Precision medicine and the overlooked mechanics of drug delivery

24 Apr 2026 12min read

Drug treatments serve as a vital line of defence against cancer alongside surgery and radiotherapy. They include chemotherapy, hormone therapy and immunotherapy. Most drug treatments are delivered systemically, circulating through the bloodstream to reach cancer cells. Systemic cancer drug delivery, however, presents challenges such as toxicity, poor tumour penetration and low efficacy, often requiring higher volumes of expensive drugs.

Precision medicine is the future of drug delivery, yet the focus often remains on biomarkers and genetics while the simple mechanics are often overlooked. While the active pharmaceutical ingredient (API) is critical to therapeutic efficacy, it is just one component of the entire treatment. With over 120 different routes of administration as characterised by the FDA there are many options to consider. Tissue characterisation, delivery device selection, the precise location of delivery and real-time feedback should be more than an after-thought during development as these will all impact the therapeutic outcome.

Poor drug delivery to and distribution within the target site is one reason many therapeutics fail in clinical trials despite excellent pre-clinical results. The standard preclinical models used to screen drugs do not provide many of the physical barriers experienced in humans, such as rapid clearance of the drug, poor cellular access to the therapeutic or the target being inaccessible.

Intratumoural injections opportunities and challenges

Various drug delivery routes are often implemented incorrectly, leading to less effective treatment outcomes. For instance:

Over 70% of intradermal injections performed by a clinician are incorrectly delivered to the hypodermis.
Needle misplacement in anterolateral injections by surgeons treating osteoarthritis occurs in nearly 30% of cases.
The needle length of autoinjectors for intramuscular injections often cause under or over-penetration for different demographics.

Although not commonly used, intratumoural injections have proven their utility, as evidenced by the FDA approval of talimogene laherparepvec (T‑VEC) for intratumoural treatment of melanoma. In the past, there was a concern that intratumoural injections would need to be performed at all tumour sites, something infeasible once a tumour has metastasised. Immunotherapies and combination therapies have shown that intratumoural injections can yield results equivalent to systemic treatments by helping the immune system identify and clear remaining tumours.

Intratumoural injections also present key advantages as described below.

01) Reduced systemic toxicity

Only a small fraction of an injected therapeutic typically reaches the intended target site. As a result, a significant portion affects healthy tissues, leading to off‑target toxicity. This is especially problematic in conventional chemotherapy, where the therapeutic window overlaps with levels of unacceptable systemic toxicity.

02) Bypassing clearance pathways

The body is highly efficient at eliminating foreign substances, with organs like the liver rapidly clearing therapeutics before they reach the tumour. Direct delivery helps avoid these clearance mechanisms, increasing the proportion of drug that reaches the target site.

03) Mitigating the effects of a tumour’s disorganised vasculature

Tumours often are supported by irregular and tortuous blood vessels, resulting in uneven and limited blood flow. This can leave regions of the tumour undertreated or entirely inaccessible to systemically delivered agents.

04) Overcoming high interstitial pressure and dense extracellular matrix (ECM) barriers

Tumours often present elevated interstitial fluid pressure, generating a negative pressure gradient that impedes the extravasation of therapeutics from blood vessels into a tumour. This challenge is compounded by the dense ECM, a physical barrier composed of structural proteins such as collagen and elastin, along with other macromolecules. Thus, even when therapeutics reach intratumoural vessels, diffusion into the tumour mass remains inefficient.

05) Greater flexibility in formulation selection

Instead of injecting a therapeutic as a solution that can safely circulate in the blood, it can be prepared at higher concentrations in slow release formulations that expose cancer cells to a therapeutic dose over an extended period of time.

While delivery of therapeutics via intratumoural injection can enhance effectiveness of treatment, it presents unique challenges. The treatment relies on manual injection from the clinician therefore, clinical error can occur with injection into healthy tissue. There are also potential pitfalls with accuracy from the injection itself from uneven drug distribution within the tumour, to injectates leaking out of the target site either into surrounding healthy tissue or back up the needle.

Drug manufacturers should give careful consideration to the tumour’s physical characteristics, drug formulation, delivery method and real-time feedback to help overcome these challenges. Addressing these challenges could place developers in a better position to have success in clinical trials for their therapeutics that would have otherwise been rejected from reaching the market.

The importance of understanding the target tissue

The microenvironment of tumours is characterised as being composed of extensive but poorly organised vasculature, a dense ECM, a central necrotic region, poor lymphatic drainage, high interstitial fluid pressure, elevated solid stress and high stiffness. The extent of these characteristics is influenced by the age, size and type of tumour. However, this is an oversimplification. Even when considering these parameters, tumours remain extremely heterogeneous, in stark contrast to the consistency of healthy tissue.

A tumour’s characteristics can be difficult to predict and can range from a mushy lump to a dense, impenetrable mass. This heterogeneity means that assumptions about a tumour’s properties cannot be made without thorough characterisation. It is crucial to characterise a tumour before deciding on treatment, considering the following:

Local nearby structures – not just key blood vessels but proximity to, for example, the central nervous system or critical airways. Injections will always follow the path of least resistance and so intratumoural injections will be more challenging if there is an easy exit route.
Vasculature within the tumour, interstitial pressures and the density of the ECM – even when injecting intratumoural, good distribution will rely on the network of blood vessels in the tumour, something even more critical if interstitial pressures are high or the ECM is dense.
Porosity and stiffness of tissue – both the amount of drug that can be injected and the speed with which it can be injected will be dependent on these characteristics.

