Towards Personalized Oncology: A Stage-Adapted Synergetic Model Using Gene Editing Tools, Platinum Therapeutics and ROS Modulation

Abstract

The increasing incidence of cancer worldwide, exacerbated by diagnostic delays during the COVID-19 pandemic, necessitates the development of innovative and precise molecular therapies. This manuscript explores a multidimensional approach towards cancer treatment, integrating cutting-edge genome editing tools, targeted chemotherapy agents, and reactive oxygen species (ROS)-based mechanisms. Special emphasis is placed on CRISPR-Cas9 technology for cancer immunotherapy, platinum-based drugs, and theoretical applications of electronegativity principles to design novel fluorine-containing compounds. The therapeutic potential of adenoviral vectors and noble gas-derived ROS inducers is critically examined. The proposed model advocates a stage-specific, personalized treatment strategy combining molecular targeting and immune modulation to improve clinical outcomes. This theoretical framework aims to guide future experimental studies and translational research in modern oncology.

Introduction

Cancer is still one of the most difficult problems in present-day medicine, projected as a growing number of new cases worldwide, which will eventually burden health care systems substantially. The COVID-19 pandemic has further exacerbated cancer treatment due to diagnostic delay which might result in adverse patient outcomes¹. Hence, there is an urgent need to promote therapeutic strategies that go beyond the systemic approach of chemo and radiotherapy and embrace molecular and precision medicine strategies, that specifically look to the cause of cancer at its genetic and biochemical basis. 

Recent breakthroughs in molecular biology have paved the way for the development of cutting-edge treatments, such as genome editing techniques (e.g. CRISPR-Cas9), that can be used to make specific genetic alterations to restore normal cellular homeostasis or to augment the antitumour immune response². At the same time,  platinum-based chemotherapies remain essential drugs for their potential to cause DNA damage, and recent insights into ROS-associated apoptosis have further opened up the possibilities for selectively killing cancer cells³. 

Moreover, theoretical investigations of electronegativity, along with new chemical species such as fluorine-containing species and rare gas adducts, show promise to advance in drug research. Yet these concepts need to be carefully evaluated for chemical feasibility, toxicity, and mode of delivery. 

This review is an attempt to try and unite this multifaceted molecular approach to bring it into one more convenient cancer therapy strategy. It emphasizes the opportunities and challenges in translating these state-of-the-art principles into solid clinical practice through an exploration of the available evidence and a stage-specific treatment model.

Molecular Medicine Oriented Strategies in Cancer Therapy

2.1 Methods of Using the CRISPR-Cas9 System in Cancer Therapies

The CRISPR-Cas9 approach has transformed gene editing as it allows just such pinpoint adjustments to DNA. Based on a prokaryotic protective system, this technology uses a guide RNA (gRNA) to guide the Cas9 endonuclease to a genomic site, where it creates a double-strand break (DSB). Said break is resolved by NHEJ (normally leading to gene disruption) or HDR to make it possible for accurate correction with the aid of a donor template⁴.

CRISPR-Cas9 is mostly used for cancer therapeutic purposes in two areas: immune cell modification and the direct correction of genes. T lymphocytes or other immune cells can be edited so that they become better at finding and destroying tumour cells. For instance, T cells modified using CRISPR to delete genes including PD-1, or to insert tumour-targeting receptors, have held out hope in early clinical investigation, and CRISPR-modified T cells have the potential to ‘recognise’ a broader range of tumour antigens⁵. The technology has also been applied to the targeting of oncogenic mutations, KRAS and reconstitution of tumor suppressors. TP53 in several cancer models⁶.

Despite its promise, it faces delivery, specificity, and safety hurdles. Efficient delivery of CRISPR components could be achieved using viral vectors or non-viral alternatives, such as lipid nanoparticles. Off-target activity and immunogenicity are also major issues. In this regard, tools such as high-fidelity variants of Cas9 and base editing systems have been developed to overcome those limitations⁷.

The flexibility and high potency of CRISPR-Cas9 thus provide a versatile tool for next-generation oncology, especially when combined with multimodal personalized treatment approaches.

