation was successful. The TFO encapsulation efficiency and drug loading percentage were 46.1± 3.6% and 40.8±5.3%, respectively. TFO-NP-Apt showed a more efficient cellular uptake than TFO-NP or TFO in LNCaP cells. TFO-NP-Apt was significantly more cytotoxic than TFO-NP and TFO in the CCK-8 test (p<0.001). TFO-NP-Apt silenced the AR gene better than unconjugated Apt, naked TFO, NP or saline. TFO-NP-Apt were more effective than TFO-NP, naked TFO, NP and saline at inhibiting prostate cancer growth in vivo (p<0.05). Aptamer-modified TFO-loaded PLGA nanoparticles may prove useful in targeted therapy for advanced prostate cancer.

Nanoparticle delivery of TFOs is a novel targeted therapy for HER2 amplified breast cancer

“…TFO binds to double-stranded DNA in a sequence-specific manner to form a local triple-stranded helical structure, which can inhibit protein binding at the promoter region, block the extension of transcription, and induce DNA mutation and recombination [ 21 ]. Since TFO is a linear hydrophilic nucleic acid molecule, and the cell membrane is a lipid-soluble bilayer membrane with no nucleic acid channel, it is difficult for naked TFO to go through the cell membrane [ 11 ]. Tum cells' uptake rate of TFO increased significantly after encapsulation of ZW-128 nano-particles.…”

“…However, there are still some challenges in delivering TFO to target cells. Tiwari et al and Jiao et al used nano-particles to transfer TFO fragments [ 10 , 11 ]. The main obstacles of nanoparticles are enzyme degradation, short half-life, and poor cellular uptake [ 12 ].…”

Drug-loaded PEG-PLGA nanoparticles for cancer treatment

“…In addition, EpCAM aptamer-conjugated PEG-PLGA NPs enhanced the cellular uptake and cytotoxicity of DOX against human breast adenocarcinoma cells (Alibolandi et al, 2015a;Alibolandi et al, 2015b). Conjugation of A10 aptamer to PEG-PLGA NPs loaded with triplex-forming oligonucleotides led to specific targeting of prostate cancer cells and inhibition of tumor growth, and the modified NPs silenced the androgen receptor gene more effectively than unmodified NPs (Jiao et al, 2016).…”

Protease-triggered bioresponsive drug delivery for the targeted theranostics of malignancy

“…Concretely, tumor lesions targeted delivery of PSA-specific motif-conjugated nanocomplexes carrying a variety of therapeutics either alone or in combination, mainly included DOX 181 , 182 , 183 , 184 , 185 , PTX 186 , DTX 187 , SN38 188 , camptothecin 189 , thapsigargin 190 , boron-containing reagents 191 , zinc chelator 192 , antibody-drug conjugates 193 , 194 , kinase inhibitors 195 , siRNA ( Fig. 7 ) 196 , 197 , 198 , 199 , 200 , miRNA 201 , oligonucleotide 202 , therapeutic proteins 203 , and chemotherapy-based combination regimens with molecular targeted therapy 204 , antibiotic therapy 205 , gene therapy 206 , 207 , and anti-inflammatory therapy 208 .

Figure 7 Schematic diagram displays the multifunctional envelope-type nanoplatform for PSA-targeted siRNA delivery and prostate cancer therapy.

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