High molar mass of MP enhances the blood and body residence time of the conjugated drug well over that for its non-conjugated counterpart. Physiology of the human body favors accumulation of MP in tumors making these tools naturally attractive for delivery of anticancer drugs.
What are macromolecular prodrugs?
Another major class of macromolecular prodrugs is represented by polymer-drug conjugates (Fig. 2b), in which low-molecular weight cytotoxins are conjugated vialabile linkers to hydrophilic, biocompatible polymers such as N-(2-hydroxypropyl)methacrylamide copolymers (HPMA) (51).
What are prodrugs for cancer?
Go to: Abstract Prodrugs are widely used in the targeted delivery of cytotoxic compounds to cancer cells. To date, targeted prodrugs for cancer therapy have achieved great diversity in terms of target selection, activation chemistry, as well as size and physicochemical nature of the prodrug.
What are the advantages of prodrugs?
This type of prodrug strategy takes advantage of the enhanced permeability and retention effect—the preferential accumulation of small molecules in the tumor microenvironment, which is thought to result from the abnormal “leaky” vasculature of tumors and lack of a lymph drainage system, among other factors. 13
Are antibody-drug conjugates the best prodrugs for cancer?
Thus far, antibody—drug conjugates (ADCs) have been the most promising class of prodrugs in anticancer therapy, with several agents now approved by the FDA.
What is MP in medicine?
Macromolecular prodrugs (MP) represent a successful, elaborate tool of drug delivery developed at the interface of medicinal chemistry and polymer science [1], [2•], [3], [4]. These prodrugs are typically engineered to carry multiple copies of a drug (or a combination of drugs) [5] and in doing so, enhance the deliverable payload. High molar mass of MP enhances the blood and body residence time of the conjugated drug well over that for its non-conjugated counterpart. Physiology of the human body favors accumulation of MP in tumors making these tools naturally attractive for delivery of anticancer drugs [6]. Additional engineering of receptor targeting enhances rates of cell entry and further facilitates drug delivery. Development of MP can be traced back over several decades and the field is well reviewed and updated [2•], [7], [8]. To keep this presentation within limits, we therefore do not aim to provide an exhaustive account of the documented accomplishments of MP. Instead, we provide a brief statement of prior successes in the design of MP and then focus on specific aspects of macromolecular design that were developed recently and, in our opinion, may spur academic and/or translational development of MP. Specifically ( Fig. 1 ), we focus on#N#i)#N#Engineering of high molar mass MP using main-chain degradable polymers;#N#ii)#N#Drug delivery based on endogenous macromolecular carriers such as albumin;#N#iii)#N#Intracellularly degradable linkage (s) coupled to self-immolative linkers; and#N#iv)#N#MP for delivery of gasotransmitters (NO, H 2 S, CO).
What is MP in drug delivery?
Macromolecular prodrugs (MP) are high molar mass conjugates, typically carrying several copies of a drug or a drug combination, designed to optimize delivery of the drug, that is — its pharmacokinetics. From its advent several decades ago, design of MP has undergone significant development and established solid guidelines for engineering successful MP in terms of the choice of the polymer carrier, its molar mass, and the choice of the linkage between the drug and the polymer. This review provides a brief account of the state-of-the-art in the development of MP and details the advantages of these tools of drug delivery. We also identify the challenges that need to be further addressed and offer a view on what is currently being done towards these goals. Specifically, we focus on i) the design of high molar mass, main-chain degradable polymers as drug carriers; ii) drug delivery using endogenous macromolecules such as albumin; iii) the choice of biodegradable linkages for drug delivery, and iv) the emerging interest in delivery of short-lived gasotransmitters. With this analysis and presentation, we aim to spur broader interest into MP to facilitate academic and translational development of MP.
Why do we need prodrugs?
Prodrugs are designed to modify the physical and chemical characteristics of a drug to make it more effective. A prodrug strategy can help ensure that a drug is active just at a particular time or place to both maximize cancer cell killing and minimize off-target toxicity.
Why are prodrugs so sophisticated?
As researchers gain a better understanding of the unique aspects of individual tumor types and their surrounding microenvironment, the design of novel therapies categorized as prodrugs is become increasingly sophisticated, and several novel constructs show particular promise.
What is the function of a protein in a vector?
A protein in the vector phosphorylates the prodrug, leading to cell death and the release of tumor neoantigens. This sets off a chain of signaling via the STING pathway that ultimately results in the activation of T cells that promote cytotoxic immunotherapy.
What is CD in drug therapy?
It converts these prodrugs into toxic triphosphates that cause cell death primarily by blocking DNA synthesis. CD is used in conjunction with 5-FC, which it converts into 5-FU. 20,21. Tocagen, a drugmaker based in San Diego, California, has developed Toca FC, a novel extended-release formulation of 5-FC.
What is the drug that inhibits DNA?
Temozolomide, another prodrug, is a derivative of the alkylating agent dacarbazine. Capecitabine, used in the treatment of breast and colorectal cancers, is a prodrug that has little cytotoxic activity itself until it is enzymatically metabolized into the active drug 5-fluorouracil (5-FU), which inhibits DNA synthesis.
What are the ADCs for cancer?
The FDA has approved 4 ADCs for these targets and tumor types: ado-trastuzumab emtansine (Kadcyla) for HER2 in metastatic breast cancer; brentuximab vedotin (Adcetris), CD30 in Hodgkin and anaplastic large cell lymphoma; inotuzumab ozogamicin (Besponsa), CD22 in acute lymphoblastic leukemia (ALL); and gemtuzumab ozogamicin (Mylotarg), CD33 in acute myeloid leukemia (AML). A variety of ADCs are among the prodrugs in clinical development, many of which are in phase III trials ( Table ), suggesting the list of FDA-approved agents may expand in the near future. 9-10 ADCs are an example of a carrier-linked prodrug, wherein the parent drug itself is not modified but attached to a secondary molecule that dictates its activity. Alternatively, prodrugs can involve specific alterations to the parent drug.
What are the differences between cancerous and normal cells?
Passively activated prodrugs exploit the differences between cancerous and normal cells, such as the overexpression of certain cell surface receptors by cancer cells, or the unique nature of the microenvironment surrounding the tumor, such as lower pH, reduced oxygen levels, and aberrant vasculature.