Ijeoma Florence Uchegbu

Human serum albumin (HSA) has attracted significant attention in drug delivery since the approval of Abraxane in 2005. Abraxane is a nanoparticle albumin-bound paclitaxel (nab-PTX) formulation. Although HSA offers advantages such as prolonged circulation time (half-life ~19 days) and intrinsic hydrophobic pockets, the translation of other HSA-based nanomedicines remains limited. In fact, the significant differences between native and pharmaceutical HSA in protein structure and biological interactions could hinder their translational use in drug delivery. In this study, we demonstrate that pharmaceutical HSA (α-helix = 17%) is structurally denatured compared with native HSA (α-helix = 68%), leading to rapid clearance (ζ = -13.7 mV), leading to aggregation, and low colloidal stability, resulting in premature drug release upon dilution (ζ = -27.4 mV) and improved colloidal stability to reduce the premature release of encapsulated PTX upon dilution (p < 0.01) and superior antitumor efficacy compared with Abraxane. These improvements further suggest that optimization may require only a simple modification when guided by proper theoretical principles.

Combination therapies have largely replaced monotherapies in oncology. Thermal therapy has been developed as an adjunctive treatment owing to its safety and high compatibility with established theraypy options. However, bulky equipment and non-standardized protocols have limited its clinical use. The emergence of gold nanoparticle (AuNP)-based photothermal therapy (PTT) offers a simpler approach using injectable formulations and portable near-infrared (NIR) laser devices. However, poor excretion of AuNPs raises safety concerns and hinders translation. Here, we designed a gold nanoplatform that retains the photothermal capacity of AuNPs while enabling efficient excretion. Ultrasmall AuNPs (p-methoxybenzenethiol (MBT) to stabilize ultrasmall AuNPs, clustered them with poly(lactic-co-glycolic acid) (PLGA), and coated said clusters with acetylated human serum albumin (Ac-HSA). The resulting Ac-HSA-PLGA-AuNCs demonstrated reduced hepatic retention along with renal excretion of ultrasmall gold species. Intratumoral injection followed by 10 min NIR irradiation achieved efficient tumor ablation, outperforming conventional hyperthermia that usually requires hours of heating. Furthermore, combining Ac-HSA-PLGA-AuNC-based PTT with high-dose paclitaxel (160 mg/kg) was safe and yielded enhanced antitumor efficacy. This developed gold nanoplatform offers a promising strategy for translatable PTT-chemotherapy combinations.

Efficient formulation of SN-38 for broad-spectrum chemotherapy remains an unmet medical need. The limited solubility of SN-38 in both aqueous and organic solvents poses a major challenge for formulation development. As a result, the predominant strategy, polymer-SN-38 drug conjugates, often involves complex synthetic procedures and low drug loading (1-5% w/w). Such limitations hinder their large-scale production and clinical translation. In this study, we developed an encapsulation strategy that utilizes the reversible lactone-carboxylate equilibrium of SN-38 to simplify the formulation process and achieve enhanced drug loading. The major issue of SN-38 solubility in organic solvents was effectively addressed by sodium hydroxide (NaOH)-induced conversion of the lactone to the carboxylate form. We have demonstrated that SN-38 carboxylate, once encapsulated within human serum albumin-polylactic acid (HSA-PLA) nanoparticles, retains its reversibility and can be converted back to the active lactone form simply by the addition of hydrochloric acid (HCl). The drug loading capacity of SN-38 in the HSA-PLA nanoparticles was increased to 19% w/w. In vitro cytotoxicity assays confirmed that HSA-PLA (SN-38) nanoparticles exhibited significantly lower IC₅₀ values (0.5-194 nM) across multiple cancer cell lines compared to the clinical standard, irinotecan (CPT-11), indicating superior potency under physiological conditions. In vivo studies in 4T1 and MDA-MB-231 tumor-bearing mice further validated the enhanced therapeutic efficacy of this formulation. Overall, this study presents a promising alternative strategy for SN-38 delivery via encapsulation rather than polymer-drug conjugation, significantly simplifying the formulation process and enhancing the translational potential of SN-38 for broad chemotherapeutic applications.

Introduction: Gold nanoclusters (AuNCs) have emerged as promising agents for photothermal cancer therapy due to their unique optical properties and potential for tumour targeting. Methods: In this study, we developed clustered, excretable AuNCs using a glycol chitosan derivative (GCPQ) and investigated their physicochemical properties, photothermal effect, and therapeutic efficacy. Results: The AuNCs exhibited tunable surface plasmon resonance peaks dependent on the polymer:AuNP ratio, with optimized clusters showing surface enhanced Raman scattering and photothermal heating. In vivo studies in a mouse tumour model demonstrated significant tumour growth inhibition (334% growth vs 607% growth for untreated animals after 6 days) when combining intratumoural AuNC injection with near-infrared laser irradiation. Conclusion: The results provide proof-of-concept for the potential of these AuNCs in photothermal cancer therapy. Future work should focus on improving tumour targeting, optimizing treatment parameters, and assessing long-term safety to advance this platform toward clinical translation.

Glioblastoma multiforme (GBM) is a fast-growing and aggressive brain tumour, which remains largely resistant to treatment; the prognosis for patients is poor, with a median survival time of about 12–18 months, post diagnosis. In an effort to bring more efficacious treatments to patients, we targeted the down regulation of ITCH, an E3 ligase that is overexpressed in a variety of cancers, and which inhibits P73, a tumour suppressor gene. 6-O-glycolchitosan (GC) was used to deliver siRNA ITCH (GC60-siRNA-ITCH) and gemcitabine via the nose to brain route in CD-1 nude mice which had previously been implanted intracranially with U87-MG-luc2 cells. Prior to this in vivo study, an in vitro study established the synergistic effect of siRNA-ITCH in combination with a chemotherapy drug—gemcitabine. A downregulation of ITCH, an upregulation of p73 and enhanced apoptosis were observed in vitro in U87-MG cells, using qPCR, Western blot analysis, confocal laser scanning microscopy, flow cytometry and cytotoxicity assays. When GC60-siRNA-ITCH was combined with gemcitabine, there was a resultant decrease in cell proliferation in vitro. In CD1 mice, the administration of siRNA-ITCH (7 doses of 0.081 mg/kg) alone did not significantly affect animal survival (increasing mean survival from 29 to 33 days when compared to untreated animals), whereas intranasal gemcitabine had a significant effect on survival (increasing survival from 29 to 45 days when compared to untreated animals, p < 0.01). The most significant effect was seen with combination therapy (GC60-siRNA-ITCH plus gemcitabine), where survival increased by 89%, increasing from 29 to 54 days (p < 0.01). Our data demonstrate that siRNA chemosensitises brain tumours to gemcitabine and that the nose-to-brain delivery route may be a viable route for the treatment of intracranial tumours.