Polymeric Nanobiotics

Sponsor(s)

Partnerships

	University of Sheffield https://sheffield.ac.uk/
	Royal Papworth Hospital https://royalpapworth.nhs.uk/

Type of technology

Polymer-based particles

Administration route

Intramuscular, Intravenous

Development state and regulatory approval

Isoniazid

Pre-clinical

Not provided

Description

Polymeric nanobiotics are a novel nanoparticle drug-delivery system designed to treat Mycobacterium tuberculosis. They are created by covalently bonding antibiotics, like isoniazid, directly to a biodegradable polymer chain. In acidic environments—such as inside infected macrophages and granulomas—the polymer undergoes hydrolysis to trigger a sustained, targeted release of the active drug. Furthermore, these nanoparticles can encapsulate a second hydrophobic drug, like clofazimine, enabling synchronized multi-drug therapy that maximizes bacterial killing while minimizing systemic toxicity.

Technology highlight

1) Core Design: Polymeric nanobiotics are nanoparticles formed by covalently bonding antibiotics (e.g., isoniazid) directly to biodegradable polymer chains. 2) Triggered Release: α-keto polyester undergo hydrolysis in acidic environments—like inside Mtb-infected macrophages and granulomas—triggering targeted, sustained drug release. 3) Multi-Drug Therapy: They can encapsulate a second hydrophobic drug (like clofazimine) for synchronized combination chemotherapy. 4) High Payload: Direct conjugation achieves a massive drug payload (up to 25% by weight) with excellent long-term structural stability. 5) Targeted Uptake: They are avidly engulfed by macrophages, delivering drugs directly to intracellular bacteria and extracellular granulomas.

Technology main components

1. α keto polyester 2. Conjugated API (eg: isoniazid (INH)) 3. Conjugated API (eg: clofazimine (CFZ)) 4. Stabilizer (eg: poly(vinyl alcohol) (PVA)

Information on the raw materials sourcing, availability and anticipated price

Not provided

Delivery device(s)

No delivery device

API desired features

Water-soluble molecules

Water-insoluble molecules

Small molecules

Anti-tubercular drugs are targeted for polymer nanobiotics such as Isoniazid and clofazimine

Additional solubility data

Not provided

Additional stability data

Not provided

API loading: Maximum drug quantity to be loaded

10-30 wt%

API co-administration

2 different APIs : Two small molecules (hydrophilic and hydrophobic)

LogP

Min: -0.7 Max: 7.5
Polymer Nanobiotics has the capacity to encapsulate both hydrophilc and hydrophobic drugs

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

Not provided

Manufacturing

Not provided

Specific analytical instrument required for characterization of formulation

Not provided

Proprietary excipients used

Not provided

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

Poly(vinyl alcohol) (PVA)

Residual solvents used

No residual solvent used

Other features of the technology

• Biodegradable
• Monolithic

Release properties

The nanobiotics exhibit greater and more rapid drug release in acidic environments (pH 5.0 and 6.0) bu the release is significantly slower at physiological pH (7.4), which represents systemic circulation. Invitro studies demonstrates that the drug release has a sustained release upto 30 days

Injectability

Polymer nanobiotics are intended to be adminstered through Intravenous and Intramuscular injections.

Stability

Polymer nanobiotics are stable in solution for at least 9 months at room temperature.

Storage conditions and cold-chain related features

Not provided

Safety

Safety studies were not conducted yet.

Efficacy

Preclinical studies: (i) In vitro studies - indicate that Isoniazid (INH) Polymer nanobiotic showed equivalent potency to free INH against intracellular M. tuberculosis (100 μM free INH versus 100 μM INH delivered as nanodrug) for 48 hours. This was demonstrated in both THP-1 cells and primary human macrophages. Intracellular bacterial burden was assessed using relative luminescence units normalised to untreated cells. (ii) In vivo studies - In an M. marinum-infected zebrafish model, treatment with INH nanobiotics +/- clofazimine. The nanobiotics effectively trigger sustained drug release via hydrolysis in acidic environments. Nanoparticles were taken up by >70% of infected macrophages. Both Nano-INH and Nano-INH + CFZ significantly reduced bacterial burden (0.6 and 0.45-0.5).

Evidence Summary

Preclinical studies show that the Nano-INH retained INH activity intracellularly and demonstrated superior in-vivo effects versus equivalent free drug in the M. marinum zebrafish model. Further safety studies of polymer nanobiotics is required.

Therapeutic area(s)

Use case(s)

Use of technology

There are either no relevant patents or these were not yet submitted to LAPaL

Publications

<p>Batalha, I. L., Bernut, A., Schiebler, M., Ouberai, M. M., Passemar, C., Klapholz, C., Kinna, S., Michel, S., Sader, K., Castro-Hartmann, P., Renshaw, S. A., Welland, M. E., &amp; Floto, R. A. (2019). Polymeric nanobiotics as a novel treatment for mycobacterial infections. <em>Journal of controlled release : official journal of the Controlled Release Society</em>, <em>314</em>, 116–124. <a target="_blank" rel="noopener noreferrer" href="https://doi.org/10.1016/j.jconrel.2019.10.009">https://doi.org/10.1016/j.jconrel.2019.10.009</a></p>

Iris L Batalha — Journal of Controlled Release — 2019-12-18

Summary: Preclinical efficacy studies (in vitro cell line and in vivo zebrafish studies) of Polymer Nanobiotics (Isoniazid +/- Clofazamine).

Mycobacterium tuberculosis (Mtb) remains a major challenge to global health, made worse by the spread of multidrug resistance. Currently, the efficacy and safety of treatment is limited by difficulties in achieving and sustaining adequate tissue antibiotic concentrations while limiting systemic drug exposure to tolerable levels. Here we show that nanoparticles generated from a polymer-antibiotic conjugate (‘nanobiotics’) deliver sustained release of active drug upon hydrolysis in acidic environments, found within Mtb-infected macrophages and granulomas, and can, by encapsulation of a second antibiotic, provide a mechanism of synchronous drug delivery. Nanobiotics are avidly taken up by infected macrophages, enhance killing of intracellular Mtb, and are efficiently delivered to granulomas and extracellular mycobacterial cords in vivo in an infected zebrafish model. We demonstrate that isoniazid (INH)-derived nanobiotics, alone or with additional encapsulation of clofazimine (CFZ), enhance killing of mycobacteria in vitro and in infected zebrafish, supporting the use of nanobiotics for Mtb therapy and indicating that nanoparticles generated from polymer-small molecule conjugates might provide a more general solution to delivering co-ordinated combination chemotherapy

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