Cold-Responsive Nanoparticles for Cryoimmune Engineering
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Solution Overview
Problem
Current cancer therapies, including cryosurgery and immunotherapy, are limited in effectively targeting and destroying both primary and metastatic tumors due to the immunosuppressive tumor microenvironment, and there is a lack of effective nanotechnology that responds to cold temperatures during cryosurgery to enhance cancer treatment outcomes.
Innovation Solution
Development of cold-responsive nanoparticles (CRNPs) that co-encapsulate chemotherapy and immunotherapy agents, designed to release at cold temperatures in the periphery of a frozen tumor iceball, activating a potent cryoimmune response against primary and distant metastatic tumors, while also targeting cancer cells and promoting immunogenic cell death.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cryosurgery is applied to freeze the tumor iceball, then cancer cells in the frozen region are killed, but the peripheral region with temperature above -20°C cannot ensure complete cancer cell death
Solution Approach 1:
The patent uses cold-responsive nanoparticles with a lower critical solution temperature (LCST) of -4°C that undergo phase transition when exposed to cold temperatures. This parameter change allows the nanoparticles to remain stable at body temperature but activate and release therapeutic agents when the tumor is cooled during cryosurgery, enabling effective treatment in the peripheral region where temperature remains above -20°C
Solution Approach 2:
The patent introduces cold-responsive nanoparticles as an intermediary substance that mediates between the cryosurgery cooling process and the cancer cells. These nanoparticles act as carriers that deliver chemotherapy and immunotherapy agents specifically to cancer cells in the peripheral region, enabling cell death without requiring direct freezing
2Reliability
If conventional nanotechnology is used for cancer treatment, then cancer cells can be targeted, but there is no nanotechnology that responds to cold temperatures during cryosurgery to enhance treatment outcomes
Solution Approach 1:
The patent develops nanoparticles with temperature-responsive properties, specifically a lower critical solution temperature (LCST) of -4°C. This parameter change enables the nanoparticles to adapt to cold temperatures during cryosurgery by undergoing phase transition from a collapsed state at body temperature to an expanded state at cold temperatures, triggering controlled release of therapeutic agents
Solution Approach 2:
The patent creates a multi-functional nanoparticle system that combines several functions: (1) serving as a carrier for both chemotherapy and immunotherapy agents, (2) responding to cold temperatures through phase transition, (3) targeting cancer cells specifically, and (4) enhancing both local and systemic antitumor effects. This multi-functionality addresses the lack of temperature-responsive nanotechnology in the field
3Reliability
If the tumor microenvironment is immunosuppressive, then immune cell infiltration is limited, but the goal is to stimulate a potent immunotherapeutic effect
Solution Approach 1:
The patent converts the immunosuppressive tumor microenvironment into an immunostimulatory one by using cold-responsive nanoparticles to deliver immunotherapy agents. The nanoparticles trigger the release of immunostimulatory molecules that reverse the immunosuppressive state, transforming the harmful immunosuppressive environment into a beneficial immunostimulatory environment that promotes cancer cell death and immune cell infiltration
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The CRNPs effectively enhance cancer cell killing at subzero temperatures, stimulate a potent antitumor immune response, and reverse the immunosuppressive tumor microenvironment, leading to improved treatment outcomes with minimal side effects, including the ability to target and destroy both primary and distant tumors without additional cryosurgery.
Implementation Method 1
utilizing a synthesized series of polymers that have lower critical solution temperatures (LCSTs) below positive four degrees Celsius (4° C.) to control release of a drug into a cytosol of said cancerous cells
Implementation Method 2
inducing cold-triggered endo/lysosomal escape of small interfering RNA (siRNA or siR) into the cytosol
Implementation Method 3
Cryosurgery is done by cooling to cause ice formation (i.e., frostbite) in tumor, which leads to cryoinjury and cancer cell death inside the frozen tissue iceball
Implementation Method 4
there is a temporary (a few hours) reperfusion of the tumor immediately after thawing a frozen tumor iceball
Data Source
AI summary
Cancer immunotherapy deploys the host's immune system to recognize and attack cancerous tumors. However, the efficacy is greatly restricted by the immunosuppressive (i.e., immunologically cold) tumor microenvironment (TME). In-situ cryo-immune engineering (ICIE) strategy turns the TME from immunologically “cold” into “hot”. In particular, after the ICIE treatment, the ratio of the CD8+ cytotoxic T cells to the immunosuppressive regulatory T cells is increased in primary tumors and distant tumors without freezing. The ICIE treatment causes “frostbite” of tumor with cold-responsive nanoparticles that target cancer cells. This rapidly releases both anticancer drug(s) and PD-L1 silencing siRNA into the cytosol. This ICIE treatment leads to potent immunogenic cell death, which promotes maturation of dendritic cells and activation of CD8+ cytotoxic T cells and memory T cells. Collectively, ICIE enables an efficient and durable way to leverage the immune system for combating cancer and its metastasis.