Nanocapsules loaded hydrogels for intra-articular and intra-peritoneal drug delivery

Surikutchi, Bhanu Teja (2020) Nanocapsules loaded hydrogels for intra-articular and intra-peritoneal drug delivery. PhD thesis, University of Nottingham and Universidade de Santiago de Compostela.

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In this thesis, composite hydrogels containing polymeric nanocapsules (NCs) were developed and evaluated for sustained drug delivery through intra-articular (IA) and intra-peritoneal (IP) administrations, for the treatment of osteoarthritis (OA) and peritoneal malignancies. IA corticosteroids or hyaluronic acid (HA) injections are prescribed to manage the moderate stage of OA. Despite their long clinical use, the therapeutic efficacy of these formulations is often limited because of their short joint residence time. Nanoparticles, after IA administration, could penetrate into the synovial membrane and show enhanced efficacy. They have been incorporated into hydrogels to form composite systems to further enhance joint retention. In this study, dexamethasone (DXM), a model anti-inflammatory agent, has been incorporated into hyaluronic acid (HA) NCs to yield a maximum drug loading of 6 mg/mL. These DXM NCs were found to have a particle size, PDI and zeta potential of 250 ± 30 nm, 0.2 and -17 ± 3 mV respectively, which were stable up to 1 month at 2 – 8 ºC. Further, a fibrin (Fn) – HA hydrogel, previously developed in our lab, was optimized to incorporate up to 34% w/w of DXM NCs. Oscillatory amplitude and frequency sweep tests performed on Fn-HA gel showed a viscoelastic behaviour comparable to commercial IA hydrogels. An in vitro release study performed on DXM NCs-loaded Fn-HA gel exhibited a DXM release of up to 70% in 48 h. Further, in vivo local residence and biodistribution studies, performed with 111In-labelled NCs indicated that the NCs were cleared through popliteal lymph nodes from the knee cavity and that this behaviour was not influenced by the presence of the Fn-HA gel. A long and short-term anti-inflammatory efficacy study performed in antigen induced arthritis (AIA) rats showed no beneficial anti-inflammatory activity, as observed from knee diameters and synovial histology. Hence, the developed formulation did not overcome the current challenge associated with ineffective steroid anti-inflammatory IA injections.

Another part of the thesis involved the development and evaluation of a composite formulation for IP drug delivery in the management of peritoneal malignancies. IP administration of chemotherapeutic drugs would be beneficial in patients with peritoneal malignancies. Nanoparticles could be used as potential drug delivery strategy for IP administration because of their potential to offer higher tumour penetration. Incorporation of nanoparticles in the hydrogel delays their clearance from the IP cavity and provides sustained release. Hence, in chapters 3 and 4, different hydrogels have been developed for IP delivery to incorporate NCs. A fluorescent dye, DiR, was first incorporated into HA NCs to allow the determination of in vivo local residence and biodistribution through IVIS® imaging in immunodeficient BALB/c nude mice. Further, two different hydrogels, Fn-HA gel and a self-assembling 2ʹ-dC-N4-C8 gel, were optimized to incorporate 30% w/w of DiR NCs. Fn-HA gel, upon IP administration showed fluorescence up to 2 weeks, which was confirmed through ex vivo analysis as uptake of the NC by the liver. Hence, it was concluded that Fn-HA gel failed to retain the NCs in the peritoneal cavity. This finding triggered the development of a covalently cross-linked hydrogel that could offer better sustained release. Branched poly(ethylene glycol) (PEG) polymers, 4-arm PEG norbornene (PEG-NB) and 4-arm PEG maleimide (PEG-MAL), were selected to develop covalently cross-linked hydrogels. A linear PEG was chemically modified to include thiol-end groups through an ester linkage to form a cross-linker, PEG-SH. PEG-NB and PEG-SH underwent photocrosslinking reaction to form a hydrogel, which was mediated by photoinitators LAP or Irgacure® 2959 in presence of UV. However, DiR was degraded in the gel due to incompatibility with the photoinitiators. Alternatively, PEG-MAL reacted with PEG-SH to form a hydrogel through Michael-type addition reaction, incorporating DiR NCs without degradation of DiR. In vitro release studies showed that PEG-MAL – thiol gel (10% w/w PEG-MAL concentration with equimolar PEG-SH) showed 45% cumulative DiR release in 5 days. IVIS® imaging study showed that this hydrogel resided in the IP cavity between 24 h and 1 week, after implantation in the cavity through a surgical procedure. This in vivo study also demonstrated the biodegradability and tolerability of PEG-MAL – thiol gel within the experimental timeframe. DCX, a model chemotherapeutic agent was then incorporated into NCs, which were then incorporated into PEG-MAL – thiol gel to yield a final DCX concentration of 0.9 mg/mL. The in vitro release study showed a cumulative DCX release of 45 % in 2 days, indicating that the hydrogel has shown control over the DCX release. In summary, PEG-MAL – thiol gel showed potential residence in the IP cavity and demonstrated the controlled release of DCX.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Marlow, Maria
Grabowska, Anna
Crecente Campo, José
Alonso Fernández, Maria José
Keywords: Drug delivery, Hydrogels, Nanocapsules, Arthritis, Ovarian cancer, drug delivery systems, Intra-articular, Intra-peritoneal
Subjects: R Medicine > R Medicine (General) > R855 Medical technology. Biomedical engineering. Electronics
R Medicine > RS Pharmacy and materia medica
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 59548
Depositing User: Surikutchi, Bhanu
Date Deposited: 05 Oct 2023 14:24
Last Modified: 05 Oct 2023 14:24

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