Potent Engineered PLGA Nanoparticles by Virtue of Exceptionally High Chemotherapeutic Loadings

Enlow, Elizabeth M.; Luft, J. Christopher; Napier, Mary E.; DeSimone, Joseph M.

doi:10.1021/nl104117p

Cited by 130 publications

(114 citation statements)

References 35 publications

(49 reference statements)

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“…The SNA-NC structure is highly tailorable, and the gold core can serve as a scaffold for multicomponent functionalization, not just with siRNAs, but with targeting antibodies or peptides, and small molecule drugs as well (22). As such, these SNA conjugates are part of the growing arsenal of nanomaterials that are showing promise as alternatives to conventional molecular formats for the development of novel and effective therapies for a wide variety of diseases (22,(37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Zheng

Giljohann

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

363

288

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Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application. Significantly, these structures can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. SNANCs targeting epidermal growth factor receptor (EGFR), an important gene for epidermal homeostasis, are >100-fold more potent and suppress longer than siRNA delivered with commercial lipid agents in cultured keratinocytes. Topical delivery of 1.5 uM EGFR siRNA (50 nM SNA-NCs) for 3 wk to hairless mouse skin almost completely abolishes EGFR expression, suppresses downstream ERK phosphorylation, and reduces epidermal thickness by almost 40%. Similarly, EGFR mRNA in human skin equivalents is reduced by 52% after 60 h of treatment with 25 nM EGFR SNA-NCs. Treated skin shows no clinical or histological evidence of toxicity. No cytokine activation in mouse blood or tissue samples is observed, and after 3 wk of topical skin treatment, the SNA structures are virtually undetectable in internal organs. SNA conjugates may be promising agents for personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders.T he recent development of small molecule inhibitors and antibodies that target components of signaling pathways has revolutionized the treatment of cancers, inflammatory diseases, and genetic disorders, including those that largely manifest in skin (1-3). These protein-based therapeutics, however, are costly, have limited targeting ability, and, when delivered through traditional intravenous or gastrointestinal routes, can lead to systemic toxicity (4, 5). Topical delivery is particularly attractive for the therapy of skin disorders. However, proteins larger than a few hundred daltons cannot easily enter the skin, and high concentrations of proteins must be applied for a cutaneous effect (6). An alternative to protein-based pathway inhibition involves the blocking and/or degradation of precursor mRNA before translation into protein. Gene silencing leads to down-regulation of protein expression and functions with greater specificity than inhibitors of protein function (7). In fact, targeted gene suppression by antisense DNA and siRNA has shown promising preclinical results, and/or is currently in clinical trials for a variety of diseases, including many forms of cancer (e.g., melanoma, neuroblastoma, and pancreatic adenocarcinoma), genetic disorders, and macular degeneration (8). For gene su...

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Section: Discussionmentioning

confidence: 99%

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Zheng

Giljohann

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

363

288

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“…utilized the PRINT technique to encapsulate diverse bioactive agents such as proteins, DNA, and small-molecule therapeutics into these particles [30]. Figure 8 shows the process mapping of the PRINT technique used to prepare PLGA microparticles containing high payloads of docetaxel.…”

Section: Plga Microparticles With Any Geometrical Microfeaturementioning

confidence: 99%

Innovative next-generation PLGA microparticles with multifunctional architecture

Sah¹,

Sah²

2017

Biodegradable Polymers: Recent Developments and New Perspectives

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“…A single step reaction of docetaxel with chlorodimethylethylsilane was performed to generate the C2′ alcohol of taxane, the silyl ether docetaxel prodrug C2, as previously described [13]. PRINT-C2-docetaxel and PRINT-docetaxel nanoparticles were fabricated as previously described, to form the same sized cylindrical particles of PLGA polymer with a diameter of 80 nm and height of 320 nm, with similar drug loading [13,[15][16][17][18]. Briefly, a thin film of PLGA and Docetaxel or C2-Docetaxel was deposited on a 6″ × 12″ sheet of PET (poly[ethylene terephthalate]) by spreading 150 μl of a 10 mg/ml PLGA and 10 mg/ml docetaxel or C2-docetaxel chloroform solution using a # 5 Mayer Rod (R.D.…”

Section: Pharmacologic Agentsmentioning

confidence: 99%

Efficacy and Pharmacokinetics of a Modified acid-labile docetaxel-PRINT ^® Nanoparticle Formulation Against non-small-cell Lung Cancer Brain Metastases

Sambade¹,

Deal²,

Schorzman

et al. 2016

Nanomedicine (Lond.)

