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Multifunctional albumin nanoparticles as combination drug carriers for intra-tumoral chemotherapy.

ABSTRACT: Current cancer therapies are challenged by weakly soluble drugs and by drug combinations that exhibit non-uniform biodistribution and poor bioavailability. In this study, we have presented a new platform of advanced healthcare materials based on albumin nanoparticles (ANPs) engineered as tumor penetrating, delivery vehicles of combinatorially applied factors to solid tumors. These materials were designed to overcome three sequential key barriers: tissue level transport across solid tumor matrix; uptake kinetics into individual cancer cells; therapeutic resistance to single chemotherapeutic drugs. The ANPs were designed to penetrate deeper into solid tumor matrices using collagenase decoration and evaluated using a three-dimensional multicellular melanoma tumor spheroid model. Collagenase modified ANPs exhibited 1-2 orders of magnitude greater tumor penetration than unmodified ANPs into the spheroid mass after 96 hours, and showed preferential uptake into individual cancer cells for smaller sized ANPs (<100 nm). For enhanced efficacy, collagenase coated ANPs were modified with two therapeutic agents, curcumin and riluzole, with complementary mechanisms of action for combined cell cycle arrest and apoptosis in melanoma. The collagenase coated, drug loaded nanoparticles induced significantly more cell death within 3-D tumor models than the unmodified, dual drug loaded ANP particles and the kinetics of cytotoxicity was further influenced by the ANP size. Thus, multifunctional nanoparticles can be imbued with complementary size and protease activity features that allow them to penetrate solid tumors and deliver combinatorial therapeutic payload with enhanced cancer cytotoxicity but minimal collateral damage to healthy primary cells.

SUBMITTER: Cui M

PROVIDER: S-EPMC5720860 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Multifunctional albumin nanoparticles as combination drug carriers for intra-tumoral chemotherapy.

Cui Mingjie M Naczynski Dominik J DJ Zevon Margot M Griffith Craig K CK Sheihet Larisa L Poventud-Fuentes Izmarie I Chen Suzie S Roth Charles M CM Moghe Prabhas V PV

Advanced healthcare materials 20130312 9

Current cancer therapies are challenged by weakly soluble drugs and by drug combinations that exhibit non-uniform biodistribution and poor bioavailability. In this study, we have presented a new platform of advanced healthcare materials based on albumin nanoparticles (ANPs) engineered as tumor penetrating, delivery vehicles of combinatorially applied factors to solid tumors. These materials were designed to overcome three sequential key barriers: tissue level transport across solid tumor matrix; ...[more]

PMID: 23495216

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Project description:BackgroundProgressive fibrosis is the underlying pathophysiological process of CKD, and targeted prevention or reversal of the profibrotic cell phenotype is an important goal in developing therapeutics for CKD. Nanoparticles offer new ways to deliver antifibrotic therapies to damaged tissues and resident cells to limit manifestation of the profibrotic phenotype.MethodsWe focused on delivering plasmid DNA expressing bone morphogenetic protein 7 (BMP7) or hepatocyte growth factor (HGF)-NK1 (HGF/NK1) by encapsulation within chitosan nanoparticles coated with hyaluronan, to safely administer multifunctional nanoparticles containing the plasmid DNA to the kidneys for localized and sustained expression of antifibrotic factors. We characterized and evaluated nanoparticles in vitro for biocompatibility and antifibrotic function. To assess antifibrotic activity in vivo, we used noninvasive delivery to unilateral ureteral obstruction mouse models of CKD.ResultsSynthesis of hyaluronan-coated chitosan nanoparticles containing plasmid DNA expressing either BMP7 or NGF/NKI resulted in consistently sized nanoparticles, which-following endocytosis driven by CD44+ cells-promoted cellular growth and inhibited fibrotic gene expression in vitro. Intravenous tail injection of these nanoparticles resulted in approximately 40%-45% of gene uptake in kidneys in vivo. The nanoparticles attenuated the development of fibrosis and rescued renal function in unilateral ureteral obstruction mouse models of CKD. Gene delivery of BMP7 reversed the progression of fibrosis and regenerated tubules, whereas delivery of HGF/NK1 halted CKD progression by eliminating collagen fiber deposition.ConclusionsNanoparticle delivery of HGF/NK1 conveyed potent antifibrotic and proregenerative effects. Overall, this research provided the proof of concept on which to base future investigations for enhanced targeting and transfection of therapeutic genes to kidney tissues, and an avenue toward treatment of CKD.

