Nanoscaled PAMAM Dendrimer Spacer Improved the Photothermal-Photodynamic Treatment Efficiency of Photosensitizer-Decorated Confeito-Like Gold Nanoparticles for Cancer Therapy.

A critical factor in developing an efficient photosensitizer-gold nanoparticle (PS-AuNP) hybrid system with improved plasmonic photosensitization is to allocate a suitable space between AuNPs and PS. Poly(amidoamine) (PAMAM) dendrimer is selected as a spacer between the PS and confeito-like gold nanoparticles (confeito-AuNPs), providing the required distance (≈2.5-22.5 nm) for plasmon-enhanced singlet oxygen generation and heat production upon 638-nm laser irradiation and increase the cellular internalization of the nanoconjugates. The loading of the PS, tetrakis(4-carboxyphenyl) porphyrin (TCPP), and modified zinc phthalocyanine (ZnPc1) onto PAMAM-confeito-AuNPs demonstrate better in vitro cancer cell-killing efficacy, as the combined photothermal-photodynamic therapies (PTT-PDTs) outperforms the single treatment modalities (PTT or PDT alone). These PS-PAMAM-confeito-AuNPs also demonstrate higher phototoxicity than photosensitizers directly conjugated to confeito-AuNPs (TCPP-confeito-AuNPs and ZnPc1-confeito-AuNPs) against all breast cancer cell lines tested (MDA-MB-231, MCF7, and 4T1). In the in vivo studies, TCPP-PAMAM-confeito-AuNPs are biocompatible and exhibit a selective tumor accumulation effect, resulting in higher antitumor efficacy than free TCPP, PAMAM-confeito-AuNPs, and TCPP-confeito-AuNPs. In vitro and in vivo evaluations confirm PAMAM effectiveness in facilitating cellular uptake, plasmon-enhanced singlet oxygen and heat generation. In summary, this study highlights the potential of integrating a PAMAM spacer in enhancing the plasmon effect-based photothermal-photodynamic anticancer treatment efficiency of PS-decorated confeito-AuNPs.

Chitosan-Coated-PLGA Nanoparticles Enhance the Antitumor and Antimigration Activity of Stattic - A STAT3 Dimerization Blocker.

PURPOSE: The use of nanocarriers to improve the delivery and efficacy of antimetastatic agents is less explored when compared to cytotoxic agents. This study reports the entrapment of an antimetastatic Signal Transducer and Activator of Transcription 3 (STAT3) dimerization blocker, Stattic (S) into a chitosan-coated-poly(lactic-co-glycolic acid) (C-PLGA) nanocarrier and the improvement on the drug's physicochemical, in vitro and in vivo antimetastatic properties post entrapment. METHODS: In vitro, physicochemical properties of the Stattic-entrapped C-PLGA nanoparticles (S@C-PLGA) and Stattic-entrapped PLGA nanoparticles (S@PLGA, control) in terms of size, zeta potential, polydispersity index, drug loading, entrapment efficiency, Stattic release in different medium and cytotoxicity were firstly evaluated. The in vitro antimigration properties of the nanoparticles on breast cancer cell lines were then studied by Scratch assay and Transwell assay. Study on the in vivo antitumor efficacy and antimetastatic properties of S@C-PLGA compared to Stattic were then performed on 4T1 tumor bearing mice. RESULTS: The S@C-PLGA nanoparticles (141.8 ± 2.3 nm) was hemocompatible and exhibited low Stattic release (12%) in plasma. S@C-PLGA also exhibited enhanced in vitro anti-cell migration potency (by >10-fold in MDA-MB-231 and 5-fold in 4T1 cells) and in vivo tumor growth suppression (by 33.6%) in 4T1 murine metastatic mammary tumor bearing mice when compared to that of the Stattic-treated group. Interestingly, the number of lung and liver metastatic foci was found to reduce by 50% and 56.6%, respectively, and the average size of the lung metastatic foci was reduced by 75.4% in 4T1 tumor-bearing mice treated with S@C-PLGA compared to Stattic-treated group (p < 0.001). CONCLUSION: These findings suggest the usage of C-PLGA nanocarrier to improve the delivery and efficacy of antimetastatic agents, such as Stattic, in cancer therapy.

Surfactant-Free Direct Access to Porphyrin-Cross-Linked Nanogels for Photodynamic and Photothermal Therapy.

Photosensitizing nanogels were obtained through a surfactant-free single-step protocol by using a porphyrin-based cross-linker for stabilizing self-assembled nanosized aggregates of thermoresponsive copolymers. Nanogels with varying amounts of porphyrin retained the singlet oxygen generation ability of the porphyrin core and were also capable of inducing temperature increase upon irradiation at 635 nm. Photoinduced killing efficiency was tested against three cell lines: human breast adenocarcinoma (MDA-MB-231 and MCF7) and pancreatic adenocarcinoma (AsPC-1) cells, and a predominant photodynamic mechanism at 450 nm and a mixed photodynamic and photothermal effect at 635 nm was observed. This innovative access to photosensitizing nanogels is a proof of concept, and opens new perspectives toward the preparation of optimized nanophotosensitizers.

Size-dependent effect of cystine/citric acid-capped confeito-like gold nanoparticles on cellular uptake and photothermal cancer therapy.

Physiochemical changes, including size, are known to affect gold nanoparticle cellular internalization and treatment efficacy. Here, we report the effect of four sizes of cystine/citric acid-coated confeito-like gold nanoparticles (confeito-AuNPs) (30, 60, 80 and 100nm) on cellular uptake, intracellular localization and photothermal anticancer treatment efficiency in MDA-MB231 breast cancer cells. Cellular uptake is size dependent with the smallest size of confeito-AuNPs (30nm) having the highest cellular internalization via clathrin- and caveolae-mediated endocytosis. However, the other three sizes (60, 80 and 100nm) utilize clathrin-mediated endocytosis for cellular uptake. The intracellular localization of confeito-AuNPs is related to their endocytosis mechanism, where all sizes of confeito-AuNPs were localized highly in the lysosome and mitochondria, while confeito-AuNPs (30nm) gave the highest localization in the endoplasmic reticulum. Similarly, a size-dependent trend was also observed in in vitro photothermal treatment experiments, with the smallest confeito-AuNPs (30nm) giving the highest cell killing rate, whereas the largest size of confeito-AuNPs (100nm) displayed the lowest photothermal efficacy. Its desirable physicochemical characteristics, biocompatible nature and better photothermal efficacy will form the basis for further development of multifunctional confeito-AuNP-based nanotherapeutic applications.

Doxorubicin-loaded micelles of amphiphilic diblock copolymer with pendant dendron improve antitumor efficacy: In vitro and in vivo studies.

Previously reported amphiphilic diblock copolymer with pendant dendron moieties (P71D3) has been further evaluated in tumor-bearing mice as a potential drug carrier. This P71D3-based micelle of an average diameter of 100nm was found to be biocompatible, non-toxic and physically stable in colloidal system up to 15days. It enhanced the in vitro potency of doxorubicin (DOX) in 4T1 breast tumor cells by increasing its uptake, by 3-fold, compared to free DOX. In 4T1 tumor-bearing mice, the tumor growth rate of P71D3/DOX (2mg/kg DOX equivalent) treated group was significantly delayed and their tumor volume was significantly reduced by 1.5-fold compared to those treated with free DOX. The biodistribution studies indicated that P71D3/DOX enhanced accumulation of DOX in tumor by 5- and 2-fold higher than free DOX treated mice at 15min and 1h post-administration, respectively. These results suggest that P71D3 micelle is a promising nanocarrier for chemotherapeutic agents.