Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy

Kolishetti, Nagesh; Dhar, Shanta; Valencia, Pedro M.; Lin, Lucy; Karnik, Rohit; Lippard, Stephen J.; Langer, Robert; Farokhzad, Omid C.

doi:10.1073/pnas.1011368107

Cited by 536 publications

(434 citation statements)

References 44 publications

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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.

355

284

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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.

355

284

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“…[123] Nanomedicines have the potential to load different drugs within one single carrier, therefore co-delivery of several drugs using functional nanoparticles show great potential in improving the therapeutic efficacy, while lowering the side effects. [124][125][126] However, the combination therapy is not only using several different drugs at the same time, it is a rather complicated process from the administration time to the drug dosage, and thus, the sequence of different drugs are greatly affecting the therapeutic outcomes.…”

Section: Combination Therapymentioning

confidence: 99%

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

Balasubramanian

Liu

Hirvonen

et al. 2017

Adv Healthcare Materials

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Explosive growth of nanomedicines continues to significantly impact the therapeutic strategies for effective cancer treatment. Despite the significant progress in the development of advanced nanomedicines, successful clinical translation remains challenging. As cancer nanomedicine is a multidisciplinary field, the fundamental problem is that the knowledge gaps stem from different vantage points in the understanding of cancer nanomedicines. The complexities and heterogenecity of both nanomedicines and cancer are further demanding the integration of highly diverse expertise to develop clinically translatable cancer nanomedicines. This progress report aims to discuss the current understanding of cancer nanomedicines between different research areas in terms of nanoparticle engineering, formulation, tumor patho-physiology and clinical medicine, as well as to identify the knowledge gaps lying at the interface between the different fields of research in nanomedicine. Here we also highlight for the necessity to harmonize the multidisciplinary effort in the research of nanomedicines in order to bridge the knowledge and to advance the full understanding in cancer nanomedicines. A paradigm shift is needed in the strategic development of disease specific nanomedicines in order to foster the successful translation into clinic of future cancer nanomedicines.

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“…It is known that calf-thymus DNA adopts a typical B-type DNA conformation in solution [25], with a characteristic positive peak centred around 275 nm, a negative peak centred around 12 DNA aptamer displays a similar CD spectrum with a positive peak around 275 nm, which is indicative of the DNA aptamer strand possessing 10.4 bases per turn and adopting a B-type DNA conformation [25]. The characteristic negative peak at 240 nm of the B-type DNA is shown to be present but at a lower intensity and slightly higher wavelength, centred around 250 nm.…”

Section: Aptamer Structurementioning

confidence: 99%

“…Because the platinum drugs are sequestered within the delivery vehicle they do not interact or irreversibly bind to the guanosine and adenosine bases of the aptamer [9][10][11][12]. The need for both a separate delivery vehicle and a conjugated targeting aptamer is complicated to construct and control, with respect to particle size and consistent drug loading.…”

Section: Introductionmentioning

confidence: 99%

DNA-based aptamer fails as a simultaneous cancer targeting agent and drug delivery vehicle for a phenanthroline-based platinum(II) complex

McGinely

Plumb

Wheate

2013

Journal of Inorganic Biochemistry

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The sgc8c aptamer is a 41-base DNA oligonucleotide that binds to leukaemia cells with high affinity and specificity. In this work we examined the utility of this aptamer as both a delivery vehicle and an active targeting agent for an inert platinum complex [(1,10-phenathroline)(ethylenediamine)platinum(II)] 2+ . The aptamer forms a stem-and-loop confirmation as determined by circular dichroism. This conformation is adopted in both water and phosphate buffered saline solutions. The metal complex binds to the aptamer through intercalation into the aptamer's double helical stem with a binding constant of approximately 4.3 × 10 4 M -1 . Binding of the metal complex to the aptamer had a significant effect on the aptamer's global conformation, and increased its melting temperature by 28 o C possibly through lengthening and stiffening of the aptamer stem. The effect of the aptamer on the metal complex's cytotoxicity and cellular uptake was determined using in vitro assays with the target leukaemia cell line CCRF-CEM and the off-target ovarian cancer cell lines A2780 and A2780cp70. The aptamer has little inherent cytotoxicity and when used to deliver the metal complex results in a significant decrease in the metal complex's cytotoxicity and uptake. The reason(s) for the poor uptake and activity may be due to the change in aptamer conformation which affects its ability to recognise leukaemia cells.

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Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy

Cited by 536 publications

References 44 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

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

DNA-based aptamer fails as a simultaneous cancer targeting agent and drug delivery vehicle for a phenanthroline-based platinum(II) complex

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