Project description:Background: Prostate cancer (PCa) influences its surrounding habitat, which tends to manifest as different phenotypic appearances on magnetic resonance imaging (MRI). This region surrounding the PCa lesion, or the peri-tumoral region, may encode useful information that can complement intra-tumoral information to enable better risk stratification. Purpose: To evaluate the role of peri-tumoral radiomic features on bi-parametric MRI (T2-weighted and Diffusion-weighted) to distinguish PCa risk categories as defined by D'Amico Risk Classification System. Materials and Methods: We studied a retrospective, HIPAA-compliant, 4-institution cohort of 231 PCa patients (n = 301 lesions) who underwent 3T multi-parametric MRI prior to biopsy. PCa regions of interest (ROIs) were delineated on MRI by experienced radiologists following which peri-tumoral ROIs were defined. Radiomic features were extracted within the intra- and peri-tumoral ROIs. Radiomic features differentiating low-risk from: (1) high-risk (L-vs.-H), and (2) (intermediate- and high-risk (L-vs.-I + H)) lesions were identified. Using a multi-institutional training cohort of 151 lesions (D1, N = 116 patients), machine learning classifiers were trained using peri- and intra-tumoral features individually and in combination. The remaining 150 lesions (D2, N = 115 patients) were used for independent hold-out validation and were evaluated using Receiver Operating Characteristic (ROC) analysis and compared with PI-RADS v2 scores. Results: Validation on D2 using peri-tumoral radiomics alone resulted in areas under the ROC curve (AUCs) of 0.84 and 0.73 for the L-vs.-H and L-vs.-I + H classifications, respectively. The best combination of intra- and peri-tumoral features resulted in AUCs of 0.87 and 0.75 for the L-vs.-H and L-vs.-I + H classifications, respectively. This combination improved the risk stratification results by 3-6% compared to intra-tumoral features alone. Our radiomics-based model resulted in a 53% accuracy in differentiating L-vs.-H compared to PI-RADS v2 (48%), on the validation set. Conclusion: Our findings suggest that peri-tumoral radiomic features derived from prostate bi-parametric MRI add independent predictive value to intra-tumoral radiomic features for PCa risk assessment.

Project description:Some experimental and clinical studies have been conducted for the usage of chemotherapeutic drugs encapsulated into nanoparticles (NPs). However, no study has been conducted so far on the co-encapsulation of doxorubicin (Dox) and epoxomicin (Epo) into NPs as biocompatible drug delivery carriers. Therefore, we investigated if co-encapsulation of doxorubicin (Dox) and/or epoxomicin (Epo) into NPs enhance their anticancer efficiency and prevent drug resistance and toxicity to normal cells. We synthesized Dox and/or Epo loaded poly (lactic-co-glycolic acid) (PLGA) NPs using a multiple emulsion solvent evaporation technique and characterized them in terms of their particle size and stability, surface, molecular, thermal, encapsulation efficiency and in vitro release properties. We studied the effects of drug encapsulated NPs on cellular accumulation, intracellular drug levels, oxidative stress status, cellular viability, drug resistance, 20S proteasome activity, cytosolic Nuclear Factor Kappa B (NF-κB-p65), and apoptosis in breast cancer and normal cells. Our results proved that the nanoparticles we synthesized were thermally stable possessing higher encapsulation efficiency and particle stability. Thermal, morphological and molecular analyses demonstrated the presence of Dox and/or Epo within NPs, indicating that they were successfully loaded. Cell line assays proved that Dox and Epo loaded NPs were less cytotoxic to single-layer normal HUVECs than free Dox and Epo, suggesting that the NPs would be biocompatible drug delivery carriers. The apoptotic index of free Dox and Epo increased 50% through their encapsulation into NPs, proving combination strategy to enhance apoptosis in breast cancer cells. Our results demonstrated that the co-encapsulation of Dox and Epo within NPs would be a promising treatment strategy to overcome multidrug resistance and toxicity to normal tissues that can be studied in further in vivo and clinical studies in breast cancer.

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Multifunctional albumin nanoparticles as combination drug carriers for intra-tumoral chemotherapy.

Publications

Multifunctional albumin nanoparticles as combination drug carriers for intra-tumoral chemotherapy.

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