Reductively Responsive Hydrogel Nanoparticles with Uniform Size, Shape, and Tunable Composition for Systemic siRNA Delivery <i>in Vivo</i>

Ma, Da; Tian, Shaomin; Baryza, Jeremy; Luft, J. Christopher; DeSimone, Joseph M.

doi:10.1021/acs.molpharmaceut.5b00054

Cited by 32 publications

(29 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…47 Our previous work demonstrated that cationic hydrogel particles were able to efficiently deliver siRNA to cytosol, resulting in efficient gene silencing. 48,49 Furthermore, Fromen et al demonstrated significanlty higher lung and systemic antibody titers when cationic particles were used to deliver ovalbumin, as compared to anionic particles. 50 Therefore, amine groups on the NP surface were used to conjugate cysteine labeled SIINFEKL peptide via reduction sensitive, heterobifunctional linkers SPDP or NHS-PEG(2k)OPSS in a two step-process (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…48,53–55 Due to the versatility of the PRINT platform, it has been employed to study the impact of various particle parameters in a biological system such as biodistribution of intravenously administered NPs as well as lymphatic trafficking of particles after intramuscular administration. 56,57 Utilizing immunologically inert materials to mimic size, shape, and surface functionality of pathogens, PRINT provides an excellent platform to engineer subunit vaccines investigating various combinations of antigens and adjuvants to tune the immune response.…”

Section: Discussionmentioning

confidence: 99%

“…Cationic formulations enhance NP cellular internalization and endosomal escape thereby delivering cargo in the reductive environment of cytosol. 48,49,58 Being able to take advantage of these cellular events should favor antigen cross presentation through the classical pathway. Neumann et al has also reported inflammasome activation by cationic charged particles alone, which may potentially provide adjuvanticity and contribute to the high potency of our particle vaccines.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Reduction Sensitive PEG Hydrogels for Codelivery of Antigen and Adjuvant To Induce Potent CTLs

Kapadia¹,

Tian²,

Perry³

et al. 2016

Mol. Pharmaceutics

Self Cite

View full text Add to dashboard Cite

Educating our immune system via vaccination is an attractive approach to combat infectious diseases. Eliciting antigen specific cytotoxic T cells (CTLs), CD8+ effector T cells, is essential in controlling intracellular infectious diseases such as influenza (Flu), tuberculosis (TB), hepatitis, and HIV/AIDS, as well as tumors. However, vaccination utilizing subunit peptides to elicit a potent CD8+ T cell response with antigenic peptides is typically ineffective due to poor immunogenicity. Here we have engineered a reduction sensitive nanoparticle (NP) based subunit vaccine for intracellular delivery of an antigenic peptide and immunostimulatory adjuvant. We have co-conjugated an antigenic peptide (ovalbumin-derived CTL epitope [OVA257–264: SIINFEKL]) and an immunostimulatory adjuvant (CpG ODNs, TLR9 agonist) to PEG hydrogel NPs via a reduction sensitive linker. Bone-marrow derived dendritic cells (BMDCs) treated with the SIINFEKL conjugated NPs efficiently cross-presented the antigenic peptide via MHC-I surface receptor and induced proliferation of OT-I T cells. CpG ODN-conjugated NPs induced maturation of BMDCs as evidenced by the overexpression of CD80 and CD40 costimulatory receptors. Moreover, codelivery of NP conjugated SIINFEKL and CpG ODN significantly increased the frequency of IFN-γ producing CD8+ effector T cells in mice (~6-fold improvement over soluble antigen and adjuvant). Furthermore, the NP subunit vaccine-induced effector T cells were able to kill up to 90% of the adoptively transferred antigenic peptide-loaded target cell. These results demonstrate that the reduction sensitive NP subunit vaccine elicits a potent CTL response and provide compelling evidence that this approach could be utilized to engineer particulate vaccines to deliver tumor or pathogen associated antigenic peptides to harness the immune system to fight against cancer and infectious diseases.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Reduction Sensitive PEG Hydrogels for Codelivery of Antigen and Adjuvant To Induce Potent CTLs

