Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma
International Journal of Nanomedicine
Mithramycin-loaded mPeg-Plga nanoparticles exert potent antitumor efficacy against pancreatic carcinoma
0 Institute of Medicinal Biotechnology, c hinese a cademy of Medical s ciences and Peking Union Medical College , Beijing , People's Republic of China
Previous studies have shown that mithramycin A (MIT) is a promising candidate for the treatment of pancreatic carcinoma through inhibiting transcription factor Sp1. However, systemic toxicities may limit its clinical application. Here, we report a rationally designed formulation of MIT-loaded nanoparticles (MIT-NPs) with a small size and sustained release for improved passive targeting and enhanced therapeutic efficacy. Nearly spherical MIT-NPs with a mean particle size of 25.0±4.6 nm were prepared by encapsulating MIT into methoxy poly(ethylene glycol)-block-poly(d ,l -lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) with drug loading of 2.11%±0.51%. The in vitro release of the MIT-NPs lasted for .48 h with a sustained-release pattern. The cytotoxicity of MIT-NPs to human pancreatic cancer BxPC-3 and MIA Paca-2 cells was comparable to that of free MIT. Determined by flow cytometry and confocal microscopy, the NPs internalized into the cells quickly and efficiently, reaching the peak level at 1-2 h. In vivo fluorescence imaging showed that the prepared NPs were gradually accumulated in BxPC-3 and MIA Paca-2 xenografts and retained for 168 h. The fluorescence intensity in both BxPC-3 and MIA Paca-2 tumors was much stronger than that of various tested organs. Therapeutic efficacy was evaluated with the poorly permeable BxPC-3 pancreatic carcinoma xenograft model. At a well-tolerated dose of 2 mg/kg, MIT-NPs suppressed BxPC-3 tumor growth by 96%. Compared at an equivalent dose, MIT-NPs exerted significantly higher therapeutic effect than free MIT (86% versus 51%, P,0.01). Moreover, the treatment of MIT and MIT-NPs reduced the expression level of oncogene c-Myc regulated by Sp1, and notably, both of them decreased the protein level of CD47. In summary, the novel formulation of MIT-NPs shows highly therapeutic efficacy against pancreatic carcinoma xenograft. In addition, MIT-NPs can downregulate CD47 expression, implying that it might play a positive role in cancer immunotherapy.
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Owing to perineural and vascular local growth and early
distant metastases, pancreatic cancer is usually unresectable
in most patients diagnosed at first. Effective chemotherapy
is needed for patients who undergo surgical resection or
are unable to have a curative surgery. However, pancreatic
cancer is generally associated with a remarkable resistance to
most conventional therapies.1 Thus, novel chemotherapeutic
methods are urgently needed to treat pancreatic cancer.
Mithramycin A (MIT), also called plicamycin, is a natural
aureolic acid-type polyketide isolated from various strains
of streptomyces.3 MIT has been used clinically as a
chemotherapeutic agent to treat several cancer types, including
testicular embryonal carcinoma and glioblastoma, although
systemic toxicities limited its clinical use. In recent years,
there has been renewed interest in the capability of MIT to
bind to the minor groove of guanine and cytosine-rich DNA
regions, since pharmacologically mediated modulation of
DNA/protein complex formation represents a promising
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aggressive clinical behavior and Sp1 overexpression increased
the probability of cancer metastasis.17 MIT can exhibit an
inhibitory effect on pancreatic cancer growth through distinct
mechanisms of Sp1 inhibition. Treatment with MIT resulted
in the inhibition of Sp1 recruitment onto vascular
endothelial growth factor (VEGF) and transforming growth factor
(TGF)-β type II receptor (TGF-β RII) promoters, leading to
downregulation of VEGF and TGF-β RII protein expression
in pancreatic cancer cells.15,18,19 Meanwhile, MIT can sensitize
pancreatic cancer cells to TRAIL-induced apoptosis.20 In spite
of promising preclinical findings, the clinical use of MIT,
especially as an anticancer drug requiring higher doses, has
been hampered by its systemic toxicity. In order to enhance its
safety and efficacy, one of the feasible strategies is to develop
efficient formulations of drug delivery systems.
Nanotechnology has attracted growing interest in cancer
therapies due to its uniquely appealing features for drug
delivery. The nanoparticle (NP) platforms for the targeted
delivery of therapeutic drugs to solid tumors hold great
promise for improving drug bioavailability and minimizing
systemic toxicity. NPs are widely used as drug carriers
because large molecules can avoid renal clearance and
circulate in the body for prolonged time in comparison to
small molecules. NPs accumulate in the tumor through the
enhanced permeability and retention (EPR) effect, which
enter the tumor interstitial space by enhanced permeability of
the abnormal tumor microvasculature and re (...truncated)