Intratumoral delivery（ITM） of drug represents a compelling solution to directly address local barriers to tumor immunity. Direct delivery into target tumor lesions affords several advantages over systemic delivery, including increased local concentrations and potentially diminished systemic toxicities. Off-target delivery is a substantial problem during intratumoral injections; this can lead to diminished drug efficacy and systemic toxicities. Three variables that influence intratumoral drug delivery: injection technique, drug formulation and tumor microenvironment.
Direct injection at the tumor site ensures access to tumor infiltrating macrophages, T cells already in the tumor microenvironment and potentially enriched for tumor antigen recognition. Recent studies have noted intratumor differences in T cell density and clonality, possibly due to differences in neoantigens in different tumor regions. As a result, local immunotherapy may elicit an immune response where systemic administration of immunotherapy is not efficacious by leveraging the rich pool of antigens within the tumor to provide better priming of polyclonal antitumor response.
Intratumoral administration exerts several advantages over the traditional systemic approach. However, intratumoral immunotherapy also has its disadvantages. Not all tumors are accessible for direct injection, limiting the applicability of this approach to certain cancer types and locations. Local treatments can cause reactions at the injection site, including undesired pain, swelling, and inflammation. The variability within the tumor microenvironment can also affect the uniformity and effectiveness of the treatment. Moreover, the administration of intratumoral immunotherapies requires precise delivery techniques, such as image-guided injections, which can complicate the process. Contrary to systemic therapies, intratumorally administered agents may not reach undetected lesions. Finally, while strong local immune activation is an advantage, it may not always result in a sufficiently robust systemic response to control metastatic disease. This risk of insufficient systemic response remains a challenge in effectively managing cancer with intratumoral immunotherapy.
Tumour-associated macrophages, TAMs, play a pivotal role in tumour growth and metastasis by promoting tumour angiogenesis. Treatment with clodronate encapsulated in liposomes efficiently depleted these phagocytic cells in the mouse tumour models resulting in significant inhibition of tumour growth, depending on therapy and schedule. The depletion of tumor-associated macrophages (TAMs), involved in different stages of cancer development and progression, is an appealing strategy in cancer therapy.
Why Administration Route Matters in Liposomal Delivery
The choice of administration route plays a pivotal role in determining how liposomes behave in biological systems. Factors such as tissue penetration, macrophage uptake, release kinetics, and immune response are significantly impacted by how and where liposomes are introduced. Whether the goal is targeted depletion of specific cell populations, localized drug delivery, or systemic circulation, selecting the appropriate route is essential to achieving optimal experimental or therapeutic outcomes.
Different administration methods can be designed to:
• Maximize site-specific accumulation of liposomes
• Minimize systemic toxicity
• Improve cellular uptake and retention
• Extend circulation half-life
• Facilitate passage across biological barriers (e.g., blood-brain barrier, mucosal membranes)
Key Considerations for Route Selection
Each administration route offers distinct advantages and limitations based on the biological target, therapeutic goals, and the nature of the encapsulated agent (e.g., clodronate, RNA, proteins). Some routes are ideal for localized depletion of macrophages, while others are preferred for systemic effects or mucosal immunity studies. Considerations include:
• Target tissue or organ system
• Desired duration of action
• Accessibility of the administration site
• Volume and formulation characteristics
• Species-specific anatomical factors