Kapadia¹,

Tian²,

Perry³

et al. 2016

Mol. Pharmaceutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…The PEG modified with pyridyl disulphide could be directly conjugated to siRNA containing a thiol group, since a pyridyl disulfide will readily undergo an interchange reaction with a free sulfhydryl to yield a single mixed disulfide product 33. , 34. .…”

Section: Resultsmentioning

confidence: 99%

Improved method for synthesis of low molecular weight protamine–siRNA conjugate

Pei

et al. 2018

Acta Pharmaceutica Sinica B

View full text Add to dashboard Cite

RNAi technology has aroused wide public interest due to its high efficiency and specificity to treat multiple types of diseases. However, the effective delivery of siRNA remains a challenge due to its large molecular weight and strong anionic charge. Considering their remarkable functions in vivo and features that are often desired in drug delivery carriers, biomimetic systems for siRNA delivery become an effective and promising strategy. Based on this, covalent attachment of synthetic cell penetrating peptides (CPP) to siRNA has become of great interest. We developed a monomeric covalent conjugate of low molecular weight protamine (LMWP, a well-established CPP) and siRNA via a cytosol-cleavable disulfide linkage using PEG as a crosslinker. Results showed that the conjugates didn't generate coagulation, and exhibited much better RNAi potency and intracellular delivery compared with the conventional charge-complexed CPP/siRNA aggregates. Three different synthetic and purification methods were compared in order to optimize synthesis efficiency and product yield. The methodology using hetero-bifunctional NHS–PEG–OPSS as a crosslinker to synthesize LMWP–siRNA simplified the synthesis and purification process and produced the highest yield. These results pave the way towards siRNA biomimetic delivery and future clinical translation.

show abstract

“…A different polymerization technique was the PRINT (particle replication in non-wetting templates) particle fabrication technique, which is characterized by a higher degree of difficulty, but by complete, orthogonal control over particle characteristics, and an easiness of scaling up [33]. Ma et al proposed a PRINT particle fabrication technique for the production of hydrogel nanoparticles conjugated with siRNA (short interfering RNA, highly used for gene therapy) [34]. The same technique was used by Kai et al for the nano-encapsulation of cisplatin, a cytotoxic drug used in therapy against a wide variety of cancers [33].…”

Section: Polymerization Methodsmentioning

confidence: 99%

An Engineering Point of View on the Use of the Hydrogels for Pharmaceutical and Biomedical Applications

Lamberti¹,

Barba²,

Cascone³

et al. 2016

Emerging Concepts in Analysis and Applications of Hydrogels

View full text Add to dashboard Cite

In this chapter, the modern uses of hydrogels in pharmaceutical and biomedical applications are revised following an engineering point of view, i.e. focusing the attention on material properties and process conditions. The chapter discusses the applications following the increase in scale-size. First, the nanoscale systems, i.e. hydrogel nanoparticles HNPs , are analysed in terms of preparative approaches polymerization methods and uses of preformed polymers and with a brief mention of the future trends in the field. Secondly, systems based on hydrogel microparticles HMPs are examined following the same scheme polymerization methods, uses of preformed polymers, a mention of novel and future trends . Thirdly, and last but not the least, the hydrogel-based drug delivery systems macroscopic HB-DDSs are presented, focusing in particular on tablets made of hydrogels, discussing the characterization methods and on the modelling approaches used to describe their behaviour. Other macroscopic systems are also discussed in brief. Even if the vastness of the field makes its discussion impossible in a single chapter, the presented material can be a good starting point to study the uses of hydrogels in pharmaceutical and biomedical sciences.

show abstract

Reductively Responsive Hydrogel Nanoparticles with Uniform Size, Shape, and Tunable Composition for Systemic siRNA Delivery in Vivo

Cited by 32 publications

References 54 publications

Reduction Sensitive PEG Hydrogels for Codelivery of Antigen and Adjuvant To Induce Potent CTLs

Reduction Sensitive PEG Hydrogels for Codelivery of Antigen and Adjuvant To Induce Potent CTLs

Improved method for synthesis of low molecular weight protamine–siRNA conjugate

An Engineering Point of View on the Use of the Hydrogels for Pharmaceutical and Biomedical Applications

Contact Info

Product

Resources

About