Drug formulation augments the therapeutic response of carboplatin administered through a lymphatic drug delivery system

Abstract

Treatment of metastatic lymph nodes (LNs) is challenging due to their unique architecture and biophysical traits. Systemic chemotherapy fails to impede tumor progression in LNs due to poor drug uptake and retention by LNs, resulting in fatal systemic metastasis. To effectively treat LN metastasis, achieving specific and prolonged retention of chemotherapy drugs in the tumor‐draining LNs is essential. The lymphatic drug‐delivery system (LDDS) is an ultrasound‐guided drug‐delivery methodology for administration of drugs to LNs that addresses these requirements. However, early‐stage metastatic LNs have an additional set of drug transport barriers, such as elevated intranodal pressure and viscosity, that negatively impact drug diffusion. In the present study, using formulations of elevated osmotic pressure and viscosity relative to saline, we sought to favorably alter the LN's physical environment and study its impact on pharmacokinetics and consequently the therapeutic efficacy of carboplatin delivered using the LDDS. Our study confirmed the capability of a drug formulation with elevated osmotic pressure and viscosity to alter the architecture of LNs, as it caused notable expansion of the lymphatic sinus. Additionally, the study delineated an optimal range of osmotic pressure and viscosity, centered around 1897 kPa and 11.5 mPa·s, above and below which therapeutic efficacy was found to decline markedly. These findings suggest that formulation osmotic pressure and viscosity are parameters that require critical consideration as they can both hinder and promote tumorigenesis. The facile formulation reported here has wide‐ranging applicability across cancer spectrums and is thus anticipated to be of great clinical benefit.

Metastatic lymph node targeted CTLA4 blockade: a potent intervention for local and distant metastases with minimal ICI-induced pneumonia

“…indicating the absence of IL10 mediated CD8T cell activation. Significant upregulation of CD8T cells and its effector function, and downregulation of its CTLA4 expression, in the case of tbLN specific administration of anti-CTLA4 may be reflective of the superior pharmacokinetics of intranodal drug administration as opposed to systemic approaches [ 9 , 60 ]. In such a scenario, tumor can outcompete non-diseased tissues in terms of drug availability.…”

“…But, in view of likelihood of fatal consequences of lymphadenectomy [ 6 ], inefficiency of systemic drug delivery approaches [ 9 , 21 , 87 ], low economic burden, FDA approval [ 11 ], and simplicity of translation of present approach, we believe the findings of the present study have great clinical utility in the context of patients of N positive status with accessible LNs.…”

“…Anti-CTLA4 monoclonal antibody (9H10, Biolegend, San Diego, CA, USA), 5 mg/kg (cumulative dosage: 10 mg/kg), was administered to tumor-bearing SiLN (tbLN), or to non-tumor bearing SiLN (ntbLN) through a LDDS [ 9 ], or intraperitoneally, on day 4 and 8, to mice inoculated unilaterally to study the impact of drug administration strategy on anti-tumor response of ICI. For immunome characterization, mice treated as above were euthanized on day 9.…”

“…However, lymphadenectomy can lead to activation of latent tumor cells at distant sites, making it counterproductive [ 6 – 8 ]. Additionally, efficient drug delivery to metastatic LNs (MLNs) by systemic drug delivery approaches is challenging due to the existence of a unique set of drug transport barriers [ 9 , 10 ].…”

“…Previously we have shown that intranodal administration of chemotherapeutic agents using an ultrasound-guided lymphatic drug delivery system (LDDS) significantly improves drug pharmacokinetics and is thus a promising strategy for the treatment of MLNs [ 9 , 21 ]. Additionally, LN is a reservoir of immunotherapeutic targets.…”