Microparticulate Formulations for the Controlled Release of Interleukin-2

Thomas, Tommy; Kohane, Daniel S.; Wang, Audrey; Langer, Robert

doi:10.1002/jps.20009

Cited by 27 publications

(21 citation statements)

References 52 publications

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“…1a) . Hence, we modified a double emulsion protocol 38–40 to encapsulate G114 in PLGA MPs. Drug amounts, polymer molecular weight, MP size, solubility parameters and homogenization velocity were rigorously iterated to accomplish high drug loading and encapsulation efficiency of the intact, peptide-containing prodrug (M.W.…”

Section: Resultsmentioning

confidence: 99%

“…PLGA is already present in FDA-approved products; it is a biodegradable, biocompatible polymer that enables tunable drug release 33–35 and we have previously used PLGA MPs to encapsulate small molecules to control cell phenotype 36–38 . Following an intricate iteration of a double emulsion protocol 39,40 , we succeeded in encapsulating G114, a peptide-containing prodrug (M.W. >1600g/mole), in PLGA particles (~950nm in diameter), achieving high drug loading (>13%) and encapsulation efficiency (>88%).…”

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confidence: 99%

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A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer

et al. 2016

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Despite considerable advances in prostate cancer research, there is a major need for a systemic delivery platform that efficiently targets anti-cancer drugs to sites of disseminated prostate cancer while minimizing host toxicity. In this proof-of-principle study, human mesenchymal stem cells (MSCs) were loaded with poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) that encapsulate the macromolecule G114, a thapsigargin-based prostate specific antigen (PSA)-activated prodrug . G114-particles (~950nm in size) were internalized by MSCs, followed by the release of G114 as an intact prodrug from loaded cells. Moreover, G114 released from G114 MP-loaded MSCs selectively induced death of the PSA-secreting PCa cell line, LNCaP. Finally, G114 MP-loaded MSCs inhibited tumor growth when used in proof-of-concept co-inoculation studies with CWR22 PCa xenografts, suggesting that cell-based delivery of G114 did not compromise the potency of this pro-drug in-vitro or in-vivo. This study demonstrates a potentially promising approach to assemble a cell-based drug delivery platform, which inhibits cancer growth in-vivo without the need of genetic engineering. We envision that upon achieving efficient homing of systemically infused MSCs to cancer sites, this MSC-based platform may be developed into an effective, systemic ‘Trojan Horse’ therapy for targeted delivery of therapeutic agents to sites of metastatic PCa.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer

et al. 2016

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“…Coencapsulation of immunomodulatory reagents with the Ag of choice should be possible (46). For instance, CpG oligonucleotides are potent activators of the innate immune system, and recent data suggest that their cognate receptor, TLR 9, interacts with CpGbearing motifs in the endosomal compartment, presumably to permit DCs to scan for DNA from invading microorganisms that have been phagocytosed (12,13,21).…”

Section: Discussionmentioning

confidence: 99%

pH-Triggered Microparticles for Peptide Vaccination

Haining

Anderson

Little

et al. 2004

The Journal of Immunology

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Improving vaccine delivery to human APCs is a way to increase the CTL response to vaccines. We report the use of a novel pH-triggered microparticle that exploits the ability of APCs to cross-present MHC I-restricted Ags that have been engulfed in the low pH environment of the phagosome. A model MHC class I-restricted peptide Ag from the influenza A matrix protein was encapsulated in spray-dried microparticles composed of dipalmitoylphosphatidylcholine and the pH-sensitive polymethacrylate Eudragit E100. Release of the peptide from the particle was triggered by a drop in pH to the acidity normally found in the phagosome. The particles were efficiently phagocytosed by human monocytes and dendritic cells with minimal cellular toxicity and no functional impairment. Encapsulation of the peptide in the microparticles resulted in efficient presentation of the peptide to CD8+ T cells by human dendritic cells in vitro, and was superior to unencapsulated peptide or peptide encapsulated in an analogous pH-insensitive particle. Vaccination of human HLA-A*0201 transgenic mice with peptide encapsulated in pH-triggering microparticles resulted in priming of CTL responses. These microparticles can be modified to coencapsulate a range of adjuvants along with the Ag of interest. Encapsulation of MHC I epitopes in pH-triggered microparticles increases Ag presentation and may improve CD8+ T cell priming to peptide vaccines against viruses and cancer.

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“…Sharma et al (42) reported that 40% of IL-2 released from nanospheres made of fumaric and sebacic acids was bioactive after 1 week of release. Thomas et al (32) reported that the bioactivity of IL-2 released from doubleemulsion-based PLGA (50/50) formulations was around 80% for the first 5 days, then rapidly dropped to less than 40% by day 10. In our study, protein bioactivity was greatly improved by using osmotic pressure-driven release, which drove protein release before significant elastomer bulk degradation occurred.…”

Section: Bioactivity Of the Released Proteinsmentioning

confidence: 98%

“…It was shown that severe toxicity can be induced by the prolonged high doses of systemic IL-2 (28). Previous attempts on localized IL-2 delivery include the use of dextran gels (29), liposomes (30,31), PLGA microspheres (32,33), and HEMA films (34). These studies showed that VEGF and IL-2 can be released for a 1-to 3-week period, but these delivery methods suffered from the rapid initial burst release, low total fraction released, nonlinear release, and rapid protein denaturation within the first week of release.…”

Section: Introductionmentioning

confidence: 99%