131I-Traced PLGA-Lipid Nanoparticles as Drug Delivery Carriers for the Targeted Chemotherapeutic Treatment of Melanoma

Abstract

Herein, folic acid (FA) conjugated Poly(d,l-lactide-co-glycolide) (PLGA)-lipid composites (FA-PL) were developed as nanocarriers for the targeted delivery of insoluble anti-cancer drug paclitaxel (PTX), resulting FA-PLP nanoparticles. Furthermore, 131I, as a radioactive tracer, was used to label FA-PLP nanoparticles (FA-PLP-131I) to evaluate their cell uptake activity, in vivo blood circulation, and biodistribution. The FA-PLP-131I nanoparticles had a spherical morphology with great stability, a narrow size distribution (165.6 and 181.2 nm), and −22.1 mV in average zeta potential. Confocal laser scanning microscopy indicated that the targeting molecule FA promotes PLP-131I uptake by melanoma B16F10 cells, which was further confirmed by the cell incorporation rate via 131I activity detection as measured by a gamma counter. FA-PLP-131I without PTX (FA-PL-131I) shows minor cytotoxicity, good biocompatibility, while FA-PLP-131I was demonstrated to have efficient cell viability suppression compared to free PTX and PLP-131I. Following intravenous injection, the blood circulation half-life of free PTX (t 1/2 = 5.4 ± 0.23 h) was prolonged to 18.5 ± 0.5 h by FA-PLP-131I. Through FA targeting, the tumor uptake of FA-PLP-131I was approximately 4.41- and 12.8-fold higher compared to that of PLP-131I and free PTX-131I, respectively. Moreover, following 40 days of treatment, FA-PLP-131I showed an improved tumor inhibition effect compared to free PTX and PLP-131I, with no relapse and no remarkable systemic in vivo toxicity. The results demonstrate that the 131I-labeled PLGA-lipid nanoparticle can be simultaneously applied for targeted drug delivery and reliable tracking of drugs in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s11671-017-2140-7) contains supplementary material, which is available to authorized users.

<p>Folate-mediated and pH-responsive chidamide-bound micelles encapsulating photosensitizers for tumor-targeting photodynamic therapy</p>

“…In addition, Pha@FPPC micelles had lower dark cytotoxicity against B16-F10 and A2780 cells and a better therapeutic index because of its higher dark cytotoxicity/photocytotoxicity ratio. More encouragingly, Pha@FPPC not only significantly strengthened the PDT antitumor efficacy on B16-F10-bearing mice of free Pha due to both its FA-mediated tumor-targeting17–19 and EPR effect of tumor as micelle nanoparticles21–23 but also remarkably prevented pulmonary metastasis of mice melanoma due to chidamide segment as a HDACi, resulting in a significant synergistic antitumor effect of photosensitizer and HDACi. All in all, as a new modality of photodynamic therapy, folate-mediated and acid-activated chidamide-grafted drug-delivery polymer micelles, Pha@FPPC indeed have great potential to inhibit tumor metastasis and relapse in clinical photodynamic treatment.…”

“…Compared with the control group, on day 3 after PDT, Pha@FPPC, and Pha@PPC groups initiated significant difference ( P <0.01 and P <0.05, respectively), while other groups indicated significant difference on day 4–6 in variety, demonstrating encapsulation of Pha into drug-delivery carrier FPPC could significantly enhance the PDT antitumor effect of Pha in vivo due to EPR effect of tumor as micelle nanoparticles 21–23. On day 7 after PDT, the destiny Pha@FPPC group showed a significant difference compared with every other group, indicating the advantage of folate-targeting strategy in retarding tumor proliferation due to its FA-mediated tumor targeting 17–19. Additionally, compared with the control group, the FPPC group showed significant difference on day 5 after PDT, hinting the antitumor effect of chidamide bound to the polymer vehicle.

Figure 5PDT antitumor efficacy of Pha@FPPC on mice bearing B16-F10 melanoma in vivo. Notes: ( A ) Mice bearing B16-F10 melanoma irradiated by the diode laser at 660 nm with a light dosage of 90 J/cm 2 at 45 mins after intravenous administration with a drug dosage of 2 mg/kg; ( B ) tumor growth curve (*Represented the differences of control group vs every other group, and # represented the differences of Pha@FPPC vs every other group, * P, # P <0.05, ** P, ## P <0.01 and *** P, P <0.001); ( C ) survival curves of C57BL/6J (control vs Pha@FPPC, * P =0.0127; control vs Pha@PPC, * P =0.0499; Pha@FPPC vs Pha, # P =0.0471; Pha@FPPC vs FPPC, & P =0.0364), the data were shown as the mean ± standard deviation, n =5; ( D ) the posteroanterior photographs of lung tissues with metastatic nodules of the first dead mice bearing B16-F10 melanoma in each group after PDT.

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“…After tumor cellular uptake of the Pha@FPPC micelles through FA-receptor-mediated endocytosis,17–19 endosomes evolve into lysosome due to the proton pump effects in the membrane of endosomes 20. Therefore, pH value of the lysosome finally could reach to 5.2 or even lower, and pH-responsive segment polymer poly(aspartic acid) (PAsp) was to turn to hydrophilicity from hydrophobicity in neutral solution, and Pha molecules were then directionally released in the lysosome from the micelles.…”

Artesunate-Loaded and Near-Infrared Dye-Conjugated Albumin Nanoparticles as High-Efficiency Tumor-Targeted Photo-Chemo Theranostic Agent

“…5b ). The results demonstrated that the conjugated FA facilitated the nanoparticles to target the FA receptors on tumor cells and thus enhance FA-IHA NPs cell uptake [ 39 , 40 , 41 ].

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Chamaejasmin B Decreases Malignant Characteristics of Mouse Melanoma B16F0 and B16F10 Cells

“…As melanoma is characterized by rapid progression, poor prognosis, and high mortality, various treatments have been developed. Chemotherapy is the optimal treatment for melanoma, although it results in low bioavailability, side effects, poor tumor selectivity, and dose-limiting systemic toxicity (2). In addition, uncontrolled melanoma cell proliferation results in resistance to conventional treatment approaches.…”