These properties can be characterised using various methods:

Doppler ultrasound – a modality which measures blood speed and direction in the body in real-time, although it may not provide the desired resolution or, in low-flow situations, require ultrasound contrast agents. Standard ultrasound imaging can also be used to estimate tissue density.
Force and stress measurements during tissue compression – dependent on access, can provide valuable insights into porosity and stiffness.
MRI and CT scans – offer good resolution for structural information including density.
Biopsy and histochemistry – give the most detailed information about cancer cell density and ECM but is a destructive method that cannot be performed in real-time.
Pressure catheters – can measure interstitial pressure.

Each of these methods offer a more accurate characterisation of tumours, which can lead to a more informed choice when considering the method of delivery. However, it is infeasible to expect all these measurements to be performed and so the value of each must be assessed.

Optimising intratumoural delivery

Selecting the appropriate delivery device is crucial in optimising intratumoural delivery and it can be as straightforward as choosing the right needle. Syringes and vials remain the most common administration method, this is partly because clinicians are less familiar with alternative combination products, which can lead to resistance. Additionally, these combination products tend to have a greater regulatory burden, adding another barrier to their adoption.

While delivery of therapeutics via intratumoural injection can enhance effectiveness of treatment, it presents unique challenges. The treatment relies on manual injection from the clinician therefore, clinical error can occur with injection into healthy tissue. There are also potential pitfalls with accuracy from the injection itself from uneven drug distribution within the tumour, to injectates leaking out of the target site either into surrounding healthy tissue or back up the needle.

Needle gauge will impact shear forces during injection which, in turn, can affect the integrity of delicate therapeutics across various delivery systems. While bevel design and needle material both can influence the accuracy of delivery. All of these factors can influence the chance of successful delivery in systemic administration, but these challenges are often amplified in local delivery settings such as intratumoural injections.

Making greater adjustments to the type of needle can be a simple yet effective improvement to standard treatment. For instance, in cases involving stiff tissue, using multi-side hole needles has been shown to enhance the distribution of the drug in stiff tissue.

Dosage

Rather than adhering to the current practice of basing dosage on patient weight or tumour volume, the focus should be on the amount that can be effectively injected and the risk of misadministration. The size of the dose and the fractionation strategy must be carefully considered. Greater fractionation, which involves dividing the total dose into smaller, more frequent injections, can result in a more comprehensive distribution across the tumour. However, this approach also increases the risk of drug leakage.

Effective characterisation can help identify regions within the tumour that require deposition to maximise distribution. This is particularly important when the target area is near sensitive regions, where the risk of leakage must be carefully managed.

Delivery method

The method of delivery is another crucial factor. For needle-based delivery, techniques such as fanning can be employed to enhance distribution. If the tumour is not easily accessible, alternative delivery methods such as a catheter or endoscope may be necessary.

The optimum speed of delivery is dictated by the tumour’s properties. For non-porous, stiff tumours with high interstitial pressure, a slow injection or the use of a wearable device may be necessary to ensure homogeneous drug distribution. Alternatively, modifying the formulation to allow for slow release, or incorporating an implant that releases the drug gradually, can be advantageous.

Optimising local conditions

Many drugs are only effective during specific phases of a cell’s cycle as it divides. Therefore, it is crucial for the cell to be exposed to a therapeutic dose of the drug at the right time. Controlled-release formulations such as hydrogels ensure that cells are exposed to the drug for extended periods within the therapeutic window. Additionally, slow release can facilitate further diffusion of the drug from the injection site as the microenvironment changes, allowing for more movement of the drug.

Depending on the stiffness of the tissue, it may be beneficial to remove some tissue before injection to facilitate better drug penetration. Applying heat to the tumour will increase blood flow and vascular permeability allowing for better drug penetration. This heat can be supplied by a range of methods such as microwaves, ultrasound, photothermal therapy or magnetic hyperthermia.

By thoroughly characterising the tissue and tailoring the delivery method accordingly, the effectiveness of the treatment can be significantly improved, leading to better patient outcomes.

Monitoring delivery

Continuous measurement of the delivery will allow optimum delivery of the drug to the target site while minimising off-target toxicity. Several methods can be employed to achieve continuous measurement, some of which are similar to those used for initial characterisation, while others are unique to the delivery process.

Back pressure monitoring is a technique used to ensure that the drug is being delivered to the correct location. By measuring the back pressure, it is possible to determine if the drug delivery device is in the right location initially. If there is a significant change in back pressure, it may indicate a leak or blockage in the delivery system. Additionally, inserting a pressure gauge nearby can help understand how the surrounding tissue is being affected by the injection.

Monitoring the distribution of the drug in real-time can be achieved by adding contrast agents to the drug formulation. These contrast agents allow for visualisation of the drug’s movement and distribution within the body using various imaging techniques. Some of the most commonly used imaging methods include MRI, fluoroscopy, PET, ultrasound, fluorescence/luminescence (dependent on the location of drug delivery) and electrical sensing.

Conclusion

Precision medicine must evolve beyond molecular targeting to embrace mechanical and spatial precision in drug delivery. By integrating tissue characterisation, tailored delivery methods and real-time monitoring, we can unlock the full potential of therapeutics and bring more promising treatments to market.

Want to read more on advanced drug delivery?

This article was taken from our latest edition of Insight magazine. Sign up for your copy here.

Join the conversation

Looking for industry insights? Click below to get our opinions and thoughts into the world of
medical devices and healthcare.