Multistep, effective drug distribution within solid tumors

Abstract

The distribution of drugs within solid tumors presents a long-standing barrier for efficient cancer therapies. Tumors are highly resistant to diffusion, and the lack of blood and lymphatic flows suppresses convection. Prolonged, continuous intratumoral drug delivery from a miniature drug source offers an alternative to both systemic delivery and intratumoral injection. Presented here is a model of drug distribution from such a source, in a multistep process. At delivery onset the drug mainly affects the closest surroundings. Such ‘priming’ enables drug penetration to successive cell layers. Tumor ‘void volume’ (volume not occupied by cells) increases, facilitating lymphatic perfusion. The drug is then transported by hydraulic convection downstream along interstitial fluid pressure (IFP) gradients, away from the tumor core. After a week tumor cell death occurs throughout the entire tumor and IFP gradients are flattened. Then, the drug is transported mainly by ‘mixing’, powered by physiological bulk body movements. Steady state is achieved and the drug covers the entire tumor over several months. Supporting measurements are provided from the LODER™ system, releasing siRNA against mutated KRAS over months in pancreatic cancer in-vivo models. LODER™ was also successfully employed in a recent Phase 1/2 clinical trial with pancreatic cancer patients.

Modelling of combination therapy using implantable anticancer drug delivery with thermal ablation in solid tumor

“…This result is not surprising due to the lake of the lymph vasculature in the tumor compared to the normal tissue. The trend of the results agrees well with the previous studies in the literature 1,27,28 .…”

“…Cancer is one of the most dangerous and deadliest diseases that cause deaths of millions of people around the world each year. More than 85% of human cancers appear as solid tumors 1 . Minimally invasive and image-guided thermal ablation techniques such as radiofrequency ablation (RFA) and high-intensity focused ultrasound (HIFU) ablation have been used for local treatment of malignant solid tumors as an alternative for systemic chemotherapy and surgical resection 2 .…”

A Totally Absorbable Multilayer PLGA Implant Device Containing Doxorubicin Inhibited Tumor Growth and Metastasis without Systemic Toxicity in Murine Breast Cancer and an Ideal Pharmacological Paradigm for Regional Chemotherapy

“…Or the implants established a sharp zone of drug gradient near the surrounding tissue, and drop very quickly further away from the surface of the implant [16] [18]. Or the pharmacokinetic measurements will be vastly different from the systemic administrated route in other possibilities [21]. Yet this leads to another striking question: during those 21 days, close to 700 mcg of doxorubicin was released from the implant, twice that of the IV group.…”

“…Drug exposure in this manner leads to higher resistance and is yet another way tumor cells to escape. Placement of a solid chemotherapy implant within or near the tumor mass might address this dilemma [21].…”

Theranostic Role of 32P-ATP as Radiopharmaceutical for the Induction of Massive Cell Death within Avascular Tumor Core

“…Development of methods to avoid this limitation is an important challenge in medical oncology. Strategies that have been assessed to address this challenge in the last decades include: combination therapies aimed at improving tumor vascularization or reducing IFP 32 , 33 , development of drugs that selectively target hypoxic regions 34 , and the use of devices that allow a controlled and continuous release of therapeutic drugs 35 . All these strategies, when successful, result in a significant increase of necrotic/apoptotic cell death throughout the entire tumor parenchyma, thus indicating the successful delivery of therapeutic drugs in regions that are normally inaccessible.…”