Therapeutic potential of polypeptide-based conjugates: Rational design and analytical tools that can boost clinical translation

Melnyk, Tetiana; Đorđević, Snežana; Conejos‐Sánchez, Inmaculada; Vicent, Marı́a J.

doi:10.1016/j.addr.2020.10.007

Cited by 51 publications

(45 citation statements)

References 354 publications

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“…Alternatively, supercritical precipitation, electrospraying, or spray-drying have seen more success at the production level. Self-assembly strategies [98,99] and bioconjugation approaches, such as those required to achieve polymer-drug conjugates [100] or antibody-drug conjugates [101], present additional chemical and analytical challenges.…”

Section: Manufacturing and Scale-upmentioning

confidence: 99%

Current hurdles to the translation of nanomedicines from bench to the clinic

Đorđević

Medel

Conejos‐Sánchez

et al. 2021

Drug Deliv. and Transl. Res.

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138

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The field of nanomedicine has significantly influenced research areas such as drug delivery, diagnostics, theranostics, and regenerative medicine; however, the further development of this field will face significant challenges at the regulatory level if related guidance remains unclear and unconsolidated. This review describes those features and pathways crucial to the clinical translation of nanomedicine and highlights considerations for early-stage product development. These include identifying those critical quality attributes of the drug product essential for activity and safety, appropriate analytical methods (physical, chemical, biological) for characterization, important process parameters, and adequate pre-clinical models. Additional concerns include the evaluation of batch-to-batch consistency and considerations regarding scaling up that will ensure a successful reproducible manufacturing process. Furthermore, we advise close collaboration with regulatory agencies from the early stages of development to assure an aligned position to accelerate the development of future nanomedicines. Graphical abstract

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Section: Manufacturing and Scale-upmentioning

confidence: 99%

Current hurdles to the translation of nanomedicines from bench to the clinic

Đorđević

Medel

Conejos‐Sánchez

et al. 2021

Drug Deliv. and Transl. Res.

Self Cite

138

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“…Compared to synthetic polymers such as N-(2-hydroxypropyl) methacrylamide (HPMA), polypeptidebased nanocarriers show several bene ts, which include higher biodegradability, lower immunogenicity and a lack of long term-accumulation (vacuolisation), and the number of polypeptide-based constructs reaching clinical evaluation has signi cantly increased in the recent years [75][76][77] . We employed St-PGAbased nanoconjugates that consist of three linear chains (~ 50 glutamic acids each) linked to a central core.…”

Section: Discussionmentioning

confidence: 99%

Depletion of CD206+ tumour macrophages by mUNO targeted nanoconjugate inhibits tumourigenesis and dissemination in triple negative breast cancer

Lepland

Malfanti

Haljasorg

et al. 2021

Preprint

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Chemotherapy is the standard of care for patients with triple negative breast cancer (TNBC), an aggressive breast cancer subtype with a poor prognosis. In many solid tumours, M2-skewed tumour-associated macrophages (TAMs) are known to promote progression, immunosuppression, relapse, and dissemination of the malignant disease. Although TAM depletion has been explored as an anticancer strategy, the currently available TAM depleting compounds suffer from poor efficacy and dose-limiting side effects. Here, we develop of a novel TAM-depleting agent that specifically targets CD206+ macrophages and show that it is efficacious as an anti-TNBC agent and well tolerated. This new TAM-depleting compound, called “OximUNO”, is a star-shaped polyglutamate decorated with the CD206-targeting peptide mUNO and carrying doxorubicin through a pH-responsive linker. In the orthotopic and experimental metastases of TNBC, fluorescent reporter mUNO-guided polyglutamate construct homed to CD206+ macrophages in the primary cancer lesions and at the sites of metastases. OximUNO displayed enhanced cytotoxicity towards primary M2 macrophages in vitro and exhibited no acute liver or kidney toxicity in vivo. In TNBC mouse models, OximUNO reduced the progression of primary breast cancer lesions and metastatic dissemination of malignant cells. Treatment with OximUNO had an immunomodulatory effect on the tumour microenvironment: besides reducing the number of CD206+ TAMs, it resulted in increased ratio of the CD8/FOXP3 expression. These studies suggest the potential utility of OximUNO based CD206+ TAM depletion strategies for the treatment of TNBC, and possibly, other types of solid tumours.

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“…1) and ANG via a bioresponsive disulfide linker (St-Cl-Pr-Cy5.5-ANG, Fig. 1) (8,13). All conjugates displayed a similar size (around 40 nm in diameter) and z potential (−30 to −40 mV) according to dynamic light scattering measurements and corroborated by cryo-transmission electron microscopy (TEM) images (further details regarding conjugate characterization such as dye/peptide loading can be found in table S1 and fig.…”

Section: Targeted Cross-linked Star-polyglutamates Cross the Bbb And Become Internalized By Cells Of The Cnsmentioning

confidence: 99%

“…We used polyglutamic acid (PGA), a water-soluble, biodegradable, and multivalent polypeptide with high loading capacity, and demonstrated clinical benefits (7,8), as the nanocarrier for our multimodal treatment approach. Because of a highly controlled and versatile polymerization process and proven structure-activity relationships (9), linear PGA (as a homopolymer or in multiblocks) is a key component of polymer-drug conjugates and polymeric micelles (some in an advanced clinical stage) used in cancer treatment and tissue regeneration (8). PGA-based globular structures, such as our recently described sphere-like cross-linked self-assembled star-shaped PGAs (St-Cl), exhibit extended blood circulation times and, therefore, represent an ideal option to maximize passive targeting (9).…”

Section: Introductionmentioning

confidence: 99%

Targeting Alzheimer’s disease with multimodal polypeptide-based nanoconjugates

et al. 2021

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Alzheimer’s disease (AD), the most prevalent form of dementia, remains incurable mainly due to our failings in the search for effective pharmacological strategies. Here, we describe the development of targeted multimodal polypeptide-based nanoconjugates as potential AD treatments. Treatment with polypeptide nanoconjugates bearing propargylamine moieties and bisdemethoxycurcumin or genistein afforded neuroprotection and displayed neurotrophic effects, as evidenced by an increase in dendritic density of pyramidal neurons in organotypic hippocampal culture. The additional conjugation of the Angiopep-2 targeting moiety enhanced nanoconjugate passage through the blood-brain barrier and modulated brain distribution with nanoconjugate accumulation in neurogenic areas, including the olfactory bulb. Nanoconjugate treatment effectively reduced neurotoxic β amyloid aggregate levels and rescued impairments to olfactory memory and object recognition in APP/PS1 transgenic AD model mice. Overall, this study provides a description of a targeted multimodal polyglutamate-based nanoconjugate with neuroprotective and neurotrophic potential for AD treatment.

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Therapeutic potential of polypeptide-based conjugates: Rational design and analytical tools that can boost clinical translation

Cited by 51 publications

References 354 publications

Current hurdles to the translation of nanomedicines from bench to the clinic

Current hurdles to the translation of nanomedicines from bench to the clinic

Depletion of CD206+ tumour macrophages by mUNO targeted nanoconjugate inhibits tumourigenesis and dissemination in triple negative breast cancer

Targeting Alzheimer’s disease with multimodal polypeptide-based nanoconjugates

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