Sirolimus loaded chitosan functionalized poly (lactic-co-glycolic acid) (PLGA) nanoparticles for potential treatment of age-related macular degeneration.

The usefulness of sirolimus (SIR) in the treatment of diseases that involve retinal degeneration like age-related macular degeneration (AMD) has been well documented. However, the problem still remains probably owing to the peculiar environment of the eye and/or unfavourable physiochemical profile of SIR. In the present work, we aimed to fabricate sirolimus loaded PLGA nanoparticles (SIR-PLGA-NP) and chitosan decorated PLGA nanoparticles (SIR-CH-PLGA-NP) to be administered via non-invasive subconjunctival route. Both the nanoparticles were characterized in terms of size, zeta potential, DSC, FTIR and XRD analysis. Quality by Design (QbD) approach was employed during the preparation of nanoparticles and the presence of chitosan coating was confirmed through thermogravimetric analysis and contact angle studies. Cationic polymer modification showed sustained in-vitro SIR release and enhanced ex-vivo scleral permeation and penetration. Further, SIR-CH-PLGA-NP revealed enhanced cellular uptake and thus, reduced lipopolysaccharide (LPS)-induced free-radicals generation by RAW 264.7 cells. The prepared nanoparticles were devoid of residual solvent and were found to be safe in HET-CAM analysis, RBCs damage analysis and histopathology studies. Moreover, high anti-angiogenic potential was observed in SIR-CH-PLGA-NP compared with SIR-PLGA-NP in chorioallantoic membrane (CAM) test. Overall, the current work opens up an avenue for further investigation of CH-PLGA-NP as SIR nanocarrier in the treatment of AMD.

Recent theranostic paradigms for the management of Age-related macular degeneration.

Degenerative diseases of eye like Age-related macular degeneration (AMD), that affects the central portion of the retina (macula), is one of the leading causes of blindness worldwide especially in the elderly population. It is classified mainly as wet and dry form. With expanding knowledge about the underlying pathophysiology of the disease, various treatment strategies are being employed to halt the course of the disease progression. Hitherto, there is no ideal therapy which can cure the disease completely, and targeting the posterior segment of the eye is yet another challenge. The purpose of this review is to summarize the recent advances in the management and treatment stratagems (therapies, delivery systems and diagnostic tools) pertaining to AMD viz. molecular targeting, stem cell therapy, nanotechnology and exosomes with special reference to newer technologies like artificial intelligence and 3D printing. Furthermore, the role of diet and nutritional supplements in the prevention and treatment of the disease has also been highlighted. The alarming increase in the said disorder around the globe demands exhaustive research and investigations in the treatment zone. This review thus additionally directs the attention towards the challenges and future perspectives of different treatment approaches for AMD.

Polyoliposomes: novel polyol-modified lipidic nanovesicles for dermal and transdermal delivery of drugs.

Various lipid nanovesicular systems have been developed with the aim to enhance the delivery of drugs via transdermal route. However, their clinical applications are often limited due to the barrier nature of skin and lack of flexibility. Herein, we have modified the conventional nanoliposomes (CLs) prepared by a thin-film hydration method by the addition of a polyol (glycerol) to form novel lipid nanovesicular structures termed 'POLYOLIPOSOMES' (PLs). They were further named as PL-B (before film formation) and PL-A (after film formation), depending on the stage of glycerol addition during production. Optimized CLs, PL-B and PL-A showed spherical nanovesicles and hydrodynamic diameter of 181.3 ± 4.11 nm, 114.2 ± 7.21 nm and 170.2 ± 6.51 nm, respectively. PLs showed significantly higher % entrapment efficiency and deformability index in comparison to CLs, indicating their higher flexibility. Furthermore, DSC and attenuated total relection (ATR)-Fourier transform infrared (FTIR) studies revealed the intercalation of glycerol into the lipid bilayer of PLs and interaction between nanovesicles and skin. Moreover, ex vivo and in vivo skin permeation studies confirmed the enhanced drug delivery of PLs via the transdermal route. Taken together, these results illustrate the potential of PLs as a novel lipid nanovesicular system for drug delivery via the transdermal route for both systematic (PL-B) as well as cutaneous diseases (PL-A).

Sirolimus loaded polyol modified liposomes for the treatment of Posterior Segment Eye Diseases.

Posterior Segment Eye Diseases (PSED) are the major cause of visual impairment globally that directly affects the patients' quality of life, especially in the aging population. Vascular degenerative disorders of posterior eye are the vision threatening disorders, involving inflammation as one of the main pathological mechanisms. Use of current treatment regimens for PSED is significantly limited on account of unique environment of the eye that offers a major barrier to the delivery of efficient drug doses to the posterior segment. Sirolimus, a mTOR inhibitor, acts by inhibiting the T-cell proliferation and the release of inflammatory cytokines, have been widely investigated for its potential role in the treatment of PSED. Clinical application of the sirolimus, however, has been limited due to its poor physico-chemical properties like poor aqueous solubility, low bioavailable, high molecular weight and high instability. Although nanocarriers like liposomes have shown a great promise in shuttling the cargo to the target site for various applications, yet, due to distinct anatomical and physiological barriers of the eye, these conventional liposomes are inefficient to shuttle the cargo to the posterior segment. Therefore, in this hypothesis, we propose to incorporate edge activators (polyol) in the liposomal bilayer thereby to enhance the liposomal fluidity and deformability. Such polyol modified liposomes would successfully penetrate the blood retinal barrier and would efficiently shuttle the sirolimus to the posterior segment of the eye making this a promising strategy for the treatment of PSED.

Proglycosomes: A novel nano-vesicle for ocular delivery of tacrolimus.

Tacrolimus is an emerging candidate for the treatment of immune-mediated inflammatory ocular disorders (IIODs) however its ocular delivery remained a challenge due to its hydrophobic nature, high molecular weight and physiological and anatomical constraints of the eye. The present work describes vesicles composed of propylene glycol, phospholipid and water, proglycosomes (PNVs), as novel carriers for ocular delivery of tacrolimus. Addition of propylene glycol decreases vesicle aggregation, increases encapsulation of tacrolimus and prevented drug leakage. Developed PNVs were of nanosize (111.5±3.2nm) and 5-fold more elastic than conventional liposomes. PNVs showed prolonged drug release over period of 12h and higher corneal permeation, 5-fold and 13-fold, compared to conventional liposomes and tacrolimus solution, respectively. Studies in rabbits demonstrated prolonged precorneal retention (upto 8h) and manifestly improved intraocular drug levels, well above therapeutic levels, at all tested time-points following topical application of PNV formulation compared to drug solution. Further, PNVs were found to be safe for ocular use. In conclusion, the developed PNVs are prospective carriers for enhanced ocular delivery of tacrolimus.