2.2 Platinum Drugs, the Choice of Chemo Drugs

Platinum drugs such as cisplatin, carboplatin, and oxaliplatin cross-link DNA primarily at the N7 position of guanine and thereby inhibit replication and transcription and cause apoptosis in cancer cells. These medications are specifically tailored for conventional chemotherapy and are being used in hospitals to combat cancer⁸.

Platinum-DNA interaction model

   

: Concentration of DNA-platinum adducts

: Concentration of administered platinum drug

: Max adduct for rate

: Affinity constant (lower+ stronger binding)

: Repair/degradation of adducts

The remarkable effectiveness of such platinum medication has been a cornerstone in the fight against various forms of cancer, and its existence has offered hope to millions of patients worldwide. Their mechanism of action is to intercalate as adducts into DNA, not just preventing the cancer cells from dividing but also triggering a cascade of cell events culminating in the induced cell death known as apoptosis. Such cancer-targeted delivery has significantly improved survival and quality of life for hundreds of thousands of cancer patients. 

The journey of these drugs from the research laboratory to the bedside of the patients is a testament to the ferocity of medical research and the one-pointed effort of the scientists to combat this disease that is far from being overcome. With researchers going deeper into the subtleties of the biology of cancer, hopes for even more effective platinum-based treatments await, possibly with lesser toxicities and greater specificity for cancer cells.

Efficacy is compromised, however, against systemic toxicity and acquired resistance. Novel delivery systems, like ferritin nanocages, are being studied to improve tumour specificity and mitigate side effects⁹.

Drug	Mechanism	Common Side Effects	Delivery Improvements
Cisplatin	DNA crosslinking	Nephrotoxicity neuropathy	Nanoparticle carriers
Carboplatin	DNA crosslinking	Myelosuppression	Ferritin nanocages
Oxaliplatin	DNA crosslinking	Neurotoxicity	Targeted drug delivery

2.3 Apoptosis Induced by ROS (Reactive Oxygen Species)

Reactive oxygen species (ROS) such as superoxide anions, hydrogen including peroxide, and hydroxyl radicals (·OH), are highly reactive oxidant molecules from oxygen metabolism. Increased ROS levels lead to oxidative stress, which causes injury to cellular macromolecules including DNA, lipids, or proteins and thus can initiate apoptosis or programmed cell death. Some cancer cells maintain a higher basal ROS level than normal cells, resulting in increased (tumourigenic) proliferation potential but are also rendered more sensitive to subsequent oxidative stress¹⁰.

ROS Modulation Dynamics

   

Where:

: ROS concentration at time t

: Rate of ROS induction by platinum therapy

:Natural antioxidant clearance rate 

: ROS self-amplification via Fenton-type reactions

Strategies for the treatment of cancer have imaging the goal to use the indicated sensitivity of cancer cells to elevated intracellular ROS levels in the attempt to increase intracellular ROS in tumour cells selectively and thereby to stimulate the cells beyond their oxidative threshold to execute cell death through a series of pathways implicating p53 activation, BCL-2 scalar expression, and mitogen-activated protein kinases (MAPK)¹¹. Furthermore, normal cells which have a stronger antioxidant system like GSH are not damaged.

It is this targeted ROS production which is the foundation for many chemotherapeutic agents and radiation treatments, rendering ROS modification a very attractive goal in cancer therapeutics.

2.4 Halogenated Compounds for Cytolethality by Dipole Introduction

Contemporary medicinal chemistry strategy utilises halogenated molecules to augment drug reactivity by introducing the molecular dipoles to increased drug affinity and cytotoxicity for better target binding and cellular uptake¹². In place of elaborate architectures of fluorine/octahedral nitrogen complex, the introduction of electron-withdrawing halogen atoms (e.g. F, Cl, Br) into a known anticancer drug can improve the pharmacokinetics and tumour cell cytotoxicity.