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Aim: Particle Replication in Nonwetting Templates (PRINT ® ) PLGA nanoparticles of docetaxel and acid-labile C2-dimethyl-Si-Docetaxel were evaluated with small molecule docetaxel as treatments for non-small-cell lung cancer brain metastases. Materials & methods: Pharmacokinetics, survival, tumor growth and mice weight change were efficacy measures against intracranial A549 tumors in nude mice. Treatments were administered by intravenous injection. Results: Intracranial tumor concentrations of PRINT-docetaxel and PRINT-C2-docetaxel were 13-and sevenfold greater, respectively, than SM-docetaxel. C2-docetaxel conversion to docetaxel was threefold higher in intracranial tumor as compared with nontumor tissues. PRINT-C2-docetaxel increased median survival by 35% with less toxicity as compared with other treatments. Conclusion: The decreased toxicity of the PRINT-C2-docetaxel improved treatment efficacy against non-small-cell lung cancer brain metastasis. PLGA nanoparticleLung cancer, 80% comprised of non-smallcell lung cancer (NSCLC), is one of the leading causes of cancer worldwide and the USA [1][2][3]. Lung cancer is the most common primary tumor responsible for brain metastases [19]. Among those diagnosed with NSCLC, 20-50% of patients will develop metastatic brain disease [2], 10% with brain metastases at initial diagnosis [4] and another 30% later in their disease course following standard therapies.Despite multimodality therapy with combinations of surgery, radiation therapy and chemotherapy, median survival remains less than one year for NSCLC brain metastatic patients [1,2]. NSCLC brain metastases are generally nonresponsive to first-line, single agent platinum-based chemotherapy [2,5]. Docetaxel (Taxotere ® ) is a standard second line systemic chemotherapy for NSCLC brain metastases [2]. As brain metastasis recurrence is common among patients with advanced NSCLC, optimizing the passage of anticancer agents across the blood-brain barrier, increasing chemotherapeutic concentrations in intracranial and extracranial tumors and decreasing systemic toxicities are important considerations to improve treatment of this disease. Newer delivery techniques, like nanoparticles and carrier-mediated technologies, have illustrated these advantages in the setting of intracranial cancer [6][7][8][9][10]. Clinically, activity of nanoparticle-based systemic therapy has been illustrated in the setting of breast cancer brain metastases, another solid tumor type where brain metastasis recurrence is common [11].While several studies have shown the superiority of nanoparticle anticancer agents in intracranial malignancies over standard formulations, the mechanism underlying this

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Potent Engineered PLGA Nanoparticles by Virtue of Exceptionally High Chemotherapeutic Loadings

Cited by 130 publications

References 35 publications

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Innovative next-generation PLGA microparticles with multifunctional architecture

Efficacy and Pharmacokinetics of a Modified acid-labile docetaxel-PRINT ^® Nanoparticle Formulation Against non-small-cell Lung Cancer Brain Metastases

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Potent Engineered PLGA Nanoparticles by Virtue of Exceptionally High Chemotherapeutic Loadings

Cited by 130 publications

References 35 publications

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Innovative next-generation PLGA microparticles with multifunctional architecture

Efficacy and Pharmacokinetics of a Modified acid-labile docetaxel-PRINT ® Nanoparticle Formulation Against non-small-cell Lung Cancer Brain Metastases

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Product

Resources

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Efficacy and Pharmacokinetics of a Modified acid-labile docetaxel-PRINT ^® Nanoparticle Formulation Against non-small-cell Lung Cancer Brain Metastases