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Porphyrin-Gold Nanomaterial for Efficient Drug Delivery to Cancerous Cells.

ABSTRACT: With an aim to overcome multidrug resistance (MDR), nontargeted delivery, and drug toxicity, we developed a new nanochemotherapeutic system with tetrasodium salt of meso-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) armored on gold nanoparticles (TPPS-AuNPs). The nanocarrier is able to be selectively internalized within tumor cells than in normal cells followed by endocytosis and therefore delivers the antitumor drug doxorubicin (DOX) particularly to the nucleus of diseased cells. The embedment of TPPS on the gold nanosurface provides excellent stability and biocompatibility to the nanoparticles. Porphyrin interacts with the gold nanosurface through the coordination interaction between gold and pyrrolic nitrogen atoms of the porphyrin and forms a strong association complex. DOX-loaded nanocomposite (DOX@TPPS-AuNPs) demonstrated enhanced cellular uptake with significantly reduced drug efflux in MDR brain cancer cells, thereby increasing the retention time of the drug within tumor cells. It exhibited about 9 times greater potency for cellular apoptosis via triggered release commenced by acidic pH. DOX has been successfully loaded on the porphyrin-modified gold nanosurface noncovalently with high encapsulation efficacy (?90%) and tightly associated under normal physiological conditions but capable of releasing ?81% of drug in a low-pH environment. Subsequently, DOX-loaded TPPS-AuNPs exhibited higher inhibition of cellular metastasis, invasion, and angiogenesis, suggesting that TPPS-modified AuNPs could improve the therapeutic efficacy of the drug molecule. Unlike free DOX, drug-loaded TPPS-AuNPs did not show toxicity toward normal cells. Therefore, higher drug encapsulation efficacy with selective targeting potential and acidic-pH-mediated intracellular release of DOX at the nucleus make TPPS-AuNPs a "magic bullet" for implication in nanomedicine.

SUBMITTER: Bera K

PROVIDER: S-EPMC6045359 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Porphyrin-Gold Nanomaterial for Efficient Drug Delivery to Cancerous Cells.

Bera Kaushik K Maiti Samarpan S Maity Mritunjoy M Mandal Chitra C Maiti Nakul C NC

ACS omega 20180426 4

With an aim to overcome multidrug resistance (MDR), nontargeted delivery, and drug toxicity, we developed a new nanochemotherapeutic system with tetrasodium salt of <i>meso</i>-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) armored on gold nanoparticles (TPPS-AuNPs). The nanocarrier is able to be selectively internalized within tumor cells than in normal cells followed by endocytosis and therefore delivers the antitumor drug doxorubicin (DOX) particularly to the nucleus of diseased cells. The embed ...[more]

PMID: 30023896

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Project description:Photodynamic therapy (PDT) is a potential non-invasive approach for application in oncological diseases, based on the activation of a photosensitizer (PS) by light at a specific wavelength in the presence of molecular oxygen to produce reactive oxygen species (ROS) that trigger the death tumor cells. In this context, porphyrins are interesting PS because they are robust, have high chemical, photo, thermal, and oxidative stability, and can generate singlet oxygen (1O2). However, porphyrins exhibit low solubility and a strong tendency to aggregate in a biological environment which limits their clinical application. To overcome these challenges, we developed hybrid nanostructures to immobilize 5,10,15,20-tetrakis[(4-carboxyphenyl) thio-2,3,5,6-tetrafluorophenyl] (P), a new third-generation PS. The biological effect of this system was evaluated against bladder cancer (BC) cells with or without light exposition. The nanostructure composed of lipid carriers coated by porphyrin-chitosan (P-HNP), presented a size of ca. 130 nm and low polydispersity (ca. 0.25). The presence of the porphyrin-chitosan (P-chitosan) on lipid nanoparticle surfaces increased the nanoparticle size, changed the zeta potential to positive, decreased the recrystallization index, and increased the thermal stability of nanoparticles. Furthermore, P-chitosan incorporation on nanoparticles increased the stability and enhanced the self-organization of the system and the formation of spherical structures, as observed by small-angle X-ray scattering (SAXS) analysis. Furthermore, the immobilization process maintained the P photoactivity and improved the photophysical properties of PS, minimizing its aggregation in the cell culture medium. In the photoinduction assays, the P-HNP displayed high phototoxicity with IC50 3.2-folds lower than free porphyrin. This higher cytotoxic effect can be correlated to the high cellular uptake of porphyrin immobilized, as observed by confocal images. Moreover, the coated nanoparticles showed mucoadhesive properties interesting to its application in vivo. Therefore, the physical and chemical properties of nanoparticles may be relevant to improve the porphyrin photodynamic activity in BC cells.

Project description:BackgroundPeptide-drug-conjugates (PDCs) are being developed as an effective strategy to specifically deliver cytotoxic drugs to cancer cells. However one of the challenges to their successful application is the relatively low stability of peptides in the blood, liver and kidneys. Since AuNPs seem to have a longer plasma half-life than PDCs, one approach to overcoming this problem would be to conjugate the PDCs to gold nanoparticles (AuNPs), as these have demonstrated favorable physico-chemical and safety properties for drug delivery systems. We set out to test whether PEG coated-AuNPs could provide a suitable platform for the non-covalent loading of pre-formed PDCs and whether this modification would affect the bioavailability of the PDCs and their cytotoxicity toward target cancer cells.MethodsPeptides specifically internalized by A20 murine lymphoma cells were isolated from a phage library displaying 7mer linear peptides. Peptide specificity was validated by flow cytometry and confocal microscopy. PDCs were synthesized containing a selected peptide (P4) and either chlorambucil (Chlor), melphalan (Melph) or bendamustine (Bend). Gold nanoparticles were sequentially coated with citrate, PEG-6000 and then PDC (PDC-PEG-AuNP). The physico-chemical properties of the coated particles were analyzed by electrophoresis, TEM, UV-VIS and FTIR. Stability of free and PDC-coated AuNP was determined.ResultsBiopanning of the phage library resulted in discovery of several novel peptides that internalized into A20 cells. One of these (P4) was used to synthesize PDCs containing either Chlor, Melph or Bend. All three PDCs specifically killed A20 target cells, however they had short half-lives ranging from 10.6 to 15.4 min. When coated to PEG-AuNPs, the half-lives were extended to 21.0-22.3 h. The PDC-PEG-AuNPs retained cytotoxicity towards the target cells. Moreover, whereas pre-incubation for 24 h of free PDCs almost completely abolished their cytotoxic activity, the PDC-PEG-AuNPs were still active even after 72 h pre-incubation.ConclusionsPeptide-drug-conjugates hold potential for improving the target efficacy of chemotherapeutic drugs, however their short half-lives may limit their application. This hurdle can be overcome by easily conjugating them to gold nanoparticles. This conjugation also opens up the possibility of developing slow release formulations of targeted drug delivery systems containing PDCs.

Dataset Information

Porphyrin-Gold Nanomaterial for Efficient Drug Delivery to Cancerous Cells.

Publications

Porphyrin-Gold Nanomaterial for Efficient Drug Delivery to Cancerous Cells.

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