Nanomedicine Strategies to Enhance Tumor Drug Penetration in Pancreatic Cancer

Figures & data

Figure 1 Key features of the PDAC microenvironment. This diagram highlights highly dense stroma and its impact on immune infiltration (entrapped immune cells) leading to immunosuppression, collapsed blood vessels due to high interstitial pressure, and poor enhanced permeability and retention (EPR) effect hindering nanoparticles to penetrate into the tumor.

Table 1 Pancreatic Cancer Clinical Trials of Nanomedicine Strategies for Drug Delivery (Referring from https://clinicaltrials.gov/)

Agent and Nanotechnology Approach	Status and Relevant Findings
NASOX: liposomal irinotecan with S-1 and oxaliplatin	Phase I/IIa
PanDox: thermoliposome doxorubicin	Phase I
Liposomal irinotecan with vactosertib, 5-FU and LV	Phase I
AGuIX gadolinium-chelated polysiloxane based nanoparticles with radiotherapy	Phase I/II
NBTXR3: hafnium oxide-containing nanoparticles with radiotherapy	Phase I
Nanoparticle paclitaxel albumin-bound protein in combination with ascorbic acid, cisplatin and gemcitabine	Phase I/II
Nanoparticle paclitaxel albumin-bound protein in combination with 5-FU, gemcitabine, cisplatin, irinotecan and folinic acid and radiotherapy	Phase II

Table 2 Summarizing the PDAC Features Effecting Tumor Perfusion and Penetration and Potential Solutions

Key Features of PDAC	Mechanisms	Impact on Different Therapeutics	Potential Strategies to Enhance Penetration
Highly dense stroma (Increased stiffness and solid stress)	- Excessive ECM production by CAFs - Reduced ECM degradation - Crosslinked matrix - Contractile CAFs	Poor diffusion and penetration of - Macromolecules, eg, monoclonal antibodies - Nanomedicine	- Inducing ECM degradation - Targeting CAFs (inhibit CAF-induced matrix production and CAF contraction)
Compressed and collapsed vasculature	- Infantile vasculature - High interstitial fluid pressure - Non-functional lymphatics	Poor perfusion of - Small drug molecules, eg, chemotherapeutics - Nanomedicine	- Reduce IFP using hypotensive agents - vasculature normalization
Poor EPR* effect	- Compressed and collapsed blood vessels - Excessive matrix deposition	Reduced extravasation - Macromolecules, eg, monoclonal antibodies - Nanomedicine	- Improve blood perfusion, eg, normalization of vasculature - Enhance ECM degradation and inhibit ECM deposition
Immuno-suppressive environment	- Interaction between TAMs and cancer cells - Dense stroma	- Poor immuno-surveillance and efficacy of immunotherapy, eg, cell-based therapies and checkpoint inhibitors	- Targeting immune cells, eg, reprogram TAMs into anti-tumoral type - Anti-stromal agents to enhance penetration

Abbreviation: *EPR, Enhanced Permeability and Retention effect.

Figure 2 Diagrammatic representation of different strategies to enhance tumor penetration of nanomedicine. To enhance the penetration, either nanomedicine can be engineered or the tumor stroma can be re-programmed. Nanomedicines can be tuned by size reduction strategy in which the size of nanoparticles (NP) is reduced upon reaching the tumor site, which allows deeper penetration into the tumor. In another strategy, one may induce triggered release of drug allowing rapid diffusion of small molecules into the tumor. In the third strategy, use of a transcytosis mechanism is interesting to induce penetration of nanoparticles through endothelial cells, for example using iRGD peptide. Other approaches are based on reprogramming of tumor stroma. In this approach, one may induce degradation of ECM using enzymes such as MMPs to reduce the physical barrier and solid stress or by reducing stiffness by normalization of CAFs. These approaches help in enhancing penetration by modulating physical microenvironment. Although reduction of ECM will lead to decompression of blood vasculature, relaxation of blood vessels using anti-hypertensive agents can induce tumor blood perfusion.