Relationship between halogen electronegativity, molecular dipole moment, and the rate of DNA double-stranded break (DSB) induction

   

: Rate of inducing double-stranded breaks
: Electronegativity of halogen atoms
: Change in molecular dipole moment

Halogen-substitution may alter the lipophilicity of the drug and consequently, its metabolic stability and the interaction with DNA or proteins in cancer cell, and ultimately enhances the drug therapeutic efficacy. This approach is currently under intensive investigation, weighing increased effectiveness against potential increased toxic side effects and needs experimental validation¹³.

2.5 Adenoviral Vector-Mediated Cancer Therapy

Adenoviral vectors have become a leading tool in cancer gene therapy due to their high transduction efficiency and their ability to infect both growing and non-proliferating cells. Oncolytic adenoviruses replicate exclusively in cancer cells, inducing cell lysis and an anti-tumour immune response. The tumour suppressor gene p53 can be introduced through replication-defective adenoviruses to restore normal cell cycle control¹⁴.

Gendicine, the first gene therapy product approved in China, which delivers wild-type p53 to patients with head and neck squamous cell carcinoma, is one such an example¹⁵. Although these safety features can promote clinical applications, host immune responses to viral vectors, transient gene expression and safety profiles may limit their broad applications. Continued vector development is aimed at altering vector tropism to increase specificity, decrease immunogenicity, and achieve a more durable therapeutic effect.

2.6 Sensitivity to Sequencing and Staged Therapeutic Combination

Individualized therapy adapted to the current tumour stage Therapy must respond dynamically to the heterogeneous progression of cancer. Platinum chemotherapy plus ROS modulation for early stages and immunotherapy with CRISPR-edited T cells for advanced stages to address immune evasion¹⁶,⁵.

Stage Adaptive Synergistic Model

   

Where
, , : Weighing constants for CRISPR, ROS, and platinum toxicity
: Fraction of viable tumour cells

This model allows simulation under different cancer stages:

Early-stage: emphasize platinum + ROS (high , )

Late-stage: shift to immunotherapy + CRISPR ( high )

Ferritin nanocage drug delivery systems represent a cutting-edge approach in the field of medical science, harnessing the unique properties of ferritin proteins to create nanoscale containers that can transport therapeutic agents directly to diseased cells. These innovative systems are designed to enhance the efficacy of drug delivery by improving circulation kinetics, ensuring that medications are released in a controlled and targeted manner. The remarkable precision of these nanocages allows for a reduction in side effects and an increase in the therapeutic index of drugs, which is particularly beneficial for patients with chronic conditions requiring long-term treatment.

A combined patient-specific sequence that integrates these advanced ferritin nanocage drug delivery systems with other diagnostic and therapeutic modalities appears to offer even better results. By tailoring the treatment to the individual’s genetic makeup and disease profile, healthcare providers can optimize the treatment plan, leading to more personalized and effective care. This approach not only promises improved patient outcomes but also sets the stage for a new era of precision medicine, where treatments are as unique as the individuals receiving them.

Challenges and Perspective

Key challenges are:

– Directed delivery of genome-editing molecules to minimize off-target effects

– Penetration obstacles presented by tumour microenvironment

– Managing immune-mediated side effects in immunotherapy patients

– Chemical and biological stability of candidate drugs

All future research should now focus on next-generation delivery systems, real-time tumour monitoring, and computational predictive models towards personalized treatment.

Conclusion

Cancer therapy today calls for sophisticated, individualized therapies that depend on shifting paradigms in molecular biology and newer technologies. Such an approach combines chemotherapy, nanotechnology, and genome editing to control patient-specific tumour heterogeneity and resistance mechanisms. Interdisciplinarity is needed to effectively translate such ideas to the clinic with the vision of eventually being of value to patients. 

The complexity of cancer, its wide variety of mutations and its adaptability need multidisciplinary therapy that can be achieved only through the combined expertise of biologists, chemists, physicians, and engineers. Imagine a future when the cancer of every patient is mapped at the molecular level, and not only one-size-fits-all therapies but tailored therapies as unique as the individual’s DNA. 

This vision is becoming more reachable as we see the merging of what once distinct sciences were. The combination of these disciplines is not only a scientific discovery but a light of hope for those who are battling the powerful foe that is cancer. 

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